HIGHLIGHTS OF PRESCRIBING INFORMATION• Renal Failure or Impairment: Withhold or discontinue for Grade 3 or 4

These highlights do not include all the information needed to use
LENVIMA safely and effectively. See full prescribing information for
LENVIMA.

• Proteinuria: Monitor for proteinuria prior to treatment and periodically

LENVIMA® (lenvatinib) capsules, for oral use
Initial U.S. Approval: 2015•----------------------------RECENT MAJOR CHANGES-------------------------Indications and Usage (1.2)
08/2021
Indications and Usage (1.4)
07/2021
Dosage and Administration (2.3, 2.6)
08/2021
Dosage and Administration (2.5)
11/2020
Warnings and Precautions (5.3)
08/2021
Warnings and Precautions (5.15)
12/2020----------------------------INDICATIONS AND USAGE--------------------------LENVIMA is a 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 adultpatients with advanced renal cell carcinoma (RCC). (1.2)

In combination with everolimus, for the treatment of adult patients withadvanced renal cell carcinoma (RCC) following one prior antiangiogenic 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 withadvanced endometrial carcinoma (EC) that is not microsatellite
instability-high (MSI-H) or mismatch repair deficient (dMMR) who havedisease progression following prior systemic therapy in any setting andare not candidates for curative surgery or radiation. (1.4)----------------------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 8 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 3 weeks. (2.5)

RCC: The recommended dosage is:o
20 mg orally once daily with pembrolizumab 200 mg administeredas an intravenous infusion over 30 minutes every 3 weeks. (2.3)
o
18 mg orally once daily with everolimus 5 mg orally once daily.
(2.3)
Modify the recommended daily dose for certain patients with renal or hepatic
impairment. (2.7, 2.8)---------------------DOSAGE FORMS AND STRENGTHS---------------------Capsules: 4 mg and 10 mg. (3)-------------------------------CONTRAINDICATIONS-----------------------------None. (4)-----------------------WARNINGS AND PRECAUTIONS------------------------• Hypertension: Control blood pressure prior to treatment and monitor during•••

treatment. Withhold for Grade 3 hypertension despite optimal
antihypertensive therapy. Discontinue for Grade 4 hypertension. (2.6, 5.1)
Cardiac Dysfunction: Monitor for clinical symptoms or signs of cardiac
dysfunction. Withhold or discontinue for Grade 3 cardiac dysfunction.
Discontinue for Grade 4 cardiac dysfunction. (2.6, 5.2)
Arterial Thromboembolic Events: Discontinue following an arterial
thromboembolic event. (2.6, 5.3)
Hepatotoxicity: Monitor liver function prior to treatment and periodicallyduring treatment. Withhold or discontinue for Grade 3 or 4 hepatotoxicity.
Discontinue for hepatic failure. (2.6, 5.4)

Reference ID: 4840228

renal failure or impairment. (2.6, 5.5)

•
•
•
•
•
•
•

•
•

during treatment. Withhold for 2 or more grams of proteinuria per 24hours. Discontinue for nephrotic syndrome. (2.6, 5.6)
Diarrhea: May be severe and recurrent. Promptly initiate management forsevere diarrhea. Withhold or discontinue based on severity. (2.6, 5.7)
Fistula Formation and Gastrointestinal Perforation: Discontinue in patients
who develop Grade 3 or 4 fistula or any Grade gastrointestinal perforation.
(2.6, 5.8)
QT Interval Prolongation: Monitor and correct electrolyte abnormalities.
Withhold for QT interval greater than 500 ms or for 60 ms or greater
increase in baseline QT interval. (2.6, 5.9)
Hypocalcemia: Monitor blood calcium levels at least monthly and replacecalcium as necessary. Withhold or discontinue based on severity. (2.6,
5.10)
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Withhold
for RPLS until fully resolved or discontinue. (2.6, 5.11).
Hemorrhagic Events: Withhold or discontinue based on severity. (2.6,
5.12)
Impairment of Thyroid Stimulating Hormone Suppression/Thyroid
Dysfunction: Monitor thyroid function prior to treatment and monthly
during treatment. (5.13)
Impaired Wound Healing: Withhold LENVIMA for at least 1 week before
elective surgery. Do not administer for at least 2 weeks following major
surgery and until adequate wound healing. The safety of resumption of
LENVIMA after resolution of wound healing complications has not been
established. (5.14)
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 a
fetus and use of effective contraception. (5.16, 8.1, 8.3)------------------------------ADVERSE REACTIONS------------------------------ 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:o 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)
o 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 1877-873-4724 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-------------------------USE IN SPECIFIC POPULATIONS---------------------
Lactation: Advise not to breastfeed. (8.2)
See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling.

Revised: 08/2021

FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1
Differentiated Thyroid Cancer
1.2
Renal Cell Carcinoma
1.3
Hepatocellular Carcinoma
1.4
Endometrial Carcinoma
2
DOSAGE AND ADMINISTRATION
2.1
Important Dosage Information
2.2
Recommended Dosage for Differentiated Thyroid Cancer
(DTC)
2.3
Recommended Dosage for Renal Cell Carcinoma (RCC)
2.4
Recommended Dosage for Hepatocellular Carcinoma (HCC)
2.5
Recommended Dosage for Endometrial Carcinoma (EC)
2.6
Dosage Modifications for Adverse Reactions
2.7
Dosage Modifications for Severe Renal Impairment
2.8
Dosage Modifications for Severe Hepatic Impairment
2.9
Preparation and Administration
3
DOSAGE FORMS AND STRENGTHS
4CONTRAINDICATIONS5WARNINGS AND PRECAUTIONS
5.1 Hypertension
5.2 Cardiac Dysfunction
5.3 Arterial Thromboembolic Events
5.4 Hepatotoxicity
5.5 Renal Failure or Impairment
5.6 Proteinuria
5.7 Diarrhea
5.8 Fistula Formation and Gastrointestinal Perforation
5.9 QT Interval Prolongation
5.10 Hypocalcemia
5.11 Reversible Posterior Leukoencephalopathy Syndrome
5.12 Hemorrhagic Events
5.13 Impairment of Thyroid Stimulating Hormone
Suppression/Thyroid Dysfunction

Reference ID: 4840228

6
7
8

10
11
12
13
14

16
17

5.14 Impaired Wound Healing
5.15 Osteonecrosis of the Jaw (ONJ)
5.16 Embryo-Fetal Toxicity
ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
DRUG INTERACTIONS
7.1 Drugs That Prolong the QT Interval
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
OVERDOSAGEDESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
CLINICAL STUDIES
14.1 Differentiated Thyroid Cancer
14.2 Renal Cell Carcinoma
14.3 Hepatocellular Carcinoma
14.4 Endometrial Carcinoma (EC)HOW SUPPLIED/STORAGE AND HANDLINGPATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are notlisted.

FULL PRESCRIBING INFORMATION

1

INDICATIONS AND USAGE

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 patientswith 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 patientswith advanced endometrial carcinoma (EC) that is not microsatellite instability-high (MSI-H)
or mismatch repair deficient (dMMR), who have disease progression following priorsystemic therapy in any setting and are not candidates for curative surgery or radiation.

2

DOSAGE AND ADMINISTRATION

2.1

Important Dosage Information

Reduce the dose for certain patients with renal or hepatic impairment [see Dosage andAdministration (2.7, 2.8)].

Take LENVIMA once daily, with or without food, at the same time each day [seeClinical Pharmacology (12.3)]. 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.

2.2

Recommended Dosage 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 RCC
The recommended dosage of LENVIMA is 20 mg orally once daily in combination withpembrolizumab 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. Aftercompleting 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

Reference ID: 4840228

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.
2.4

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

8 mg for patients less than 60 kg.

Take LENVIMA orally once daily until disease progression or until unacceptable toxicity.
2.5

Recommended Dosage for Endometrial Carcinoma (EC)The recommended dosage of LENVIMA is 20 mg orally once daily, in combination withpembrolizumab 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.
2.6

Dosage Modifications for Adverse Reactions

Recommendations for LENVIMA dose interruption, reduction and discontinuation foradverse reactions are listed in Table 1. Table 2 lists the recommended dosage reductions of
LENVIMA for adverse reactions.
Table 1: Recommended Dosage Modifications for LENVIMA for Adverse Reactions
Adverse Reaction
Hypertension [seeWarnings and Precautions(5.1)]

Severity aGrade 3

Grade 4
Cardiac Dysfunction [seeWarnings and Precautions(5.2)]

Arterial Thromboembolic
Event [see Warnings andPrecautions (5.3)]

Reference ID: 4840228

Dosage Modifications for LENVIMA
 Withhold for Grade 3 that persists despite
optimal antihypertensive therapy.
 Resume at reduced dose when hypertension iscontrolled at less than or equal to Grade 2.
 Permanently discontinue.

Grade 4

 Withhold until improves to Grade 0 to 1 orbaseline.
 Resume at a reduced dose or discontinue
depending on the severity and persistence ofadverse reaction.
 Permanently discontinue.

Any Grade Permanently discontinue.

Grade 3

Table 1: Recommended Dosage Modifications for LENVIMA for Adverse Reactions
Adverse Reaction

Reference ID: 4840228

Severity a

Dosage Modifications for LENVIMA

Hepatotoxicity [seeWarnings and Precautions(5.4)]

Grade 3 or 4

Renal Failure or
Impairment [see Warnings
and Precautions (5.5)]

Grade 3 or 4

Proteinuria [see Warnings
and Precautions (5.6)]

2 g or greater
proteinuria in
24 hours

Gastrointestinal Perforation[see Warnings andPrecautions (5.8)]

Any Grade Withhold until improves to Grade 0 to 1 orbaseline.
 Either resume at a reduced dose or discontinue
depending on severity and persistence ofhepatotoxicity.
 Permanently discontinue for hepatic failure.
 Withhold until improves to Grade 0 to 1 orbaseline.
 Resume at a reduced dose or discontinue
depending on severity and persistence of renal
impairment.
 Withhold until less than or equal to 2 grams ofproteinuria per 24 hours.
 Resume at a reduced dose.
 Permanently discontinue for nephrotic
syndrome.
 Permanently discontinue.

Fistula Formation [seeWarnings and Precautions(5.8)]

Grade 3 or 4

 Permanently discontinue.

QT Prolongation [seeWarnings and Precautions(5.9)]

Greater than
500 ms or
greater than
60 msincrease frombaseline Withhold until improves to less than or equal
to 480 ms or baseline.
 Resume at a reduced dose.

Reversible Posterior
Leukoencephalopathy
Syndrome [see Warnings
and Precautions (5.11)]

Any Grade Withhold until fully resolved.
 Resume at a reduced dose or discontinue
depending on severity and persistence ofneurologic symptoms.

Table 1: Recommended Dosage Modifications for LENVIMA for Adverse Reactions
Adverse Reaction
Other Adverse Reactions[see Warnings andPrecautions (5.7, 5.10,5.12)]

Severity a
Persistent or
intolerable
Grade 2 or 3
adversereaction

Dosage Modifications for LENVIMA
 Withhold until improves to Grade 0 to 1 orbaseline.
 Resume at reduced dose.

Grade 4laboratory
abnormality
Grade 4adversereactiona Permanently discontinue.

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
Second Dosage
Third Dosage
Reduction To
Reduction To
Reduction To
DTC
20 mg
14 mg
10 mg
once daily
once daily
once daily
RCC
14 mg
10 mg
8 mg
once daily
once daily
once daily
Endometrial Carcinoma
14 mg
10 mg
8 mg
once daily
once daily
once daily
HCC
4 mg
4 mg
8 mg
 Actual weight 60 kg or greater
once daily
once daily
every other day
4 mg
4 mg
Discontinue
 Actual weight less than 60 kg
once daily
every other day
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 shownin 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

Reference ID: 4840228

and everolimus. Refer to the everolimus prescribing information for additional dose
modification information.
2.7

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 calculatedby Cockcroft-Gault equation using actual body weight) is [see 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

2.8

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 [see 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

2.9

Preparation and Administration

LENVIMA capsules can be swallowed whole or dissolved in a small glass of liquid. To
dissolve in liquid, put capsules into 1 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 3 minutes. After drinking the mixture, add 1 tablespoon of water or apple
juice to the glass, swirl the contents a few times and swallow the water or apple juice.

3 DOSAGE FORMS AND STRENGTHS
Capsules:

4 mg: yellowish-red body and yellowish-red cap, marked in black ink with “Є” on cap
and “LENV 4 mg” on body.



10 mg: yellow body and yellowish-red cap, marked in black ink with “Є” on cap and“LENV 10 mg” on body.

4

CONTRAINDICATIONS

None.

5
5.1

WARNINGS AND PRECAUTIONSHypertension

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 8 mg or
12 mg orally once daily. The median time to onset of new or worsening hypertension was 16days in SELECT and 26 days in REFLECT. Grade 3 hypertension occurred in 44% ofReference ID: 4840228

patients in SELECT and in 24% in REFLECT. Grade 4 hypertension occurred <1% in
SELECT and Grade 4 hypertension was not reported in REFLECT.
In patients receiving LENVIMA 18 mg orally once daily with everolimus in Study 205(RCC), hypertension was reported in 42% of patients and the median time to onset of new orworsening hypertension was 35 days. Grade 3 hypertension occurred in 13% of patients.
Systolic blood pressure ≥160 mmHg occurred in 29% of patients and diastolic blood pressure≥100 mmHg occurred in 21% [see Adverse Reactions (6.1)].
Serious complications of poorly controlled hypertension have been reported.
Control blood pressure prior to initiating LENVIMA. Monitor blood pressure after 1 week,then every 2 weeks for the first 2 months, and then at least monthly thereafter during
treatment. Withhold and resume at a reduced dose when hypertension is controlled or
permanently discontinue LENVIMA based on severity [see Dosage and Administration(2.6)].
5.2

Cardiac Dysfunction

Serious and fatal cardiac dysfunction can occur with LENVIMA. Across clinical trials in 799
patients with DTC, RCC or HCC, Grade 3 or higher cardiac dysfunction (including
cardiomyopathy, left or right ventricular dysfunction, congestive heart failure, cardiac failure,
ventricular hypokinesia, or decrease in left or right ventricular ejection fraction of more than
20% from baseline) occurred in 3% of LENVIMA-treated patients.
Monitor patients for clinical symptoms or signs of cardiac dysfunction. Withhold and resume
at a reduced dose upon recovery or permanently discontinue LENVIMA based on severity[see Dosage and Administration (2.6)].
5.3

Arterial Thromboembolic 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 3 to 5 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%) andcerebrovascular accident (2.3%).
Permanently discontinue LENVIMA following an arterial thrombotic event [see Dosage andAdministration (2.6)]. The safety of resuming LENVIMA after an arterial thromboembolic
event has not been established and LENVIMA has not been studied in patients who have had
an arterial thromboembolic event within the previous 6 months.
5.4

Hepatotoxicity

Across clinical studies enrolling 1327 LENVIMA-treated patients with malignancies otherthan HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events,
including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of
patients.
In REFLECT (HCC), hepatic encephalopathy (including hepatic encephalopathy,
encephalopathy, metabolic encephalopathy, and hepatic coma) occurred in 8% of
LENVIMA-treated patients and 3% of sorafenib-treated patients. Grade 3 to 5 hepatic

Reference ID: 4840228

encephalopathy occurred in 5% of LENVIMA-treated patients and 2% of sorafenib-treatedpatients. Grade 3 to 5 hepatic failure occurred in 3% of LENVIMA-treated patients and 3%
of sorafenib-treated patients. Two percent of patients discontinued LENVIMA and 0.2%
discontinued sorafenib due to hepatic encephalopathy and 1% of patients discontinued
lenvatinib or sorafenib due to hepatic failure [see Adverse Reactions (6.1)].
Monitor liver function prior to initiating LENVIMA, then every 2 weeks for the first 2
months, and at least monthly thereafter during treatment. Monitor patients with HCC closely
for signs of hepatic failure, including hepatic encephalopathy. Withhold and resume at a
reduced dose upon recovery or permanently discontinue LENVIMA based on severity [seeDosage 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 3 to 5 renal failure or
impairment occurred in 3% (DTC) and 2% (HCC) of patients, including 1 fatality in eachstudy.
In Study 205 (RCC), renal impairment or renal failure occurred in 18% of patients receiving
LENVIMA with everolimus, including Grade 3 in 10% of patients [see Adverse Reactions(6.1)].
Initiate prompt management of diarrhea or dehydration/hypovolemia. Withhold and resume
at a reduced dose upon recovery or permanently discontinue LENVIMA for renal failure or
impairment based on severity [see Dosage and Administration (2.6)].
5.6

Proteinuria

Proteinuria occurred in 34% of LENVIMA-treated patients in SELECT (DTC) and in 26% of
LENVIMA-treated patients in REFLECT (HCC). Grade 3 proteinuria occurred in 11% and
6% in SELECT and REFLECT, respectively. In Study 205 (RCC), proteinuria occurred in
31% of patients receiving LENVIMA with everolimus and 14% of patients receiving
everolimus. Grade 3 proteinuria occurred in 8% of patients receiving LENVIMA witheverolimus compared to 2% of patients receiving everolimus [see Adverse Reactions (6.1)].
Monitor for proteinuria prior to initiating LENVIMA and periodically during treatment. If
urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24-hour urine
protein. Withhold and resume at a reduced dose upon recovery or permanently discontinue
LENVIMA based on severity [see Dosage and Administration (2.6)].
5.7

Diarrhea

Of the 737 patients treated with LENVIMA in SELECT (DTC) and REFLECT (HCC),
diarrhea occurred in 49% of patients, including Grade 3 in 6%.
In Study 205 (RCC), diarrhea occurred in 81% of patients receiving LENVIMA witheverolimus, including Grade 3 in 19%. Diarrhea was the most frequent cause of doseinterruption/reduction and diarrhea recurred despite dose reduction [see Adverse Reactions(6.1)]. Promptly initiate management of diarrhea. Withhold and resume at a reduced doseupon recovery or permanently discontinue LENVIMA based on severity [see Dosage andAdministration (2.6)].

Reference ID: 4840228

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 in2%.
Permanently discontinue LENVIMA in patients who develop gastrointestinal perforation of
any severity or Grade 3 or 4 fistula [see Dosage and Administration (2.6)].
5.9

QT Interval Prolongation

In SELECT (DTC), QT/QTc interval prolongation occurred in 9% of LENVIMA-treatedpatients 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 witheverolimus 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 3 to 4 hypocalcemia occurred in 9% of patients receiving
LENVIMA. In 65% of cases, hypocalcemia improved or resolved following calcium
supplementation, with or without dose interruption or dose reduction.
In Study 205 (RCC), Grade 3 to 4 hypocalcemia occurred in 6% of patients treated withLENVIMA with everolimus. In REFLECT (HCC), Grade 3 hypocalcemia occurred in 0.8%
of LENVIMA-treated patients [see Adverse Reactions (6.1)].
Monitor blood calcium levels at least monthly and replace calcium as necessary during
treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue
LENVIMA depending on severity [see Dosage and Administration (2.6)].
5.11

Reversible Posterior Leukoencephalopathy Syndrome

Across clinical studies of 1823 patients who received LENVIMA as a single agent [seeAdverse Reaction (6.1)], reversible posterior leukoencephalopathy syndrome (RPLS)
occurred in 0.3%.
Confirm the diagnosis of RPLS with magnetic resonance imaging. Withhold and resume at a
reduced dose upon recovery or permanently discontinue LENVIMA depending on severity
and persistence of neurologic symptoms [see Dosage and Administration (2.6)].
5.12

Hemorrhagic Events

Serious including fatal hemorrhagic events can occur with LENVIMA. Across SELECT(DTC), Study 205 (RCC) and REFLECT (HCC), hemorrhagic events of any grade occurredin 29% of the 799 patients treated with LENVIMA as a single agent or in combination with

Reference ID: 4840228

everolimus. The most frequently reported hemorrhagic events (all grades and occurring in atleast 5% of patients) were epistaxis and hematuria.
In SELECT, Grade 3 to 5 hemorrhage occurred in 2% of patients receiving LENVIMA,
including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA andhad CNS metastases at baseline. In Study 205, Grade 3 to 5 hemorrhage occurred in 8% of
patients receiving LENVIMA with everolimus, including 1 fatal cerebral hemorrhage. In
REFLECT, Grade 3 to 5 hemorrhage occurred in 5% of patients receiving LENVIMA,
including 7 fatal hemorrhagic events [see Adverse Reactions (6.1)].
Serious tumor related bleeds, including fatal hemorrhagic events, occurred in patients treatedwith LENVIMA in clinical trials and in the post-marketing setting. In post-marketingsurveillance, serious and fatal carotid artery hemorrhages were seen more frequently inpatients with anaplastic thyroid carcinoma (ATC) than in other tumor types. The safety andeffectiveness 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 infiltrationof major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose uponrecovery or permanently discontinue LENVIMA based on the severity [see Dosage andAdministration (2.6)].
5.13

Impairment of Thyroid Stimulating Hormone Suppression/Thyroid
Dysfunction

LENVIMA impairs exogenous thyroid suppression. In SELECT (DTC), 88% of all patients
had a baseline thyroid stimulating hormone (TSH) level ≤0.5 mU/L. In those patients with anormal TSH at baseline, elevation of TSH level >0.5 mU/L was observed post baseline in
57% of LENVIMA-treated patients.
Grade 1 or 2 hypothyroidism occurred in 24% of patients receiving
LENVIMA with everolimus in Study 205 (RCC) and in 21% of patients receiving
LENVIMA in REFLECT (HCC). In those patients with a normal or low TSH at baseline, anelevation 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 [seeAdverse Reactions (6.1)].
Monitor thyroid function prior to initiating LENVIMA and at least monthly during treatment.
Treat hypothyroidism according to standard medical practice.
5.14

Impaired Wound Healing

Impaired wound healing has been reported in patients who received LENVIMA [see Adverse
Reactions (6.2)].
Withhold LENVIMA for at least 1 week prior to elective surgery. Do not administer for atleast 2 weeks following major surgery and until adequate wound healing. The safety ofresumption 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 [seeAdverse Reactions (6.1)]. Concomitant exposure to other risk factors, such asbisphosphonates, denosumab, dental disease or invasive dental procedures, may increase therisk of ONJ.

Reference ID: 4840228

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 1 week prior to scheduled dental surgery orinvasive 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-Fetal Toxicity

Based on its mechanism of action and data from animal reproduction studies, LENVIMA cancause fetal harm when administered to a pregnant woman. In animal reproduction studies,oral administration of lenvatinib during organogenesis at doses below the recommended
clinical doses resulted in embryotoxicity, fetotoxicity, and teratogenicity in rats and rabbits.
Advise pregnant women of the potential risk to a fetus. Advise females of reproductive
potential to use effective contraception during treatment with LENVIMA and for at least 30
days after the last dose [see Use in Specific Populations (8.1, 8.3)].

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 [seeWarnings and Precautions (5.13)]

Impaired Wound Healing [see Warnings and Precautions (5.14)]

Osteonecrosis of the Jaw (ONJ) [see Warnings and Precautions (5.15)]

Reference ID: 4840228

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 withpembrolizumab in 406 patients with endometrial carcinoma (Study 309), LENVIMA witheverolimus 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 acrossthese five studies ranged from 6 to 16 months. The demographic and exposure data for eachclinical 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) [see Clinical Studies (14.1)]. The median treatment duration was 16.1
months for LENVIMA. Among 261 patients who received LENVIMA, median age was 64
years, 52% were females, 80% were White, 18% were Asian, and 2% were Black; and 4%
were Hispanic/Latino.
The most common adverse reactions observed in LENVIMA-treated patients (≥30%) were,in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia,
decreased appetite, decreased weight, nausea, stomatitis, headache, vomiting, proteinuria,
palmar-plantar erythrodysesthesia (PPE) syndrome, abdominal pain, and dysphonia. The
most common serious adverse reactions (at least 2%) were pneumonia (4%), hypertension(3%), and dehydration (3%).
Adverse reactions led to dose reductions in 68% of patients receiving LENVIMA; 18% of
patients discontinued LENVIMA for adverse reactions. The most common adverse reactions(at least 10%) resulting in dose reductions of LENVIMA were hypertension (13%),proteinuria (11%), decreased appetite (10%), and diarrhea (10%); the most common adverse
reactions (at least 1%) resulting in discontinuation of LENVIMA were hypertension (1%)
and asthenia (1%).
Table 3 presents adverse reactions occurring at a higher rate in LENVIMA-treated patients
than patients receiving placebo in the double-blind phase of the study.

Reference ID: 4840228

Table 3: Adverse Reactions Occurring in Patients with a Between-Group Difference of≥5% in All Grades or ≥2% in Grades 3 and 4 in SELECT (DTC)

Adverse Reaction
VascularHypertensiona
Hypotension
Gastrointestinal
Diarrhea
NauseaStomatitisb
Vomiting
Abdominal painc
Constipation
Oral paind
Dry mouth
Dyspepsia
GeneralFatiguee
Edema peripheral
Musculoskeletal and Connective Tissue
Arthralgia/Myalgiaf
Metabolism and Nutrition
Decreased appetite
Decreased weight
Dehydration
Nervous System
Headache
Dysgeusia
Dizziness
Renal and Urinary
Proteinuria
Skin and Subcutaneous Tissue
Palmar-plantar erythrodysesthesia
Rashg
Alopecia
Hyperkeratosis
Respiratory, Thoracic and Mediastinal
Dysphonia
Cough
Epistaxis
PsychiatricInsomnia
Infections
Urinary tract infection
Dental and oral infectionsh
CardiacElectrocardiogram QT prolonged

Reference ID: 4840228

LENVIMA 24 mg
N=261
All Grades Grades 3-4(%)(%)

Placebo
N=131
All Grades Grades 3-4
(%)
(%)

73
9

44
2

16
2

4
0

67
47
41
36
31
29
25
17
13

9
2
5
2
2
0.4
1
0.4
0.4

17
25
8
15
11
15
2
8
4

0
1
0
0
1
1
0
0
0

67
21

11
0.4

35
8

4
0

62

5

28

3

54
51
9

7
13
2

18
15
2

1
1
1

38
18
15

3
0
0.4

11
3
9

1
0
0

34

11

3

0

32
21
12
7

3
0.4
0
0

1
3
5
2

0
0
0
0

31
24
12

1
0
0

5
18
1

0
0
0

12

0

3

0

11
10

1
1

5
1

0
0

9

2

2

0

Table 3: Adverse Reactions Occurring in Patients with a Between-Group Difference of≥5% in All Grades or ≥2% in Grades 3 and 4 in SELECT (DTC)

Adverse Reaction
a
b
c
d
e
f
g
h

LENVIMA 24 mg
N=261
All Grades Grades 3-4(%)(%)

Placebo
N=131
All Grades Grades 3-4(%)(%)

Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure
Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation
Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness,
epigastric discomfort, and gastrointestinal pain
Includes oral pain, glossodynia, and oropharyngeal pain
Includes asthenia, fatigue, and malaise
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 infection

Clinically important adverse reactions occurring more frequently in LENVIMA-treatedpatients 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 andat a Higher Incidence in the LENVIMA Arm a, b in SELECT (DTC)
Laboratory Abnormality

Chemistry
Hypocalcemia
Hypokalemia
Increased aspartate aminotransferase(AST)
Increased alanine aminotransferase (ALT)
Increased lipase
Increased creatinine
Hematology
Thrombocytopeniaab

LENVIMA 24 mg

Placebo

Grades 3-4(%)

Grades 3-4
(%)

9
6
5

2
1
0

4
4
3

0
1
0

2

0

With at least 1 grade increase from baseline
Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least
one post baseline laboratory measurement for each parameter. LENVIMA (n = 253 to 258), Placebo (n =129 to 131)

The following laboratory abnormalities (all Grades) occurred in >5% of LENVIMA-treatedpatients 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, andhyperkalemia.
First-Line Treatment of Renal Cell Carcinoma in Combination with Pembrolizumab(CLEAR)

Reference ID: 4840228

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 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 andpembrolizumab 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 andpembrolizumab. 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% bothdrugs. 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 5 and 6 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)
Sunitinib 50 mg
LENVIMA 20 mg in
N=340
combination with
Pembrolizumab
200mg
N=352

Adverse Reactions
GeneralFatiguea
Gastrointestinal

Reference ID: 4840228

All
Grades(%)

Grade 34(%)

All
Grades(%)

Grade 34
(%)

63

9

56

8

Table 5: Adverse Reactions in ≥20% of Patients on LENVIMA plus Pembrolizumab in
CLEAR (RCC)
Sunitinib 50 mg
LENVIMA 20 mg in
N=340
combination with
Pembrolizumab
200mg
N=352

Adverse Reactions
Diarrheab
Stomatitisc
NauseaAbdominal paind
Vomiting
Constipation
Musculoskeletal and connective tissue
Musculoskeletal paine
Endocrine
Hypothyroidismf
VascularHypertensiong
Hemorrhagic eventsh
Metabolism
Decreased appetitei
Skin and subcutaneous tissue
Rashj
Palmar-plantar erythrodysaesthesia syndromek
Respiratory, thoracic, and mediastinal
Dysphonia
Renal and urinary
Proteinurial
Acute kidney injurym
Investigations
Weight decreased
Hepatobiliary
Hepatotoxicityn
Nervous system
HeadacheabcReference ID: 4840228

All
Grades
(%)
62
43
36
27
26
25

Grade 34
(%)
10
2
3
2
3
1

All
Grades
(%)
50
43
33
18
20
19

Grade 34
(%)
6
2
1
1
1
0

58

4

41

3

57

1

32

0

56
27

29
5

43
26

20
4

41

4

31

1

37
29

5
4

17
38

1
4

30

0

4

0

30
21

8
5

13
16

3
2

30

8

9

0

25

9

21

5

23

1

16

1

Includes asthenia, fatigue, lethargy and malaise
Includes diarrhea and gastroenteritis
Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation,oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, andstomatitis

Table 5: Adverse Reactions in ≥20% of Patients on LENVIMA plus Pembrolizumab in
CLEAR (RCC)
Sunitinib 50 mg
LENVIMA 20 mg in
N=340
combination with
Pembrolizumab
200mg
N=352

Adverse Reactions
d
e
f
g
h

i
j
k
l
m
n

All
Grades(%)

Grade 34(%)

All
Grades(%)

Grade 34(%)

Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastricdiscomfort, lower abdominal pain, and upper abdominal pain
Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain,
musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, noncardiac chest pain, pain in extremity, and pain in jaw
Includes hypothyroidism, increased blood thyroid stimulating hormone and secondary hypothyroidism
Includes essential hypertension, increased blood pressure, increased diastolic blood pressure,
hypertension, hypertensive crisis, hypertensive retinopathy, and labile blood pressure
Includes all hemorrhage terms. Hemorrhage terms that occurred in 1 or more subjects in either treatmentgroup include: Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urinepresent, 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 hemorrhage
Includes decreased appetite and early satiety
Includes genital rash, infusion site rash, penile rash, perineal rash, rash, rash erythematous, rash macular,rash maculo-papular, rash papular, rash pruritic, and rash pustular
Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome and plantar erythema
Includes hemoglobinuria, nephrotic syndrome, and proteinuria
Includes acute kidney injury, azotaemia, blood creatinine increased, creatinine renal clearance
decreased, hypercreatininaemia, renal failure, renal impairment, oliguria, glomerular filtration rate
decreased, and nephropathy toxic
Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubinincreased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function
abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immunemediated hepatitis, liver function test increased, liver injury, transaminases increased, and gammaglutamyltransferase increased

Clinically relevant adverse reactions (<20%) that occurred in patients receiving
LENVIMA/pembrolizumab were myocardial infarction (3%) and angina pectoris (1%).

Reference ID: 4840228

Table 6: Laboratory Abnormalities in ≥20% (All Grades) of Patients on LENVIMA plus
Pembrolizumab in CLEAR (RCC)LENVIMA 20 mg in
Sunitinib 50 mg
combination with
Pembrolizumab 200 mg
All
GradesGrades 3-4
All Grades
Grade 3-4
Laboratory
b
b
b
a
%
%
%
%b
Abnormality
Chemistry
Hypertriglyceridemia
Hypercholesterolemia
Increased lipase
Increased creatinine
Increased amylase
Increased aspartate
aminotransferase (AST)Hyperglycemia
Increased alanine
aminotransferase (ALT)
Hyperkalemia
Hypoglycemia
Hyponatremia
Decreased albumin
Increased alkaline
phosphatase
Hypocalcemia
Hypophosphatemia
Hypomagnesemia
Increased creatine
phosphokinase
Hypermagnesemia
Hypercalcemia
Hematology
Lymphopenia
Thrombocytopenia
AnemiaLeukopenia
Neutropenia
a
b

80
64
61
61
59
58

15
5
34
5
17
7

71
43
59
61
41
57

15
1
28
2
9
3

55
52

7
7

48
49

3
4

44
44
41
34
32

9
2
12
0.3
4

28
27
28
22
32

6
1
9
0
1

30
29
25
24

2
7
2
6

22
50
15
36

1
8
3
5

23
21

2
1

22
11

3
1

54
39
38
34
31

9
2
3
1
4

66
73
66
77
72

15
13
8
8
16

With at least 1 grade increase from baseline
Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one postbaseline laboratory measurement for each parameter. LENVIMA/pembrolizumab (n= 343 to 349) and sunitinib (n=329 to 335).

Grade 3 and 4 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 3

Reference ID: 4840228

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 unresectableadvanced or metastatic renal cell carcinoma (RCC) were randomized (1:1:1) to LENVIMA
18 mg orally once daily with everolimus 5 mg orally once daily (n=51), LENVIMA 24 mg
orally once daily (n=52), or everolimus 10 mg orally once daily (n=50) [see Clinical Studies(14.2)]. This data also includes patients on the dose escalation portion of the study who
received LENVIMA with everolimus (n=11). The median treatment duration was 8.1 months
for LENVIMA with everolimus. Among 62 patients who received LENVIMA witheverolimus, the median age was 61 years, 71% were men, and 98% were White.
The most common adverse reactions observed in the LENVIMA with everolimus-treatedgroup (≥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, andproteinuria. 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 7 presents the adverse reactions in >15% of patients in the LENVIMA with everolimusarm. Study 205 was not designed to demonstrate a statistically significant difference inadverse 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)

Adverse Reactions

LENVIMA 18 mg with
Everolimus 5 mg
N=62
Grade 1-4
Grade 3-4(%)(%)

Everolimus 10 mg
N=50
Grade 1-4
Grade 3-4(%)(%)

Endocrine
Hypothyroidism
Gastrointestinal
Diarrhea
Vomiting
NauseaStomatitis/Oral inflammationa
Abdominal painb
Oral painc
Dyspepsia/Gastro-esophageal

Reference ID: 4840228

24

0

2

0

81
48
45
44
37
23
21

19
7
5
2
3
2
0

34
12
16
50
8
4
12

2
0
0
4
0
0
0

Table 7: Adverse Reactions Occurring in >15% of Patients in the LENVIMA with
Everolimus Arm in Study 205 (RCC)

Adverse Reactions

LENVIMA 18 mg with
Everolimus 5 mg
N=62
Grade 1-4
Grade 3-4(%)(%)

refluxConstipation
16
GeneralFatigued73
Peripheral edema
42
Pyrexia/Increased body21
temperature
Metabolism and Nutrition
Decreased appetite
53
Decreased weight
34
Musculoskeletal and Connective Tissue
Arthralgia/Myalgiae
55
Musculoskeletal chest pain
18
Nervous System
Headache
19
PsychiatricInsomnia
16
Renal and Urinary
Proteinuria/Urine protein present
31
Renal failure eventf
18
Respiratory, Thoracic and Mediastinal
Cough37
Dyspnea/Exertional dyspnea
35
Dysphonia
18
Skin and Subcutaneous Tissue
Rashg
35
VascularHypertension/Increased blood
42
pressure
Hemorrhagic eventsh
32
a
b
c
d
e
f
g
h

Reference ID: 4840228

Everolimus 10 mg
N=50
Grade 1-4
Grade 3-4
(%)
(%)

0

18

0

18
2
2

40
20
10

2
0
2

5
3

18
8

0
0

5
2

32
4

0
0

2

10

2

2

2

0

8
10

14
12

2
2

0
5
0

30
28
4

0
8
0

0

40

0

13

10

2

6

26

2

Includes aphthous stomatitis, gingival inflammation, glossitis, and mouth ulceration
Includes abdominal discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain
Includes gingival pain, glossodynia, and oropharyngeal pain
Includes asthenia, fatigue, lethargy and malaise
Includes arthralgia, back pain, extremity pain, musculoskeletal pain, and myalgia
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, liphemorrhage, 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

Chemistry
Hypertriglyceridemia
Increased lipase
Hypercholesterolemia
Hyponatremia
Hypophosphatemia
Hyperkalemia
Hypocalcemia
Hypokalemia
Increased aspartate aminotransferase(AST)
Increased alanine aminotransferase(ALT)
Increased alkaline phosphatase
Hyperglycemia
Increased creatine kinase
Hematology
Lymphopenia
AnemiaThrombocytopeniaab

LENVIMA 18 mg
with Everolimus 5 mg

Everolimus 10 mg

Grades 3-4(%)

Grades 3-4
(%)

18
13
11
11
11
6
6
6
3

18
12
0
6
6
2
2
2
0

3

2

3
3
3

0
16
4

10
8
5

20
16
0

With at least 1 grade increase from baseline
Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least
one post baseline laboratory measurement for each parameter. LENVIMA with Everolimus (n = 62),
Everolimus (n = 50).

Hepatocellular Carcinoma
The safety of LENVIMA was evaluated in REFLECT, which randomized (1:1) patients withunresectable 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 forpatients with a baseline body weight of ≥60 kg and 8 mg orally once daily for patients with abaseline 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 andsorafenib 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.

Reference ID: 4840228

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 orinterruption 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 9 summarizes the adverse reactions that occurred in ≥10% of patients receiving
LENVIMA in REFLECT. REFLECT was not designed to demonstrate a statisticallysignificant reduction in adverse reaction rates for LENVIMA, as compared to sorafenib, forany specified adverse reaction listed in Table 9.
Table 9: Adverse Reactions Occurring in ≥10% of Patients in the LENVIMA Arm in
REFLECT (HCC)
Adverse Reaction

LENVIMA
8 mg/12 mg
N=476
Grade 1-4
Grade 3-4(%)(%)

Sorafenib
800 mg
N=475
Grade 1-4
Grade 3-4(%)(%)

Endocrine
Hypothyroidisma
21
Gastrointestinal
Diarrhea
39
Abdominal painb
30
Nausea20
Vomiting
16
Constipation
16
Ascitesc
15
d
Stomatitis
11
GeneralFatiguee
44f
Pyrexia15
Peripheral edema
14
Metabolism and Nutrition
Decreased appetite
34
Decreased weight
31
Musculoskeletal and Connective Tissue
Arthralgia/Myalgiag
31
Nervous System
Headache
10
Renal and Urinary
Proteinuriah
26

Reference ID: 4840228

0

3

0

4
3
1
1
1
4
0.4

46
28
14
8
11
11
14

4
4
1
1
0
3
1

7
0
1

36
14
7

6
0.2
0.2

5
8

27
22

1
3

1

20

2

1

8

0

6

12

2

Table 9: Adverse Reactions Occurring in ≥10% of Patients in the LENVIMA Arm in
REFLECT (HCC)
Adverse Reaction

LENVIMA
8 mg/12 mg
N=476
Grade 1-4
Grade 3-4(%)(%)
Respiratory, Thoracic and Mediastinal
Dysphonia
24
0.2
Skin and Subcutaneous Tissue
Palmar-plantar
27
3erythrodysesthesia syndrome
Rashi
14
0
VascularHypertensionj
45
24
k
Hemorrhagic events
23
4
a
b
c
d
e
f
g
h
i
j
k

Sorafenib
800 mg
N=475
Grade 1-4
Grade 3-4
(%)
(%)
12

0

52

11

24

2

31
15

15
4

Includes hypothyroidism, blood thyroid stimulating hormone increased.
Includes abdominal discomfort, abdominal pain, abdominal tenderness, epigastric discomfort, gastrointestinal pain,
lower abdominal pain, and upper abdominal pain
Includes ascites and malignant ascites
Includes aphthous ulcer, gingival erosion, gingival ulceration, glossitis, mouth ulceration, oral mucosal blistering,and stomatitis
Includes asthenia, fatigue, lethargy and malaise
Includes increased body temperature, pyrexia
Includes arthralgia, back pain, extremity pain, musculoskeletal chest pain, musculoskeletal discomfort,
musculoskeletal pain, and myalgia
Includes proteinuria, increased urine protein, protein urine present
Includes erythema, erythematous rash, exfoliative rash, genital rash, macular rash, maculo-papular rash, papular
rash, pruritic rash, pustular rash and rash
Includes increased diastolic blood pressure, increased blood pressure, hypertension and orthostatic hypertension
Includes all hemorrhage terms. Hemorrhage terms that occurred in 5 or more subjects in either treatment group
include: epistaxis, hematuria, gingival bleeding, hemoptysis, esophageal varices hemorrhage, hemorrhoidal
hemorrhage, mouth hemorrhage, rectal hemorrhage and upper gastrointestinal hemorrhage

In 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

Chemistry
Increased GGTHyponatremia
Hyperbilirubinemia
Increased aspartate aminotransferase (AST)
Increased alanine aminotransferase (ALT)
Increased alkaline phosphatase
Increased lipase
Hypokalemia
Hyperkalemia

Reference ID: 4840228

Lenvatinib(%)

Sorafenib
(%)

17
15
13
12
8
7
6
3
3

20
9
10
18
9
5
17
4
2

Table 10: Grade 3-4 Laboratory Abnormalities Occurring in ≥2% of Patients in the
LENVIMA Arma,b in REFLECT (HCC)
Laboratory Abnormality

Decreased albumin
Increased creatinine
Hematology
Thrombocytopenia
Lymphopenia
Neutropenia
Anemiaab

Lenvatinib(%)
3
2

Sorafenib
(%)
1
2

10
8
7
4

8
9
3
5

With at least 1 grade increase from baseline
Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least one postbaseline laboratory measurement for each parameter. LENVIMA (n=278 to 470) and sorafenib (n=260 to 473)

Endometrial Carcinoma
The safety of LENVIMA in combination with pembrolizumab was investigated in Study 309,
a 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 [seeClinical 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 3 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 1 day to 26.8 months) and the median duration of exposure to LENVIMA
was 6.7 months (range: 1 day to 26.8 months).
Fatal adverse reactions among these patients occurred in 4.7% of those treated withLENVIMA and pembrolizumab, including 2 cases of pneumonia, and 1 case of thefollowing: 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 andpembrolizumab. 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%).

Reference ID: 4840228

Dose interruptions of LENVIMA due to an adverse reaction occurred in 58% of thesepatients. 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, inpatients receiving LENVIMA in Study 309.
Table 11: Adverse Reactions in ≥20% of Patients Receiving LENVIMA plus
Pembrolizumab in Study 309 (EC)

Adverse Reaction
Endocrine
Hypothyroidismb
VascularHypertensionc
Hemorrhagic
eventsd
GeneralFatiguee
Gastrointestinal
Diarrheaf
NauseaVomiting
Stomatitisg

Endometrial Carcinoma(not MSI-H or dMMR)
Doxorubicin or
LENVIMA
Paclitaxel
20 mg in combination with
N=325
Pembrolizumab 200 mg
N=342
All Gradesa
Grades 3-4
All Gradesa
Grades 3-4
(%)
(%)
(%)
(%)
67

0.9

0.9

0

67

39

6

2.5

25

2.6

15

0.9

58

11

54

6

55

8

20

2.8

49
37
35

2.9
2.3
2.6

47
21
26

1.5
2.2
1.2

2.6

21

1.2

0

25

0.6

5

27

0.6

7

21

0

10

6

0.3

6

3.4

0.3

5

13

1.2

34
Abdominal painh
Constipation
27
Musculoskeletal and Connective Tissue
53
Musculoskeletalidisorders
Metabolism
44
Decreased appetitej
Investigations
Decreased weight
34
Renal and Urinary
29
Proteinuriak
Infections
31
Urinary tractlinfection

Reference ID: 4840228

Table 11: Adverse Reactions in ≥20% of Patients Receiving LENVIMA plus
Pembrolizumab in Study 309 (EC)Endometrial Carcinoma(not MSI-H or dMMR)
Doxorubicin or
LENVIMA
Paclitaxel
20 mg in combination with
N=325
Pembrolizumab 200 mg
N=342
All Gradesa
Grades 3-4
All Gradesa
Grades 3-4
(%)
(%)
(%)
(%)

Adverse Reaction
Nervous System
Headache26
Respiratory, Thoracic and Mediastinal
Dysphonia
22
Skin and Subcutaneous Tissue
23
Palmar-plantarmerythrodysesthesia
20
Rashn
a
b
c
d

e
f
g
h
i
j
k
l
m
n

Reference ID: 4840228

0.6

9

0.3

0

0.6

0

2.9

0.9

0

2.3

4.9

0

Graded per NCI CTCAE v4.03
Includes hypothyroidism, blood thyroid stimulating hormone increased, thyroiditis, primary hypothyroidism, andsecondary 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 rash

Table 12: Laboratory Abnormalities Worsened from Baselinea Occurring in ≥20% (All
Grades) or ≥3% (Grades 3-4) of Patients Receiving LENVIMA plus Pembrolizumab inStudy 309 (EC)Laboratory Testb
Chemistry
Hypertriglyceridemia
Hypoalbuminemia
Increased aspartate
aminotransferase
Hyperglycemia
Hypomagnesemia
Increased alanine
aminotransferase
Hypercholesteremia
Hyponatremia
Increased alkaline
phosphatase
Hypocalcemia
Increased lipase
Increased creatinine
Hypokalemia
Hypophosphatemia
Increased amylase
Hyperkalemia
Increased creatine
kinaseIncreased bilirubinEndometrial Carcinoma(not MSI-H or dMMR)
Doxorubicin or
LENVIMA
Paclitaxel
20 mg in combination with
N=325
Pembrolizumab 200 mg
N=342
All Gradesc
Grades 3-4
All Gradesc
Grades 3-4
(%)
(%)
(%)
(%)
70
60
58

6
2.7
9

45
42
23

1.7
1.6
1.6

58
53
55

8
6
9

45
32
21

4.4
3.8
1.2

53
46
43

3.2
15
4.7

23
28
18

0.7
7
0.9

40
36
35
34
26
25
23
19

4.7
14
4.7
10
8
7
2.4
3.7

21
13
18
24
17
8
12
7

1.7
3.9
1.9
5
3.2
1
1.2
0

18

3.6

6

1.6

50
50
49
43
31

16
8
8
3.5
6

65
30
84
83
76

20
4.7
14
43
58

Hematology
Lymphopenia
Thrombocytopenia
AnemiaLeukopenia
Neutropenia
a
b

c

6.2

With at least 1 grade increase from baseline
Laboratory abnormality percentage is based on the number of patients who had both baseline and at least one postbaseline laboratory measurement for each parameter: LENVIMA/pembrolizumab (range: 312 to 404 patients) anddoxorubicin or paclitaxel (280 to 380).
Graded per NCI CTCAE v4.03

Postmarketing Experience

The following adverse reactions have been identified during post approval use of
LENVIMA. Because these reactions are reported voluntarily from a population of uncertain

Reference ID: 4840228

size, it is not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Gastrointestinal: pancreatitis, increased amylase
General: impaired wound healing
Hepatobiliary: cholecystitis
Renal and Urinary: nephrotic syndrome
Vascular: arterial (including aortic) aneurysms, dissections, and rupture
7
7.1

DRUG INTERACTIONS
Drugs That Prolong the QT Interval

LENVIMA has been reported to prolong the QT/QTc interval. Avoid coadministration of
LENVIMA with medicinal products with a known potential to prolong the QT/QTc interval[see Warnings and Precautions (5.9)].
8
8.1

USE IN SPECIFIC POPULATIONS
Pregnancy

Risk Summary
Based on its mechanism of action and data from animal reproduction studies, LENVIMA cancause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)].
In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses
below the recommended human doses resulted in embryotoxicity, fetotoxicity, andteratogenicity in rats and rabbits (see Data). There are no available human data informing the
drug-associated risk. Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects andmiscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
In an embryofetal development study, daily oral administration of lenvatinib mesylate atdoses ≥0.3 mg/kg [approximately 0.14 times the recommended clinical dose of 24 mg basedon 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 infetal 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 therecommended clinical dose of 24 mg based on BSA). At the 0.03 mg/kg dose, increased postimplantation 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 doselevel of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg
based on BSA).

Reference ID: 4840228

8.2

Lactation

Risk Summary
It 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 (seeData). Because of the potential for serious adverse reactions in breastfed infants, advise women
to discontinue breastfeeding during treatment with LENVIMA and for at least 1 week after thelast dose.
Data
Animal Data
Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats,
lenvatinib-related radioactivity was approximately 2 times higher [based on area under the
curve (AUC)] in milk compared to maternal plasma.
8.3

Females and Males of Reproductive Potential

Pregnancy Testing
Verify the pregnancy status of females of reproductive potential prior to initiating
LENVIMA [see Use in Specific Populations (8.1)].
Contraception
Based on its mechanism of action, LENVIMA can cause fetal harm when administered to apregnant woman [see Use in Specific Populations (8.1)].
Females
Advise females of reproductive potential to use effective contraception during treatment withLENVIMA and for at least 30 days after the last dose.
Infertility
LENVIMA may impair fertility in males and females of reproductive potential [seeNonclinical Toxicology (13.1)].
8.4

Pediatric Use

The safety and effectiveness of LENVIMA in pediatric patients have not been established.
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 thewidth 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 24mg). 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.

Reference ID: 4840228

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 differencesin safety or effectiveness were observed between these subjects and younger subjects.
Of the 352 patients with renal cell carcinoma (RCC) who received LENVIMA withpembrolizumab 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 patientsand 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 andyounger 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 andyounger 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 inpatients 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 norecommended 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 andPrecautions (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 orsevere hepatic impairment.

Reference ID: 4840228

No dose adjustment is recommended for patients with DTC, RCC, or endometrial carcinoma
and mild or moderate hepatic impairment (Child-Pugh A or B). Lenvatinib concentrations
may increase in patients with DTC, RCC, or endometrial carcinoma and severe hepatic
impairment (Child-Pugh C). Reduce the dose of lenvatinib for patients with DTC, RCC, orendometrial carcinoma and severe hepatic impairment [see Dosage and Administration (2.6),
Clinical Pharmacology (12.3)].
10

OVERDOSAGE

Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable [seeClinical Pharmacology (12.3)]. Death due to multiorgan dysfunction occurred in a patient
who received a single dose of LENVIMA 120 mg orally.
11

DESCRIPTIONLENVIMA, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4-[3chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide
methanesulfonate. The molecular formula is C 21H19ClN4O4 • CH4O3S, and the molecularweight 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 waterand practically insoluble in ethanol (dehydrated). The dissociation constant (pKa value) oflenvatinib 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, andtitanium dioxide. The printing ink contains black iron oxide, potassium hydroxide, propylene
glycol, and shellac.
1212.1

CLINICAL PHARMACOLOGY
Mechanism of Action

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 (PDGFRα), KIT, and RET. Lenvatinib also exhibited antiproliferative activity
in hepatocellular carcinoma cell lines dependent on activated FGFR signaling with aconcurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation.

Reference ID: 4840228

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 andantitumor 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.
12.3

Pharmacokinetics

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 theconcentration-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 Cmax and AUC values at steady state for RCC, DTC and HCC aresummarized in the Table 13.
Table 13: Lenvatinib Cmax and AUC in Patients with Solid Tumorsa
Tumor Type

Dose
18 mg

RCC
20 mg

a

DTC

24 mg

HCC
(body weight < 60 kg)

8 mg

HCC
(body weight ≥ 60 kg)

12 mg

Parameter
Cmax (ng/mL)
AUC (ng∙h/mL)
Cmax (ng/mL)
AUC (ng∙h/mL)
Cmax (ng/mL)
AUC (ng∙h/mL)
Cmax (ng/mL)
AUC (ng∙h/mL)
Cmax (ng/mL)
AUC (ng∙h/mL)

N
350
350
346
346
251
251
150
150
318
318

Geometric Mean
267
3148
275
3135
323
3483
154
1835
172
2013

%CV
36.7
42.5
32.6
41.3
33.3
34.7
25.4
34.0
23.1
29.3

Model-predicted steady-state pharmacokinetic parameters are presented.

Absorption
The time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose.
Food Effect
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.
Distribution
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.

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Elimination
The terminal elimination half-life of lenvatinib was approximately 28 hours.
Metabolism
The main metabolic pathways for lenvatinib in humans were identified as enzymatic(CYP3A and aldehyde oxidase) and non-enzymatic processes.
Excretion
Ten days after a single administration of radiolabeled lenvatinib, approximately 64% and
25% of the radiolabel were eliminated in the feces and urine, respectively.
Specific Populations
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.
Patients with Hepatic Impairment
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-PughC) 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 were119%, 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 thoseweighing <60 kg who received a starting dose of 8 mg and those ≥60 kg who received astarting dose of 12 mg.
Drug Interaction Studies
Effect of Other Drugs on Lenvatinib
CYP3A, P-gp, and BCRP Inhibitors: 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%.
P-gp Inhibitor: Rifampicin (600 mg as a single dose) increased lenvatinib (24 mg as a single
dose) AUC by 31% and Cmax by 33%.
CYP3A and P-gp Inducers: Rifampicin (600 mg daily for 21 days) decreased lenvatinib (24mg as a single dose on Day 15) AUC by 18%. The C max was unchanged.
Population pharmacokinetic analysis demonstrated that neither everolimus nor
pembrolizumab meaningfully affect the pharmacokinetics of lenvatinib.
In Vitro Studies with Transporters: 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).

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Effect of Lenvatinib on Other Drugs
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 thepharmacokinetics 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 intissues. 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.
13
13.1

NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility

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 a 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 therecommended clinical dose of 24 mg once daily. Follicular atresia of the ovaries wasobserved in monkeys and rats at exposures 0.2 to 0.8 times and 10 to 44 times the AUC at therecommended clinical dose of 24 mg once daily, respectively. In addition, in monkeys, adecreased incidence of menstruation was reported at lenvatinib exposures lower than thoseobserved in humans at the recommended clinical dose of 24 mg once daily.

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14
14.1

CLINICAL STUDIES
Differentiated Thyroid Cancer

A multicenter, randomized (2:1), double-blind, placebo-controlled study (SELECT;
NCT01321554) was conducted in 392 patients with locally recurrent or metastaticradioactive iodine-refractory differentiated thyroid cancer and radiographic evidence ofdisease progression within 12 months prior to randomization, confirmed by independentradiologic review. Radioactive iodine (RAI)-refractory was defined as 1 or more measurable
lesions with no iodine uptake on RAI scan, iodine uptake with progression within 12 monthsof RAI therapy, or having received cumulative RAI activity >600 mCi (22 GBq) with the lastdose administered at least 6 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 1 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
Hürthle cell and 11% had clear cell subtypes. In the LENVIMA arm, 67% of patients did notdemonstrate 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 I 131 therapy; 19.2% of
patients on the LENVIMA arm and 17.6% of patients on placebo arm received priorcumulative activity of >600 mCi or 22 GBq I 131, with the last dose administered at least 6months prior to study entry. The median cumulative RAI activity administered prior to study
entry was 350 mCi (12.95 GBq).
A statistically significant prolongation in PFS was demonstrated in LENVIMA-treatedpatients compared to those receiving placebo (Table 14 and Figure 1). Upon confirmation ofprogression, 83% of patients that were randomly assigned to placebo crossed over to receive
open-label LENVIMA.

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Table 14: Efficacy Results in Differentiated Thyroid Cancer in SELECTLENVIMA
Placebo
N=261
N=131
a
Progression-Free Survival (PFS)
Number of events (%)
107 (41)113 (86)
Progressive disease
93 (36)109 (83)Death
14 (5)
4 (3)Median PFS in months (95% CI)
18.3 (15.1, NE)
3.6 (2.2, 3.7)bHazard ratio (95% CI)
0.21 (0.16, 0.28)
P-valuec<0.001a
Objective Response Rate
Objective response rate65%2%(95% CI)(59%, 71%)
(0%, 4%)Complete response
2%0%Partial response
63%2%dP-value<0.001
Overall Survival (OS)e
Number of deaths (%)
71 (27)47 (36)Median OS in months (95% CI)
NE (22.1, NE)
NE (20.3, NE)
Hazard ratio (95% CI)b0.73 (0.50, 1.07)
P-valueb
0.10
a
b
c
d
e

Reference ID: 4840228

Independent radiologic review
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)
Log-rank test stratified by region (Europe vs North America vs other), age group (≤65 years vs >65 years), andprevious VEGF/VEGFR-targeted therapy (0 vs 1)
Cochran-Mantel-Haenszel chi-square test
NE = Not estimableFigure 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), a multicenter, open-label, randomized trial that enrolled 1069 patients withadvanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor
expression status. Patients with active autoimmune disease or a 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 poorrisk).
Patients were randomized (1:1:1) to one of the following treatment arms:

Reference ID: 4840228



LENVIMA 20 mg orally once daily in combination with pembrolizumab 200 mg
intravenously every 3 weeks up to 24 months.



LENVIMA 18 mg orally once daily in combination with everolimus 5 mg orally once
daily.



Sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 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 clinicalbenefit. Pembrolizumab dosing was continued for a 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 8 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 a 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 withpembrolizumab demonstrated statistically significant improvements in PFS, OS, and ORR
compared with sunitinib. Table 15 and Figures 2 and 3 summarize the efficacy results for
CLEAR.
Table 15: Efficacy Results in Renal Cell Carcinoma Per IRC in CLEARLENVIMA20 mg with
Sunitinib 50mg
Pembrolizumab 200mg
N=357
N=355
Progression-Free Survival (PFS)
Number of events, n (%)
160 (45%)205 (57%)
Progressive disease
145 (41%)
196 (55%)Death
15 (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<0.0001
Overall Survival (OS)Number of deaths, n (%)
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
0.0049
Objective Response Rate (Confirmed)
Objective response rate, n (%)
252 (71%)129 (36%)(95% CI)(66, 76)(31, 41)
Complete response rate
16%
4%Partial responses rate55%
32%
p-valuec<0.0001
Tumor assessments were based on RECIST 1.1; only confirmed responses are included for ORR.
Data cutoff date = 28 Aug 2020
CI = confidence interval; NE= Not estimable; NR= Not reachedaHazard ratio is based on a Cox Proportional Hazards Model, stratified by geographic region and MSKCC prognostic
groups.
b
Two-sided p-value based on stratified log-rank test.
cTwo-sided p-value based upon CMH test.

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Figure 2: Kaplan-Meier Curves for Progression-Free Survival in CLEAR

L+P = Lenvatinib + Pembrolizumab; S = Sunitinib.

Figure 3: Kaplan-Meier Curves for Overall Survival in CLEAR

L+P = Lenvatinib + Pembrolizumab; S = Sunitinib.

Previously Treated RCC in Combination with Everolimus (Study 205)
The efficacy was evaluated in a multicenter, randomized (1:1:1) study (Study 205:
NCT01136733), in which 153 patients with advanced or metastatic renal cell carcinoma whohave previously received anti-angiogenic therapy received LENVIMA 18 mg orally once
daily with everolimus 5 mg orally once daily, LENVIMA 24 mg orally once daily, or
everolimus 10 mg orally once daily. Patients were required to have histological confirmationof clear cell RCC and ECOG PS of 0 or 1. Patients were stratified by hemoglobin level (≤ orReference ID: 4840228

>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% wereWhite. Metastases were present in 95% of the patients and unresectable advanced disease
was present in 5%. All patients had a baseline ECOG PS of either 0 (54%) or 1 (46%) withsimilar distribution across these two treatment arms. MSKCC favorable, intermediate, andpoor 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 4 and 5. The
treatment effect of the combination on PFS was supported by a 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 inStudy 205LENVIMA 18 mg with
Everolimus 10 mg
Everolimus 5 mg
N=51
N=50
Progression-Free Survival (PFS)a
Number of events, n (%)
26 (51)37 (74)Progressive disease21 (41)35 (70)Death
5 (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)b0.37 (0.22, 0.62)
LENVIMA with Everolimus vs
Everolimus
Overall Survival (OS)c
Number of deaths, n (%)
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)b0.67 (0.42, 1.08)
LENVIMA with Everolimus vs
Everolimus
Objective Response Rate (Confirmed)
Objective response rate, n (%)
19 (37)3 (6)(95% CI)(24, 52)(1, 17)
Number of complete responses, n (%)
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 2014
CI = confidence intervalaPoint 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 a stratified Cox regression model including treatment as a covariate factor and hemoglobin
and corrected serum calcium as strata.
c
Data cutoff date = 31 Jul 2015

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Figure 4: Kaplan-Meier Curves for Progression-Free Survival
in Study 205

Reference ID: 4840228

Figure 5: Kaplan-Meier Curves for Overall Survival in Study 205

14.3

Hepatocellular Carcinoma

The efficacy of LENVIMA was evaluated in a randomized, open-label, multicenter,international study (REFLECT; NCT01761266) conducted in patients with previously
untreated unresectable hepatocellular carcinoma (HCC). The study enrolled adults withChild-Pugh A and Barcelona Clinic Liver Cancer (BCLC) Stage C or B HCC who wereineligible for local liver-directed therapy; had an ECOG PS of 0 or 1; had received no priorsystemic therapy for HCC; and had at least one measurable target lesion according tomodified RECIST for HCC.
Patients were randomized (1:1) to receive LENVIMA (12 mg for baseline body weight ≥60
kg or 8 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 veininvasion 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.
A 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 to88 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 bonemetastasis.

Reference ID: 4840228

Macroscopic portal vein invasion, extra-hepatic spread, or both were present in 70% of
patients. HCC was categorized as Child-Pugh A and BCLC Stage C in 79% and Child-PughA and BCLC Stage B in 21% of patients. Seventy-five percent (75%) of patients hadradiographic evidence of cirrhosis at baseline. Investigator-documented primary risk factors
for the development of HCC were hepatitis B (50%), hepatitis C (23%), alcohol use (6%),
other (7%), and unknown (14%).
REFLECT demonstrated that LENVIMA was non-inferior to sorafenib for OS. REFLECT
did not demonstrate a statistically significant improvement in OS for patients randomized to
LENVIMA as compared to those in the sorafenib arm. LENVIMA was statisticallysignificantly superior to sorafenib for PFS and ORR. Efficacy results are summarized inTable 17 and Figure 6.
Table 17: Efficacy Results in Hepatocellular Carcinoma in REFLECTLENVIMA
Sorafenib
N= 478
N=476
Overall 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)a0.92 (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<0.001
Objective Response Rateb (mRECIST)
Objective response rate
41%
12%Complete responses, n (%)
10 (2.1)
4 (0.8)
Partial responses, n (%)
184 (38.5)
55 (11.6)
95% CI(36%, 45%)
(10%, 16%)
P-value<0.001
Progression-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, n (%)
2 (0.4)1 (0.2)
Partial responses, n (%)
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.
aBased on stratified Cox-model. Non-inferiority margin for HR (lenvatinib vs sorafenib) is 1.08.
b

Reference ID: 4840228

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), a multicenter, open-label, randomized, active-controlled trial thatenrolled 827 patients with advanced endometrial carcinoma who had been previously treatedwith 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 a 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, andhistory 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 3 weeks.

Investigator’s choice consisting of either doxorubicin 60 mg/m 2 every 3 weeks, or
paclitaxel 80 mg/m2 given weekly, 3 weeks on/1 week off.

Treatment with LENVIMA and pembrolizumab continued until RECIST v1.1-definedprogression of disease as verified by BICR, unacceptable toxicity, or for pembrolizumab, amaximum of 24 months. Treatment was permitted beyond RECIST v1.1-defined diseaseprogression if the treating investigator considered the patient to be deriving clinical benefit
and the treatment was tolerated. Assessment of tumor status was performed every 8 weeks.
The major efficacy outcome measures were OS and PFS as assessed by BICR according to
RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target
lesions per organ. Additional efficacy outcome measures included ORR and DOR, asassessed by BICR.

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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 investigator’s
choice of doxorubicin (n=254) or paclitaxel (n=97). The population characteristics of thesepatients 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 0 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 forendometrial carcinoma: 67% had one, 30% had two, and 3% had three or more priorsystemic 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 7 and 8.
Table 18: Efficacy Results in Endometrial Carcinoma in Study 309
Endometrial Carcinoma(not MSI-H or dMMR)
Endpoint
LENVIMA with
Doxorubicin or
pembrolizumab
Paclitaxel
N=346
N=351
OS
Number (%) 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)
a0.68 (0.56, 0.84)
Hazard ratio (95% CI)
b0.0001
p-Valuec
PFS
Number (%) 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)a0.60 (0.50, 0.72)
Hazard ratio (95% CI)
b<0.0001
p-ValueObjective Response Rate
30% (26, 36)
15% (12,19)
ORRc (95% CI)
Complete response
5%3%Partial response25%
13%<0.0001
p-Valued
Duration of Response
N=105
N=53
Median in months (range)
9.2 (1.6+, 23.7+)
5.7 (0.0+, 24.2+)abcdReference ID: 4840228

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 radiation

Figure 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)

Reference ID: 4840228

16

HOW SUPPLIED/STORAGE AND HANDLINGLENVIMA 4 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 bodyand yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 10 mg” on thebody.
LENVIMA capsules are supplied in cartons of 6 cards. Each card is a 5-day blister card asfollows:









NDC 62856-724-30: 24 mg, carton with 6 cards NDC 62856-724-05 (ten 10 mg capsulesand 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)[see USP Controlled Room Temperature].
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 careprovider 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 Events
Advise patients to seek immediate medical attention for new onset chest pain or acuteneurologic symptoms consistent with myocardial infarction or stroke [see Warnings andPrecautions (5.3)].

Reference ID: 4840228

Hepatotoxicity
Advise patients that they will need to undergo laboratory tests to monitor liver function andto report any new symptoms indicating hepatic toxicity or failure [see Warnings andPrecautions (5.4)].
Proteinuria and Renal Failure/Impairment
Advise 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)].
Diarrhea
Advise 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 maintainadequate hydration [see Warnings and Precautions (5.7)].
Fistula Formation and Gastrointestinal Perforation
Advise patients that LENVIMA can increase the risk of fistula formation or gastrointestinal
perforation and to seek immediate medical attention for severe abdominal pain [seeWarnings and Precautions (5.8)].
QTc Interval Prolongation
Advise 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)].
Hypocalcemia
Advise 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 [seeWarnings 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 Events
Advise patients that LENVIMA can increase the risk for bleeding and to contact theirhealthcare provider for bleeding or symptoms of severe bleeding [see Warnings andPrecautions (5.12)].
Impairment of Thyroid Stimulating Hormone Suppression/Thyroid Dysfunction
Advise 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 Healing
Advise patients that LENVIMA may impair wound healing. Advise patients to inform theirhealthcare 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.

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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 providerof any planned dental procedures [see Warnings and Precautions (5.15)]. Advise patients toimmediately contact their healthcare provider for signs or symptoms associated with ONJ.
Embryo-Fetal Toxicity
Advise females of reproductive potential of the potential risk to a fetus and to inform theirhealthcare provider of a 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 withLENVIMA and for at least 30 days after the last dose [see Use in Specific Populations (8.3)].
Lactation
Advise women to discontinue breastfeeding during treatment with LENVIMA and for at least
1 week after the last dose [see Use in Specific Populations (8.2)].
Distributed by:
Eisai Inc.
Woodcliff Lake, NJ 07677
LENVIMA® is a registered trademark of Eisai R&D Management Co., Ltd. and is licensed to Eisai Inc.
© 2021 Eisai Inc.

Reference ID: 4840228

PATIENT INFORMATIONLENVIMA® (lehn-veema)(lenvatinib)
capsulesWhat is LENVIMA?
LENVIMA is a prescription medicine that is used to treat people with certain kinds of cancer.
 LENVIMA is used by itself to treat differentiated thyroid cancer (DTC), a type of thyroid cancer
that can no longer be treated with radioactive iodine and is progressing.
 LENVIMA is used to treat adults with a type of kidney cancer called advanced renal cell
carcinoma (RCC):o along with the medicine pembrolizumab as your first treatment when your kidneycancer has spread or cannot be removed by surgery.
o along with the medicine everolimus after one course of treatment with another anticancer medicine.
 LENVIMA is used by itself as the first treatment for a 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, a type of uterine cancer:
o when your tumor is not microsatellite instability-high (MSI-H) or mismatch repair deficient(dMMR), ando you have received anti-cancer treatment, and it is no longer working, ando 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 a 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 a history of a 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, a dental procedure, or have had a recent surgery. You should stop taking
LENVIMA at least 1 week before planned surgery. See “What are the possible side effectsof 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 a pregnancy test before you start treatment withLENVIMA.
o You should use an effective method of birth control during treatment with LENVIMA and forat least 30 days after the last dose of LENVIMA. Talk with your healthcare provider aboutbirth 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 1 week after the lastdose.
Tell your healthcare provider about all the medicines you take, including prescription and overthe-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 a list of your medicines to show to your healthcare provider
and pharmacist when you get a new medicine.

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How should I take LENVIMA?
 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, orcompletely stop treatment with LENVIMA if you have side effects.
 Take LENVIMA 1 time each day at the same time, with or without food.
 If you miss a 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 a medicine cup to measure about one tablespoon of water or apple juice and place
into a 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.
o Stir the contents of the glass for at least 3 minutes.
o Drink the mixture. After drinking, rinse the glass with a small amount of additional water orapple juice and swallow the liquid.
 If you take too much LENVIMA, call your healthcare provider or go to the nearest hospitalemergency room right away.
What are the possible side effects of LENVIMA?
LENVIMA may cause serious side effects, including: high blood pressure (hypertension). High blood pressure is a common side effect of
LENVIMA and can be serious. Your blood pressure should be well controlled before you starttaking 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 shortnessof 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:
o severe chest pain or pressureo trouble talkingo pain in your arms, back, neck or jaw
o sudden severe headacheo shortness of breatho sudden vision changes
o numbness or weakness on one side ofyour body 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 withLENVIMA. Tell your healthcare provider right away if you have any of the following symptoms:
o your skin or the white part of your eyes turns yellow (jaundice)o dark “tea colored” urine
o light-colored bowel movements (stools)
o 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 a 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 a 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 yourdiarrhea. 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 yourdiarrhea 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 rightaway 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

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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 a 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 yourhealthcare provider if you have any signs or symptoms of bleeding during treatment withLENVIMA, including:o severe and persistent nose bleedso blood in your urine
o vomiting bloodo coughing up blood or blood clots
o red or black (looks like tar) stoolso 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.
o You should stop taking LENVIMA at least 1 week before planned surgery.
o 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 insome people who take LENVIMA. Certain risk factors such as taking a 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 aretaking LENVIMA. It is important for you to practice good mouth care during treatment withLENVIMA. 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 yourgums. 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 1 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: tiredness
 headache joint and muscle pain
 vomiting decreased appetite
 rash, redness, itching, or peeling of yourskin on your hands and feet
 weight loss stomach (abdomen) pain nausea
 hoarseness mouth sores

The most common side effects of LENVIMA when given with everolimus include: tiredness
 cough joint and muscle pain stomach (abdomen) pain decreased appetite
 trouble breathing vomiting
 rash nausea weight loss mouth sores bleeding

Reference ID: 4840228



swelling in your arms and legs
The most common side effects of LENVIMA in people treated for liver cancer include: tiredness
 rash, redness, itching, or peeling of your decreased appetite
skin on your hands and feet joint and muscle pain hoarseness weight loss bleeding stomach (abdomen) pain change in thyroid hormone levels
 nausea
The most common side effects of LENVIMA when given with pembrolizumab include: weight loss decrease in thyroid hormone
levels stomach-area (abdomen) pain
 increased blood pressure urinary tract infection
 tiredness
 protein in your urine
 diarrhea
 constipation
 joint and muscle pain headache nausea bleeding decreased appetite
 rash, redness, itching, or peeling ofyour skin on your hands and feet
 vomiting
 hoarseness mouth sores
 rashLENVIMA may cause fertility problems in males and females. Talk to your healthcare provider if
this is a concern for you.
Your healthcare provider may need to reduce your dose of LENVIMA, or delay or completely stoptreatment, 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 1-800FDA-1088.
How should I store LENVIMA?
 Store LENVIMA at room temperature, between 68°F to 77°F (20°C to 25°C).
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 a Patient Information
leaflet. Do not use LENVIMA for a 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 healthprofessionals.
What are the ingredients in LENVIMA?
Active ingredient: lenvatinib
Inactive ingredients: calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropyl
cellulose, 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., Woodcliff Lake, NJ 07677
LENVIMA® is a 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.
This Patient Information has been approved by the U.S. Food and Drug Administration.

Reference ID: 4840228

Revised: 08/2021