World of Information

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use

LENVIMA safely and effectively. See full prescribing information for

LENVIMA.

LENVIMA® (lenvatinib) capsules, for oral use

Initial U.S. Approval: 2015

----------------------------RECENT MAJOR CHANGES--------------------------

Indications and Usage, Hepatocellular Carcinoma (1.3) 8/2018

Dosage and Administration, Recommended Dose for HCC (2.4) 8/2018

Warnings and Precautions (5.1, 5.14) 8/2018

----------------------------INDICATIONS AND USAGE---------------------------

LENVIMA is a kinase inhibitor that is indicated:

• For the treatment of patients with locally recurrent or metastatic,

progressive, radioactive iodine-refractory differentiated thyroid cancer

(DTC). (1.1)

• In combination with everolimus, for the treatment of patients with

advanced renal cell carcinoma (RCC) following one prior antiangiogenic therapy. (1.2)

• For the first-line treatment of patients with unresectable hepatocellular

carcinoma (HCC). (1.3)

----------------------DOSAGE AND ADMINISTRATION-------------------------

• DTC: The recommended dosage is 24 mg orally once daily. (2.2)

• RCC: The recommended dosage is 18 mg orally once daily with

everolimus 5 mg orally once daily. (2.3)

• HCC: The recommended dosage is based on actual body weight:

o 12 mg orally once daily for patients greater than or equal to 60 kg

o 8 mg orally once daily for patients less than 60 kg. (2.4)

• Modify the recommended daily dose for certain patients with renal or

hepatic impairment. (2.6, 2.7)

---------------------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. (2.5, 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. (2.5, 5.2)

• Arterial Thromboembolic Events: Discontinue following an arterial

thromboembolic event. (2.5, 5.3)

• Hepatotoxicity: Monitor liver function prior to treatment and periodically

during treatment. Withhold or discontinue for Grade 3 or 4 hepatotoxicity.

Discontinue for hepatic failure. (2.5, 5.4)

• Renal Failure or Impairment: Withhold or discontinue for Grade 3 or 4

renal failure or impairment. (2.5, 5.5)

• Proteinuria: Monitor for proteinuria prior to treatment and periodically

during treatment. Withhold for 2 or more grams of proteinuria per 24

hours. Discontinue for nephrotic syndrome. (2.5, 5.6)

• Diarrhea: May be severe and recurrent. Promptly initiate management for

severe diarrhea. Withhold or discontinue based on severity. (2.5, 5.7)

• Fistula Formation and Gastrointestinal Perforation: Discontinue in patients

who develop Grade 3 or 4 fistula or any Grade gastrointestinal perforation.

(2.5, 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. (2.5, 5.9)

• Hypocalcemia: Monitor blood calcium levels at least monthly and replace

calcium as necessary. Withhold or discontinue based on severity (2.5, 5.10)

• Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Withhold

for RPLS until fully resolved or discontinue. (2.5, 5.11)

• Hemorrhagic Events: Withhold or discontinue based on severity. (2.5,

5.12)

• Impairment of Thyroid Stimulating Hormone Suppression/Thyroid

Dysfunction: Monitor thyroid function prior to treatment and monthly

during treatment. (5.13)

• Wound Healing Complications: Withhold LENVIMA before surgery.

Discontinue in patients with wound healing complications. (5.14)

• Embryo-Fetal Toxicity: Can cause fetal harm. Advise of potential risk to a

fetus and use of effective contraception. (5.15, 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, palmarplantar erythrodysesthesia syndrome, abdominal pain, and dysphonia. (6.1)

In RCC, 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)

To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at 1-

877-873-4724 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

-------------------------USE IN SPECIFIC POPULATIONS----------------------

• Lactation: Advise not to breastfeed. (8.2)

See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling.

Revised: 12/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Differentiated Thyroid Cancer

1.2 Renal Cell Carcinoma

1.3 Hepatocellular Carcinoma

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage Information

2.2 Recommended Dosage for DTC

2.3 Recommended Dosage for RCC

2.4 Recommended Dosage for HCC

2.5 Dosage Modifications for Adverse Reactions

2.6 Dosage Modifications for Severe Renal Impairment

2.7 Dosage Modifications for Severe Hepatic Impairment

2.8 Preparation and Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS 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

5.14 Wound Healing Complications

5.15 Embryo-Fetal Toxicity

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drugs That Prolong the QT Interval

8 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

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Differentiated Thyroid Cancer

14.2 Renal Cell Carcinoma

14.3 Hepatocellular Carcinoma

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not

listed.

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 is indicated in combination with everolimus for the treatment of patients with

advanced renal cell carcinoma (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).

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage Information

• Reduce the dose for certain patients with renal or hepatic impairment [see Dosage and

Administration (2.6, 2.7)].

• Take LENVIMA once daily, with or without food, at the same time each day [see

Clinical 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)

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 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 Dosage Modifications for Adverse Reactions

Recommendations for LENVIMA dose interruption, reduction and discontinuation for

adverse reactions are listed in Table 1. Table 2 lists the recommended dosage reductions of

LENVIMA for adverse reactions.

Table 1. Recommended Dosage Modifications for LENVIMA for Adverse Reactions

Adverse Reaction Severity a Dosage Modifications for LENVIMA

Hypertension [see

Warnings and Precautions

(5.1)]

Grade 3 • Withhold for Grade 3 that persists despite

optimal antihypertensive therapy.

• Resume at reduced dose when hypertension is

controlled at less than or equal to Grade 2.

Grade 4 • Permanently discontinue.

Cardiac Dysfunction [see

Warnings and Precautions

(5.2)]

Grade 3 • Withhold until improves to Grade 0 to 1 or

baseline.

• Resume at a reduced dose or discontinue

depending on the severity and persistence of

adverse reaction.

Grade 4 • Permanently discontinue.

Arterial Thromboembolic

Event [see Warnings and

Precautions (5.3)]

Any Grade • Permanently discontinue.

Hepatotoxicity [see

Warnings and Precautions

(5.4)]

Grade 3 or 4 • Withhold until improves to Grade 0 to 1 or

baseline.

• Either resume at a reduced dose or discontinue

depending on severity and persistence of

hepatotoxicity.

• Permanently discontinue for hepatic failure.

Renal Failure or

Impairment [see Warnings

and Precautions (5.5)]

Grade 3 or 4 • Withhold until improves to Grade 0 to 1 or

baseline.

• Resume at a reduced dose or discontinue

depending on severity and persistence of renal

impairment.

Proteinuria [see Warnings

and Precautions (5.6)]

2 g or greater

proteinuria in

24 hours

• Withhold until less than or equal to 2 grams of

proteinuria per 24 hours.

• Resume at a reduced dose.

• Permanently discontinue for nephrotic

syndrome.

Gastrointestinal Perforation

[see Warnings and

Precautions (5.8)]

Any Grade • Permanently discontinue.

Table 1. Recommended Dosage Modifications for LENVIMA for Adverse Reactions

Adverse Reaction Severity a Dosage Modifications for LENVIMA

Fistula Formation [see

Warnings and Precautions

(5.8)]

Grade 3 or 4 • Permanently discontinue.

QT Prolongation [see

Warnings and Precautions

(5.9)]

Greater than

500 ms or

greater than

60 ms

increase from

baseline

• Withhold until improves to less than or equal

to 480 ms or baseline.

• 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 of

neurologic symptoms.

Other Adverse Reactions

[see Warnings and

Precautions (5.7, 5.10,

5.12)]

Persistent or

intolerable

Grade 2 or 3

adverse

reaction

Grade 4

laboratory

abnormality

• Withhold until improves to Grade 0 to 1 or

baseline.

• Resume at reduced dose.

Grade 4

adverse

reaction

• Permanently discontinue.

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

Table 2: Recommended Dosage Reductions of LENVIMA for Adverse Reactions

Indication First Dosage

Reduction To

Second Dosage

Reduction To

Third Dosage

Reduction To

DTC 20 mg

once daily

14 mg

once daily

10 mg

once daily

RCC 14 mg

once daily

10 mg

once daily

8 mg

once daily

HCC

• Actual weight 60 kg or greater 8 mg

once daily

4 mg

once daily

4 mg

every other day

• Actual weight less than 60 kg 4 mg 4 mg Discontinue

once daily every other day

When administering LENVIMA in combination with everolimus for the treatment of renal

cell carcinoma, reduce the LENVIMA dose first and then the everolimus dose for adverse

reactions of both LENVIMA and everolimus. Refer to the everolimus prescribing

information for additional dose modification information.

2.6 Dosage Modifications for Severe Renal Impairment

The recommended dosage of LENVIMA for patients with DTC and RCC and severe renal

impairment (creatinine clearance less than 30 mL/min calculated by 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

2.7 Dosage Modifications for Severe Hepatic Impairment

The recommended dosage of LENVIMA for patients with DTC or RCC 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

2.8 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 WARNINGS AND PRECAUTIONS

5.1 Hypertension

Hypertension occurred in 73% of patients in SELECT (DTC) receiving LENVIMA 24 mg

orally once daily and in 45% of patients in REFLECT (HCC) receiving LENVIMA 8 mg or

12 mg orally once daily. The median time to onset of new or worsening hypertension was 16

days in SELECT and 26 days in REFLECT. Grade 3 hypertension occurred in 44% of

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 or

worsening 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

(2.5)].

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 (2.5)].

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)].

Permanently discontinue LENVIMA following an arterial thrombotic event [see Dosage and

Administration (2.5)]. 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 other

than HCC, serious hepatic adverse reactions occurred in 1.4% of patients. Fatal events,

including hepatic failure, acute hepatitis and hepatorenal syndrome, occurred in 0.5% of

patients.

In REFLECT (HCC), hepatic encephalopathy (including hepatic encephalopathy,

encephalopathy, metabolic encephalopathy, and hepatic coma) occurred in 8% of

LENVIMA-treated patients and 3% of sorafenib-treated patients. Grade 3 to 5 hepatic

encephalopathy occurred in 5% of LENVIMA-treated patients and 2% of sorafenib-treated

patients. 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 [see

Dosage and Administration (2.5)].

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 each

study.

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 (2.5)].

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 with

everolimus compared to 2% of patients receiving everolimus [see Adverse Reactions (6.1)].

Monitor for proteinuria prior to initiating LENVIMA and periodically during treatment. If

urine dipstick proteinuria greater than or equal to 2+ is detected, obtain 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 (2.5)].

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 with

everolimus, including Grade 3 in 19%. Diarrhea was the most frequent cause of dose

interruption/reduction and diarrhea recurred despite dose reduction [see Adverse Reactions

(6.1)].

Promptly initiate management of diarrhea. Withhold and resume at a reduced dose upon

recovery or permanently discontinue LENVIMA based on severity [see Dosage and

Administration (2.5)].

5.8 Fistula Formation and Gastrointestinal Perforation

Of 799 patients treated with LENVIMA or LENVIMA with everolimus in SELECT (DTC),

Study 205 (RCC) and REFLECT (HCC), fistula or gastrointestinal perforation occurred in

2%.

Permanently discontinue LENVIMA in patients who develop gastrointestinal perforation of

any severity or Grade 3 or 4 fistula [see Dosage and Administration (2.5)].

5.9 QT Interval Prolongation

In SELECT (DTC), QT/QTc interval prolongation occurred in 9% of LENVIMA-treated

patients and QT interval prolongation of >500 ms occurred in 2%. In Study 205 (RCC),

QTc interval increases of >60 ms occurred in 11% of patients receiving LENVIMA with

everolimus and QTc interval >500 ms occurred in 6%. In REFLECT (HCC), QTc interval

increases of >60 ms occurred in 8% of LENVIMA-treated patients and QTc interval >500

ms occurred in 2%.

Monitor and correct electrolyte abnormalities at baseline and periodically during treatment.

Monitor electrocardiograms in patients with congenital long QT syndrome, congestive heart

failure, bradyarrhythmias, or those who are taking drugs known to prolong the QT interval,

including Class Ia and III antiarrhythmics. Withhold and resume at reduced dose of

LENVIMA upon recovery based on severity [see Dosage and Administration (2.5)].

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 with

LENVIMA 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 (2.5)].

5.11 Reversible Posterior Leukoencephalopathy Syndrome

Across clinical studies of 1823 patients who received LENVIMA as a single agent [see

Adverse Reaction (6.1)], reversible posterior leukoencephalopathy syndrome (RPLS)

occurred in 0.3%.

Confirm the diagnosis of RPLS with magnetic resonance imaging. Withhold and resume at a

reduced dose upon recovery or permanently discontinue LENVIMA depending on severity

and persistence of neurologic symptoms [see Dosage and Administration (2.5)].

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 occurred

in 29% of the 799 patients treated with LENVIMA as a single agent or in combination with

everolimus. The most frequently reported hemorrhagic events (all grades and occurring in at

least 5% of patients) were epistaxis and hematuria.

In SELECT, Grade 3 to 5 hemorrhage occurred in 2% of patients receiving LENVIMA,

including 1 fatal intracranial hemorrhage among 16 patients who received LENVIMA and

had 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 treated

with LENVIMA in clinical trials and in the post-marketing setting. In post-marketing

surveillance, serious and fatal carotid artery hemorrhages were seen more frequently in

patients with anaplastic thyroid carcinoma (ATC) than in other tumor types. The safety and

effectiveness of LENVIMA in patients with ATC have not been demonstrated in clinical

trials.

Consider the risk of severe or fatal hemorrhage associated with tumor invasion or infiltration

of major blood vessels (e.g. carotid artery). Withhold and resume at reduced dose upon

recovery or permanently discontinue LENVIMA based on the severity [see Dosage and

Administration (2.5)].

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 a

normal 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, an

elevation of TSH was observed post baseline in 70% of patients receiving LENVIMA in

REFLECT and 60% of patients receiving LENVIMA with everolimus in Study 205 [see

Adverse Reactions (6.1)].

Monitor thyroid function prior to initiating LENVIMA and at least monthly during treatment.

Treat hypothyroidism according to standard medical practice.

5.14 Wound Healing Complications

Wound healing complications, including fistula formation and wound dehiscence, can occur

with LENVIMA. Withhold LENVIMA for at least 6 days prior to scheduled surgery.

Resume LENVIMA after surgery based on clinical judgment of adequate wound healing.

Permanently discontinue LENVIMA in patients with wound healing complications.

5.15 Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal reproduction studies, LENVIMA can

cause fetal harm when administered to a pregnant woman. In animal reproduction studies,

oral administration of lenvatinib during organogenesis at doses below the recommended

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 [see

Warnings and Precautions (5.13)]

• Wound Healing Complications [see Warnings and Precautions (5.14)]

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), and to

LENVIMA with everolimus in 62 patients with RCC (Study 205). 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 799 patients enrolled in randomized,

active-controlled trials (REFLECT; Study 205) or a randomized, placebo-controlled trial

(SELECT). The median duration of exposure to LENVIMA across these three studies ranged

from 6 to 16 months. The demographic and exposure data for each clinical trial population

are described in the subsections below.

Differentiated Thyroid Cancer

The safety of LENVIMA was evaluated in SELECT, in which patients with radioactive

iodine-refractory differentiated thyroid cancer were randomized (2:1) to LENVIMA (n=261)

or placebo (n=131) [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.

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

LENVIMA 24 mg

N=261

Placebo

N=131

All Grades

(%)

Grades 3-4

(%)

All Grades

(%)

Grades 3-4

(%)

Vascular

Hypertensiona 73 44 16 4

Hypotension 9 2 2 0

Gastrointestinal

Diarrhea 67 9 17 0

Nausea 47 2 25 1

Stomatitisb 41 5 8 0

Vomiting 36 2 15 0

Abdominal painc 31 2 11 1

Constipation 29 0.4 15 1

Oral paind 25 1 2 0

Dry mouth 17 0.4 8 0

Dyspepsia 13 0.4 4 0

General

Fatiguee 67 11 35 4

Edema peripheral 21 0.4 8 0

Musculoskeletal and Connective Tissue

Arthralgia/Myalgiaf 62 5 28 3

Metabolism and Nutrition

Decreased appetite 54 7 18 1

Decreased weight 51 13 15 1

Dehydration 9 2 2 1

Nervous System

Headache 38 3 11 1

Dysgeusia 18 0 3 0

Dizziness 15 0.4 9 0

Renal and Urinary

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

LENVIMA 24 mg

N=261

Placebo

N=131

All Grades

(%)

Grades 3-4

(%)

All Grades

(%)

Grades 3-4

(%)

Proteinuria 34 11 3 0

Skin and Subcutaneous Tissue

Palmar-plantar erythrodysesthesia 32 3 1 0

Rashg 21 0.4 3 0

Alopecia 12 0 5 0

Hyperkeratosis 7 0 2 0

Respiratory, Thoracic and Mediastinal

Dysphonia 31 1 5 0

Cough 24 0 18 0

Epistaxis 12 0 1 0

Psychiatric

Insomnia 12 0 3 0

Infections

Urinary tract infection 11 1 5 0

Dental and oral infectionsh 10 1 1 0

Cardiac

Electrocardiogram QT prolonged 9 2 2 0

a Includes hypertension, hypertensive crisis, increased blood pressure diastolic, and increased blood pressure

b Includes aphthous stomatitis, stomatitis, glossitis, mouth ulceration, and mucosal inflammation

c Includes abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness,

epigastric discomfort, and gastrointestinal pain

d Includes oral pain, glossodynia, and oropharyngeal pain

e Includes asthenia, fatigue, and malaise

f Includes musculoskeletal pain, back pain, pain in extremity, arthralgia, and myalgia

g Includes macular rash, maculo-papular rash, generalized rash, and rash

h Includes gingivitis, oral infection, parotitis, pericoronitis, periodontitis, sialoadenitis, tooth abscess, and tooth infection

A clinically important adverse reaction occurring more frequently in LENVIMA-treated

patients than patients receiving placebo, but with an incidence of <5% was pulmonary

embolism (3%, including fatal reports vs 2%, respectively).

Laboratory abnormalities with a difference of ≥2% in Grade 3 – 4 events and at a higher

incidence in the LENVIMA arm are presented in Table 4.

Table 4: Laboratory Abnormalities with a Difference of ≥2% in Grade 3 - 4 Events and

at a Higher Incidence in the LENVIMA Arma, b in SELECT (DTC)

Laboratory Abnormality LENVIMA 24 mg Placebo

Grades 3-4

(%)

Grades 3-4

(%)

Chemistry

Hypocalcemia 9 2

Hypokalemia 6 1

Increased aspartate aminotransferase

(AST)

5 0

Increased alanine aminotransferase (ALT) 4 0

Increased lipase 4 1

Increased creatinine 3 0

Hematology

Thrombocytopenia 2 0

a With at least 1 grade increase from baseline

b Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least

one post baseline laboratory measurement for each parameter. LENVIMA (n = 253 to 258), Placebo (n =

129 to 131)

The following laboratory abnormalities (all Grades) occurred in >5% of LENVIMA-treated

patients and at a rate that was two-fold or higher than in patients who received placebo:

hypoalbuminemia, increased alkaline phosphatase, hypomagnesemia, hypoglycemia,

hyperbilirubinemia, hypercalcemia, hypercholesterolemia, increased serum amylase, and

hyperkalemia.

Renal Cell Carcinoma

The safety of LENVIMA was evaluated in Study 205, in which patients with unresectable

advanced or metastatic renal cell carcinoma (RCC) were randomized (1:1:1) to LENVIMA

18 mg orally once daily with everolimus 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 with

everolimus, the median age was 61 years, 71% were men, and 98% were White.

The most common adverse reactions observed in the LENVIMA with everolimus-treated

group (≥30%) were, in order of decreasing frequency, diarrhea, fatigue, arthralgia/myalgia,

decreased appetite, vomiting, nausea, stomatitis/oral inflammation, hypertension, peripheral

edema, cough, abdominal pain, dyspnea, rash, decreased weight, hemorrhagic events, and

proteinuria. The most common serious adverse reactions (≥5%) were renal failure (11%),

dehydration (10%), anemia (6%), thrombocytopenia (5%), diarrhea (5%), vomiting (5%),

and dyspnea (5%).

Adverse reactions led to dose reductions or interruption in 89% of patients receiving

LENVIMA with everolimus. The most common adverse reactions (≥5%) resulting in dose

reductions in the LENVIMA with everolimus-treated group were diarrhea (21%), fatigue

(8%), thrombocytopenia (6%), vomiting (6%), nausea (5%), and proteinuria (5%).

Treatment discontinuation due to an adverse reaction occurred in 29% of patients in the

LENVIMA with everolimus-treated group.

Table 5 presents the adverse reactions in >15% of patients in the LENVIMA with everolimus

arm. Study 205 was not designed to demonstrate a statistically significant difference in

adverse reaction rates for LENVIMA in combination with everolimus, as compared to

everolimus for any specific adverse reaction listed in Table 5.

Table 5: Adverse Reactions Occurring in >15% of Patients in the LENVIMA with

Everolimus Arm in Study 205 (RCC)

LENVIMA 18 mg with

Everolimus 5 mg

N=62

Everolimus 10 mg

N=50

Adverse Reactions Grade 1-4

(%)

Grade 3-4

(%)

Grade 1-4

(%)

Grade 3-4

(%)

Endocrine

Hypothyroidism 24 0 2 0

Gastrointestinal

Diarrhea 81 19 34 2

Vomiting 48 7 12 0

Nausea 45 5 16 0

Stomatitis/Oral inflammationa 44 2 50 4

Abdominal painb 37 3 8 0

Oral painc 23 2 4 0

Dyspepsia/Gastro-esophageal

reflux

21 0 12 0

Constipation 16 0 18 0

General

Fatigued 73 18 40 2

Peripheral edema 42 2 20 0

Pyrexia/Increased body

temperature

21 2 10 2

Metabolism and Nutrition

Decreased appetite 53 5 18 0

Decreased weight 34 3 8 0

Musculoskeletal and Connective Tissue

Arthralgia/Myalgiae 55 5 32 0

Musculoskeletal chest pain 18 2 4 0

Nervous System

Headache 19 2 10 2

Psychiatric

Insomnia 16 2 2 0

Renal and Urinary

Proteinuria/Urine protein present 31 8 14 2

Renal failure eventf 18 10 12 2

Respiratory, Thoracic and Mediastinal

Cough 37 0 30 0

Dyspnea/Exertional dyspnea 35 5 28 8

Table 5: Adverse Reactions Occurring in >15% of Patients in the LENVIMA with

Everolimus Arm in Study 205 (RCC)

LENVIMA 18 mg with

Everolimus 5 mg

N=62

Everolimus 10 mg

N=50

Adverse Reactions Grade 1-4

(%)

Grade 3-4

(%)

Grade 1-4

(%)

Grade 3-4

(%)

Dysphonia 18 0 4 0

Skin and Subcutaneous Tissue

Rashg 35 0 40 0

Vascular

Hypertension/Increased blood

pressure

42 13 10 2

Hemorrhagic eventsh 32 6 26 2

a Includes aphthous stomatitis, gingival inflammation, glossitis, and mouth ulceration

b Includes abdominal discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain

c Includes gingival pain, glossodynia, and oropharyngeal pain

d Includes asthenia, fatigue, lethargy and malaise

e Includes arthralgia, back pain, extremity pain, musculoskeletal pain, and myalgia

f Includes blood creatinine increased, blood urea increased, creatinine renal clearance decreased, nephropathy toxic,

renal failure, renal failure acute, and renal impairment

g Includes erythema, erythematous rash, genital rash, macular rash, maculo-papular rash, papular rash, pruritic rash,

pustular rash, and septic rash

h Includes hemorrhagic diarrhea, epistaxis, gastric hemorrhage, hemarthrosis, hematoma, hematuria, hemoptysis, lip

hemorrhage, renal hematoma, and scrotal hematocele

In Table 6, Grade 3-4 laboratory abnormalities occurring in ≥3% of patients in the

LENVIMA with everolimus arm are presented.

Table 6: Grade 3-4 Laboratory Abnormalities Occurring in ≥3% of Patients in the

LENVIMA with Everolimus Arma,b in Study 205 (RCC)

Laboratory Abnormality LENVIMA 18 mg

with Everolimus 5 mg

Everolimus 10 mg

Grades 3-4

(%)

Grades 3-4

(%)

Chemistry

Hypertriglyceridemia 18 18

Increased lipase 13 12

Hypercholesterolemia 11 0

Hyponatremia 11 6

Hypophosphatemia 11 6

Hyperkalemia 6 2

Hypocalcemia 6 2

Hypokalemia 6 2

Increased aspartate aminotransferase

(AST)

3 0

Increased alanine aminotransferase

(ALT)

3 2

Increased alkaline phosphatase 3 0

Hyperglycemia 3 16

Increased creatine kinase 3 4

Table 6: Grade 3-4 Laboratory Abnormalities Occurring in ≥3% of Patients in the

LENVIMA with Everolimus Arma,b in Study 205 (RCC)

Laboratory Abnormality LENVIMA 18 mg

with Everolimus 5 mg

Everolimus 10 mg

Grades 3-4

(%)

Grades 3-4

(%)

Hematology

Lymphopenia 10 20

Anemia 8 16

Thrombocytopenia 5 0

a With at least 1 grade increase from baseline

b 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 with

unresectable hepatocellular carcinoma (HCC) to LENVIMA (n=476) or sorafenib (n=475)

[see Clinical Studies (14.3)]. The dose of LENVIMA was 12 mg orally once daily for

patients with a baseline body weight of ≥60 kg and 8 mg orally once daily for patients with a

baseline body weight of <60 kg. The dose of sorafenib was 400 mg orally twice daily.

Duration of treatment was ≥6 months in 49% and 32% of patients in the LENVIMA and

sorafenib groups, respectively. Among the 476 patients who received LENVIMA in

REFLECT, the median age was 63 years, 85% were men, 28% were White and 70% were

Asian.

The most common adverse reactions observed in the LENVIMA-treated patients (≥20%)

were, in order of decreasing frequency, hypertension, fatigue, diarrhea, decreased appetite,

arthralgia/myalgia, decreased weight, abdominal pain, palmar-plantar erythrodysesthesia

syndrome, proteinuria, dysphonia, hemorrhagic events, hypothyroidism, and nausea.

The most common serious adverse reactions (≥2%) in LENVIMA-treated patients were

hepatic encephalopathy (5%), hepatic failure (3%), ascites (3%), and decreased appetite

(2%).

Adverse reactions led to dose reduction or interruption in 62% of patients receiving

LENVIMA. The most common adverse reactions (≥5%) resulting in dose reduction or

interruption of LENVIMA were fatigue (9%), decreased appetite (8%), diarrhea (8%),

proteinuria (7%), hypertension (6%), and palmar-plantar erythrodysesthesia syndrome (5%).

Treatment discontinuation due to adverse reactions occurred in 20% of patients in the

LENVIMA-treated group. The most common adverse reactions (≥1%) resulting in

discontinuation of LENVIMA were fatigue (1%), hepatic encephalopathy (2%),

hyperbilirubinemia (1%), and hepatic failure (1%).

Table 7 summarizes the adverse reactions that occurred in ≥10% of patients receiving

LENVIMA in REFLECT. REFLECT was not designed to demonstrate a statistically

significant reduction in adverse reaction rates for LENVIMA, as compared to sorafenib, for

any specified adverse reaction listed in Table 7.

Table 7: Adverse Reactions Occurring in ≥10% of Patients in the LENVIMA Arm in

REFLECT (HCC)

Adverse Reaction LENVIMA

8 mg/12 mg

N=476

Sorafenib

800 mg

N=475

Grade 1-4

(%)

Grade 3-4

(%)

Grade 1-4

(%)

Grade 3-4

(%)

Endocrine

Hypothyroidisma 21 0 3 0

Gastrointestinal

Diarrhea 39 4 46 4

Abdominal painb 30 3 28 4

Nausea 20 1 14 1

Vomiting 16 1 8 1

Constipation 16 1 11 0

Ascitesc 15 4 11 3

Stomatitisd 11 0.4 14 1

General

Fatiguee 44 7 36 6

Pyrexiaf 15 0 14 0.2

Peripheral edema 14 1 7 0.2

Metabolism and Nutrition

Decreased appetite 34 5 27 1

Decreased weight 31 8 22 3

Musculoskeletal and Connective Tissue

Arthralgia/Myalgiag 31 1 20 2

Nervous System

Headache 10 1 8 0

Renal and Urinary

Proteinuriah 26 6 12 2

Respiratory, Thoracic and Mediastinal

Dysphonia 24 0.2 12 0

Skin and Subcutaneous Tissue

Palmar-plantar

erythrodysesthesia syndrome

27 3 52 11

Rashi 14 0 24 2

Vascular

Hypertensionj 45 24 31 15

Hemorrhagic eventsk 23 4 15 4

a Includes hypothyroidism, blood thyroid stimulating hormone increased.

b Includes abdominal discomfort, abdominal pain, abdominal tenderness, epigastric discomfort, gastrointestinal pain,

lower abdominal pain, and upper abdominal pain

c Includes ascites and malignant ascites

d Includes aphthous ulcer, gingival erosion, gingival ulceration, glossitis, mouth ulceration, oral mucosal blistering, and

stomatitis

e Includes asthenia, fatigue, lethargy and malaise

f Includes increased body temperature, pyrexia

g Includes arthralgia, back pain, extremity pain, musculoskeletal chest pain, musculoskeletal discomfort,

musculoskeletal pain, and myalgia

Table 7: Adverse Reactions Occurring in ≥10% of Patients in the LENVIMA Arm in

REFLECT (HCC)

Adverse Reaction LENVIMA

8 mg/12 mg

N=476

Sorafenib

800 mg

N=475

Grade 1-4

(%)

Grade 3-4

(%)

Grade 1-4

(%)

Grade 3-4

(%)

h Includes proteinuria, increased urine protein, protein urine present

i Includes erythema, erythematous rash, exfoliative rash, genital rash, macular rash, maculo-papular rash, papular rash,

pruritic rash, pustular rash and rash

j Includes increased diastolic blood pressure, increased blood pressure, hypertension and orthostatic hypertension

k 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 8, Grade 3-4 laboratory abnormalities occurring in ≥2% of patients in the

LENVIMA arm in REFLECT (HCC) are presented.

Table 8: Grade 3-4 Laboratory Abnormalities Occurring in ≥2% of Patients in the

LENVIMA Arma,b in REFLECT (HCC)

Laboratory Abnormality

Lenvatinib

(%)

Sorafenib

(%)

Chemistry

Increased GGT 17 20

Hyponatremia 15 9

Hyperbilirubinemia 13 10

Increased aspartate aminotransferase (AST) 12 18

Increased alanine aminotransferase (ALT) 8 9

Increased alkaline phosphatase 7 5

Increased lipase 6 17

Hypokalemia 3 4

Hyperkalemia 3 2

Decreased albumin 3 1

Increased creatinine 2 2

Hematology

Thrombocytopenia 10 8

Lymphopenia 8 9

Neutropenia 7 3

Anemia 4 5

a With at least 1 grade increase from baseline

b Laboratory Abnormality percentage is based on the number of patients who had both baseline and at least one post

baseline laboratory measurement for each parameter. LENVIMA (n=278 to 470) and sorafenib (n=260 to 473)

6.2 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

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: aortic dissection

7 DRUG INTERACTIONS

7.1 Drugs That Prolong the QT Interval

LENVIMA has been reported to prolong the QT/QTc interval. Avoid coadministration of

LENVIMA with medicinal products with a known potential to prolong the QT/QTc interval

[see Warnings and Precautions (5.9)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on its mechanism of action and data from animal reproduction studies, LENVIMA can

cause 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, and

teratogenicity in rats and rabbits (see Data). There are no available human data informing the

drug-associated risk. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and

miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

In an embryofetal development study, daily oral administration of lenvatinib mesylate at

doses ≥0.3 mg/kg [approximately 0.14 times the recommended clinical dose of 24 mg based

on body surface area (BSA)] to pregnant rats during organogenesis resulted in dose-related

decreases in mean fetal body weight, delayed fetal ossifications, and dose-related increases in

fetal external (parietal edema and tail abnormalities), visceral, and skeletal anomalies.

Greater than 80% postimplantation loss was observed at 1.0 mg/kg/day (approximately 0.5

times the recommended clinical dose of 24 mg based on BSA).

Daily oral administration of lenvatinib mesylate to pregnant rabbits during organogenesis

resulted in fetal external (short tail), visceral (retroesophageal subclavian artery), and skeletal

anomalies at doses greater than or equal to 0.03 mg/kg (approximately 0.03 times the

recommended clinical dose of 24 mg based on BSA). At the 0.03 mg/kg dose, increased 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 dose

level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg

based on BSA).

8.2 Lactation

Risk 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 (see

Data). Because of the potential for serious adverse reactions in breastfed infants, advise women

to discontinue breastfeeding during treatment with LENVIMA and for at least 1 week after the

last 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 a

pregnant woman [see Use in Specific Populations (8.1)].

Females

Advise females of reproductive potential to use effective contraception during treatment with

LENVIMA and for at least 30 days after the last dose.

Infertility

LENVIMA may impair fertility in males and females of reproductive potential [see

Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of LENVIMA in pediatric patients have not been established.

Juvenile Animal Data

Daily oral administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on

postnatal day 21 (approximately equal to a human pediatric age of 2 years) resulted in growth

retardation (decreased body weight gain, decreased food consumption, and decreases in the

width and/or length of the femur and tibia) and secondary delays in physical development

and reproductive organ immaturity at doses greater than or equal to 2 mg/kg (approximately

1.2 to 5 times the human exposure based on AUC at the recommended clinical dose of 24

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

general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats,

though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day

dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points

in juvenile rats.

8.5 Geriatric Use

Of the 261 patients with differentiated thyroid cancer (DTC) who received LENVIMA in

SELECT, 45% were ≥65 years of age and 11% were ≥75 years of age. No overall differences

in safety or effectiveness were observed between these subjects and younger subjects.

Of the 62 patients with renal cell carcinoma (RCC) who received LENVIMA with

everolimus in Study 205, 36% were ≥65 years of age. Conclusions are limited due to the

small sample size, but there appeared to be no overall differences in safety or effectiveness

between these subjects and younger subjects.

Of the 476 patients with hepatocellular carcinoma (HCC) who received LENVIMA in

REFLECT, 44% were ≥65 years of age and 12% were ≥75 years of age. No overall

differences in safety or effectiveness were observed between patients ≥65 and younger

subjects. Patients ≥75 years of age showed reduced tolerability to LENVIMA.

8.6 Renal Impairment

No dose adjustment is recommended for patients with mild (CLcr 60-89 mL/min) or

moderate (CLcr 30-59 mL/min) renal impairment. Lenvatinib concentrations may increase in

patients with DTC or RCC and severe (CLcr 15-29 mL/min) renal impairment. Reduce the

dose for patients with RCC or DTC and severe renal impairment [see Dosage and

Administration (2.5)]. There is no recommended dose of LENVIMA for patients with HCC

and severe renal impairment. LENVIMA has not been studied in patients with end stage

renal disease [see Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

No dose adjustment is recommended for patients with HCC and mild hepatic impairment

(Child-Pugh A). There is no recommended dose for patients with HCC with moderate or

severe hepatic impairment.

No dose adjustment is recommended for patients with DTC or RCC and mild or moderate

hepatic impairment (Child-Pugh A or B). Lenvatinib concentrations may increase in patients

with DTC or RCC and severe hepatic impairment (Child-Pugh C). Reduce the dose for

patients with DTC or RCC and severe hepatic impairment [see Dosage and Administration

(2.5), Clinical Pharmacology (12.3)].

10 OVERDOSAGE

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

Clinical Pharmacology (12.3)]. Death due to multiorgan dysfunction occurred in a patient

who received a single dose of LENVIMA 120 mg orally.

11 DESCRIPTION

LENVIMA, a kinase inhibitor, is the mesylate salt of lenvatinib. Its chemical name is 4-[3-

chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide

methanesulfonate. The molecular formula is C21H19ClN4O4 • CH4O3S, and the molecular

weight of the mesylate salt is 522.96. The chemical structure of lenvatinib mesylate is:

Lenvatinib mesylate is a white to pale reddish yellow powder. It is slightly soluble in water

and practically insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of

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

LENVIMA capsules for oral administration contain 4 mg or 10 mg of lenvatinib, equivalent

to 4.90 mg or 12.25 mg of lenvatinib mesylate, respectively. Following are inactive

ingredients: Calcium Carbonate, USP; Mannitol, USP; Microcrystalline Cellulose, NF;

Hydroxypropyl Cellulose, NF; Low-substituted Hydroxypropyl Cellulose, NF; and Talc,

USP. The hypromellose capsule shell contains titanium dioxide, ferric oxide yellow, and

ferric oxide red. The printing ink contains shellac, black iron oxide, potassium hydroxide,

and propylene glycol.

12 CLINICAL PHARMACOLOGY

12.1 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 a

concurrent inhibition of FGF-receptor substrate 2α (FRS2α) phosphorylation. The

combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor

activity as demonstrated by decreases in human endothelial cell proliferation, tube formation,

and VEGF signaling in vitro, and by decreases in tumor volume in mouse xenograft models

of human renal cell cancer that were greater than those with either drug alone.

12.3 Pharmacokinetics

In patients with solid tumors administered single and multiple doses of LENVIMA once

daily, the maximum lenvatinib plasma concentration (Cmax) and the area under the

concentration-time curve (AUC) increased proportionally over the dose range of 3.2 mg (0.1

times the recommended clinical dose of 24 mg) to 32 mg (1.33 times the recommended

clinical dose of 24 mg) with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).

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 Tmax from 2 hours

to 4 hours.

Distribution

In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99% at

concentrations of 0.3 to 30 μg/mL. The blood-to-plasma concentration ratio ranged from 0.59

to 0.61 at concentrations of 0.1 to 10 μg/mL in vitro.

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, sex, and race did not have a significant effect on apparent oral clearance (CL/F).

Patients with Renal Impairment

The pharmacokinetics of lenvatinib following a single 24 mg dose were evaluated in subjects

with mild (CLcr 60-89 mL/min), moderate (CLcr 30-59 mL/min), or severe (CLcr <30

mL/min) renal impairment, and compared to healthy subjects. Subjects with end stage renal

disease were not studied. The AUC0-inf for subjects with renal impairment were similar

compared to those for healthy subjects.

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-Pugh

C) hepatic impairment. Compared to subjects with normal hepatic function, the dose-adjusted

AUC0-inf of lenvatinib for