Lenvima (Lenvatinib) capsule
Eisai Inc.

Eisai Inc.
Catalent Pharma Solutions, LLC
Eisai Co., Ltd.
Eisai Co., Ltd.
Patheon Inc.
Pharma Packaging Solutions, LLC dba Tjoapack, LLC
Sharp Packaging Services, LLC
Lenvima
Lenvatinib
LENVATINIB
LENVATINIB
CALCIUM CARBONATE
HYDROXYPROPYL CELLULOSE (90000 WAMW)
HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED
MANNITOL
CELLULOSE, MICROCRYSTALLINE
TALC
FERRIC OXIDE RED
FERRIC OXIDE YELLOW
HYPROMELLOSES
TITANIUM DIOXIDE
FERROSOFERRIC OXIDE
POTASSIUM HYDROXIDE
PROPYLENE GLYCOL
SHELLAC
E;LENV;4;mg
Lenvima
Lenvatinib
LENVATINIB
LENVATINIB
CALCIUM CARBONATE
HYDROXYPROPYL CELLULOSE (90000 WAMW)
HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED
MANNITOL
CELLULOSE, MICROCRYSTALLINE
TALC
FERRIC OXIDE RED
FERRIC OXIDE YELLOW
HYPROMELLOSES
TITANIUM DIOXIDE
FERROSOFERRIC OXIDE
POTASSIUM HYDROXIDE
PROPYLENE GLYCOL
SHELLAC
E;LENV;4;mg
Lenvima
Lenvatinib
LENVATINIB
LENVATINIB
CALCIUM CARBONATE
HYDROXYPROPYL CELLULOSE (90000 WAMW)
HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED
MANNITOL
CELLULOSE, MICROCRYSTALLINE
TALC
FERRIC OXIDE RED
FERRIC OXIDE YELLOW
HYPROMELLOSES
TITANIUM DIOXIDE
FERROSOFERRIC OXIDE
POTASSIUM HYDROXIDE
PROPYLENE GLYCOL
SHELLAC
yellow body
yellowish-red cap
E;LENV;10;mg
Lenvima
Lenvatinib
Lenvatinib
Lenvatinib
LENVATINIB
LENVATINIB
yellow body
yellowish-red cap
E;LENV;10;mg
Lenvatinib
Lenvatinib
LENVATINIB
LENVATINIB
yellowish-red cap and body
E;LENV;4;mg
Lenvima
Lenvatinib
Lenvatinib
Lenvatinib
LENVATINIB
LENVATINIB
yellow body
yellowish-red cap
E;LENV;10;mg
Lenvatinib
Lenvatinib
LENVATINIB
LENVATINIB
yellowish-red cap and body
E;LENV;4;mg
Lenvima
Lenvatinib
LENVATINIB
LENVATINIB
CALCIUM CARBONATE
HYDROXYPROPYL CELLULOSE (90000 WAMW)
HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED
MANNITOL
CELLULOSE, MICROCRYSTALLINE
TALC
FERRIC OXIDE RED
FERRIC OXIDE YELLOW
HYPROMELLOSES
TITANIUM DIOXIDE
FERROSOFERRIC OXIDE
POTASSIUM HYDROXIDE
PROPYLENE GLYCOL
SHELLAC
yellow body
yellowish-red cap
E;LENV;10;mg
Lenvima
Lenvatinib
Lenvatinib
Lenvatinib
LENVATINIB
LENVATINIB
E;LENV;10;mg
Lenvatinib
Lenvatinib
LENVATINIB
LENVATINIB
E;LENV;4;mg
Lenvima
Lenvatinib
LENVATINIB
LENVATINIB
CALCIUM CARBONATE
HYDROXYPROPYL CELLULOSE (90000 WAMW)
HYDROXYPROPYL CELLULOSE, LOW SUBSTITUTED
MANNITOL
CELLULOSE, MICROCRYSTALLINE
TALC
FERRIC OXIDE RED
FERRIC OXIDE YELLOW
HYPROMELLOSES
TITANIUM DIOXIDE
FERROSOFERRIC OXIDE
POTASSIUM HYDROXIDE
PROPYLENE GLYCOL
SHELLAC
E;LENV;4;mg

1       INDICATIONS AND USAGE

LENVIMA is a kinase inhibitor that is indicated:   

Differentiated Thyroid Cancer (DTC) 

  • For the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). (1.1)

Renal Cell Carcinoma (RCC)

  • In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal cell carcinoma (RCC). (1.2)
  • In combination with everolimus, for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic 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 with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (1.42.1)

1.1       Differentiated Thyroid Cancer  

LENVIMA is indicated for the treatment of adult patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC). 

1.2       Renal Cell Carcinoma  

LENVIMA, in combination with pembrolizumab, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

LENVIMA, in combination with everolimus, is indicated for the treatment of adult patients with advanced RCC following one prior anti-angiogenic therapy.

1. 3       Hepatocellular Carcinoma

LENVIMA is indicated for the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC).

1. 4       Endometrial Carcinoma

LENVIMA, in combination with pembrolizumab, is indicated for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA-approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation [see Dosage and Administration ( 2.1 )].

2       DOSAGE AND ADMINISTRATION

Single Agent Therapy:

  • DTC: The recommended dosage is 24 mg orally once daily. (2.3)
  • 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. (2.5)

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. (2.6)
  • RCC: The recommended dosage is:
    •  20 mg orally once daily with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks. (2.4)
    • 18 mg orally once daily with everolimus 5 mg orally once daily. (2.4)

Modify the recommended daily dose for certain patients with renal or hepatic impairment. (2.82.9)

2. 1       Patient Selection

For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with LENVIMA in combination with pembrolizumab based on MSI or MMR status in tumor specimens [see Clinical Studies ( 14.4 )].

Information on FDA-approved tests for patient selection is available at: http://www.fda.gov/CompanionDiagnostics.

An FDA-approved test for the selection of patients who are not MSI-H is not currently available.

2. 2       Important Dosage Information

  • Reduce the dose for certain patients with renal or hepatic impairment [see Dosage and Administration ( 2.8 ,   2.9 )].
  • 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. 7       Dos age Modifications for Adverse Reactions

Recommendations for LENVIMA dose interruption, reduction and discontinuation for adverse reactions are listed in Table 1. Table 2 lists the recommended dosage reductions of LENVIMA for adverse reactions.

Table 1 : Recommended Dos ag e Modifications for LENVIMA for Adverse Reactions
Adverse Reaction Severity a Dos ag e Modifications for LENVIMA
Hypertension [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.
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
Endometrial Carcinoma 14 mg
once daily
10 mg
once daily
8 mg
once daily
HCC
  • Actual weight 60 kg or greater
8 mg
once daily
4 mg
once daily
4 mg
every other day
  • Actual weight less than 60 kg
4 mg
once daily
4 mg
every other day
Discontinue

Recommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with Pembrolizumab

When administering LENVIMA in combination with pembrolizumab, modify the dosage of one or both drugs as appropriate. Withhold, dose reduce, or discontinue LENVIMA as shown in Table 1. Refer to pembrolizumab prescribing information for additional dose modification information.

Recommended Dose Modifications for Adverse Reactions for LENVIMA in Combination with Everolimus

When administering LENVIMA in combination with everolimus, withhold or reduce the LENVIMA dose first and then the everolimus dose for adverse reactions of both LENVIMA and everolimus. Refer to the everolimus prescribing information for additional dose modification information.

2. 8       Dos ag e Modifications for Severe Renal Impairment

The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is [s ee Warnings and Precautions ( 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. 9       Dos ag e Modifications for Severe Hepatic Impairment  

The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is [s ee Warnings and Precautions ( 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. 1 0       Capsule   Administration and Preparation of Suspension for Administration

Administration

Oral: Capsule or Suspension

Capsule

  • Swallow LENVIMA capsules whole at the same time each day with or without food [see Clinical Pharmacology ( 12.3 )]. Do not crush or chew the LENVIMA capsules.

Suspension

  • Prepare [see Preparation below ] oral suspension with water or apple juice and administer at the same time each day with or without food [see Clinical Pharmacology ( 12.3 )].

Feeding Tube Administration

Suspension

  • Prepare [see Preparation below ] suspension for feeding tube administration with water and administer at the same time each day with or without food [see Clinical Pharmacology ( 12.3 )].

Preparation of Suspension

  • Place the required number of capsules, up to a maximum of 5, in a small container (approximately 20 mL capacity) or syringe (20 mL). Do not break or crush capsules.
  • Add 3 mL of liquid to the container or syringe. Wait 10 minutes for the capsule shell (outer surface) to disintegrate, then stir or shake the mixture for 3 minutes until capsules are fully disintegrated and administer the entire contents.
  • Next, add an additional 2 mL of liquid to the container or syringe using a second syringe or dropper, swirl or shake and administer. Repeat this step at least once and until there is no visible residue to ensure all of the medication is taken.
  • If 6 capsules are required for a dose, follow these instructions using 3 capsules at a time.

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

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

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.

Capsules: 4 mg and 10 mg. (3)

4       CONTRAINDICATIONS

None.

None. (4)

5       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. (2.7, 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. (2.7, 5.2)
  • Arterial Thromboembolic Events: Discontinue following an arterial thromboembolic event. (2.7, 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. (2.7, 5.4)
  • Renal Failure or Impairment: Withhold or discontinue for Grade 3 or 4 renal failure or impairment. (2.7, 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. (2.7, 5.6)
  • Diarrhea: May be severe and recurrent. Promptly initiate management for severe diarrhea. Withhold or discontinue based on severity. (2.7, 5.7)
  • Fistula Formation and Gastrointestinal Perforation: Discontinue in patients who develop Grade 3 or 4 fistula or any Grade gastrointestinal perforation. (2.7, 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. (2.7, 5.9)
  • Hypocalcemia: Monitor blood calcium levels at least monthly and replace calcium as necessary. Withhold or discontinue based on severity. (2.7, 5.10)
  • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): Withhold for RPLS until fully resolved or discontinue. (2.7, 5.11)
  • Hemorrha gic Events: Withhold or discontinue based on severity. (2.7, 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 -F etal T oxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.16, 8.1, 8.3)

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 ( 2.7 ) ].

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 ( 2.7 ) ].

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%) and cerebrovascular accident (2.3%).

Permanently discontinue LENVIMA following an arterial thrombotic event [ see Dosage and Administration ( 2.7 ) ]. 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 ( 2.7 ) ].

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   ( 2.7 ) ]

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 ( 2.7 ) ].

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 ( 2.7 ) ].

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 ( 2.7 ) ].

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   ( 2.7 )].

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   ( 2.7 ) ].

5.1 1       Reversible Posterior Leukoe ncephalopathy Syndrome

Across clinical studies of 1823 patients who received LENVIMA as a single agent [see Adverse Reaction s ( 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 ( 2.7 )].

5.1 2       Hemorrhagic E vents

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   ( 2.7 ) ].

5.1 3       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       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 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.

5.1 5       Osteonecrosis of the Jaw   (ONJ)

Osteonecrosis of the Jaw (ONJ) has been reported in patients receiving LENVIMA [see Adverse Reactions ( 6.1 )]. Concomitant exposure to other risk factors, such as bisphosphonates, denosumab, dental disease or invasive dental procedures, may increase the risk of ONJ.

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 or invasive 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. 1 6       Embryo -F etal 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 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 )]
  • Impaired Wound Healing [see Warnings and Precautions ( 5.14 )]
  • Osteonecrosis of the Jaw (ONJ) [see Warnings and Precautions ( 5.15 )]
  • 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:
    • 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)
    • 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 1-877-873-4724 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1       Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data in the Warnings and Precautions reflect exposure to LENVIMA as a single agent in 261 patients with DTC (SELECT) and 476 patients with HCC (REFLECT), LENVIMA with pembrolizumab in 406 patients with endometrial carcinoma (Study 309), LENVIMA with everolimus in 62 patients with RCC (Study 205), and LENVIMA with pembrolizumab in 352 patients with RCC (CLEAR). Safety data obtained in 1823 patients with advanced solid tumors who received LENVIMA as a single agent across multiple clinical studies was used to further characterize the risks of serious adverse reactions. Among the 1823 patients who received LENVIMA as a single agent, the median age was 61 years (20 to 89 years), the dose range was 0.2 mg to 32 mg daily, and the median duration of exposure was 5.6 months.

The data below reflect exposure to LENVIMA in 1557 patients enrolled in randomized, active-controlled trials (REFLECT; Study 205; CLEAR; Study 309), and a randomized, placebo-controlled trial (SELECT). The median duration of exposure to LENVIMA across these five studies ranged from 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
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

Clinically important adverse reactions occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of <5% were pulmonary embolism (3%, including fatal reports vs 2%, respectively) and osteonecrosis of the jaw (0.4% vs 0%, respectively).

Laboratory abnormalities with a difference of ≥2% in Grade 3 – 4 events and at a higher incidence in the LENVIMA arm are presented in Table 4.

Table 4: Laboratory Abnormalities with a Difference of ≥2% in Grade 3 - 4 Events and at a Higher Incidence in the LENVIMA Arm a, b   in SELECT (DTC)
Laboratory A bnormality LENVIMA 24   mg
Placebo
Grades 3-4
(%)
Grades 3-4
(%)
Chemistry
Hypocalcemia 9 2
Hypokalemia 6 1
Increased aspartate aminotransferase (AST) 5 0
Increased alanine aminotransferase (ALT) 4 0
Increased lipase 4 1
Increased creatinine 3 0
Hematology
Thrombocytopenia 2 0
a With at least 1 grade increase from baseline
b 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.

First-Line Treatment of Renal Cell Carcinoma in Combination with   P embrolizumab (CLEAR)

The safety of LENVIMA in combination with pembrolizumab was investigated in CLEAR [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 and pembrolizumab was 17 months (range: 0.1 to 39).

Fatal adverse reactions occurred in 4.3% of patients receiving LENVIMA in combination with pembrolizumab, including cardio-respiratory arrest (0.9%), sepsis (0.9%), and one case (0.3%) each of arrhythmia, autoimmune hepatitis, dyspnea, hypertensive crisis, increased blood creatinine, multiple organ dysfunction syndrome, myasthenic syndrome, myocarditis, nephritis, pneumonitis, ruptured aneurysm and subarachnoid hemorrhage.

Serious adverse reactions occurred in 51% of patients receiving LENVIMA and pembrolizumab. Serious adverse reactions in ≥2% of patients were hemorrhagic events (5%), diarrhea (4%), hypertension (3%), myocardial infarction (3%), pneumonitis (3%), vomiting (3%), acute kidney injury (2%), adrenal insufficiency (2%), dyspnea (2%), and pneumonia (2%).

Permanent discontinuation of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 37% of patients; 26% LENVIMA only, 29% pembrolizumab only, and 13% both drugs. The most common adverse reactions (≥2%) leading to permanent discontinuation of LENVIMA, pembrolizumab, or both were pneumonitis (3%), myocardial infarction (3%), hepatotoxicity (3%), acute kidney injury (3%), rash (3%), and diarrhea (2%).

Dose interruptions of LENVIMA, pembrolizumab, or both due to an adverse reaction occurred in 78% of patients receiving LENVIMA in combination with pembrolizumab. LENVIMA was interrupted in 73% of patients and both drugs were interrupted in 39% of patients. LENVIMA was dose reduced in 69% of patients. The most common adverse reactions (≥5%) resulting in dose reduction or interruption of LENVIMA were diarrhea (26%), fatigue (18%), hypertension (17%), proteinuria (13%), decreased appetite (12%), palmar-plantar erythrodysesthesia (11%), nausea (9%), stomatitis (9%), musculoskeletal pain (8%), rash (8%), increased lipase (7%), abdominal pain (6%), and 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)
LENVIMA 20 mg in combination with
Pembrolizumab 200mg

N=352
Sunitinib 50 mg
N=340
Adverse Reactions All Grades
(%)
Grade 3-4
(%)
All Grades
(%)
Grade 3-4
(%)
General
Fatiguea 63 9 56 8
Gastrointestinal
Diarrheab 62 10 50 6
Stomatitisc 43 2 43 2
Nausea 36 3 33 1
Abdominal paind 27 2 18 1
Vomiting 26 3 20 1
Constipation 25 1 19 0
Musculoskeletal and connective tissue
Musculoskeletal paine 58 4 41 3
Endocrine
Hypothyroidismf 57 1 32 0
Vascular
Hypertensiong 56 29 43 20
Hemorrhagic eventsh 27 5 26 4
Metabolism
Decreased appetitei 41 4 31 1
Skin and subcutaneous tissue
Rashj 37 5 17 1
Palmar-plantar erythrodysaesthesia syndromek 29 4 38 4
Respiratory, thoracic, and mediastinal
Dysphonia 30 0 4 0
Renal and urinary
Proteinurial 30 8 13 3
Acute kidney injurym 21 5 16 2
Investigations
Weight decreased 30 8 9 0
Hepatobiliary
Hepatotoxicityn  25 9 21 5
Nervous system
Headache 23 1 16 1
a Includes asthenia, fatigue, lethargy and malaise
b Includes diarrhea and gastroenteritis
c Includes aphthous ulcer, gingival pain, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral discomfort, oral mucosal blistering, oral pain, oropharyngeal pain, pharyngeal inflammation, and stomatitis
d Includes abdominal discomfort, abdominal pain, abdominal rigidity, abdominal tenderness, epigastric discomfort, lower abdominal pain, and upper abdominal pain
e Includes arthralgia, arthritis, back pain, bone pain, breast pain, musculoskeletal chest pain, musculoskeletal discomfort, musculoskeletal pain, musculoskeletal stiffness, myalgia, neck pain, non-cardiac chest pain, pain in extremity, and pain in jaw
f Includes hypothyroidism, increased blood thyroid stimulating hormone and secondary hypothyroidism
g Includes essential hypertension, increased blood pressure, increased diastolic blood pressure, hypertension, hypertensive crisis, hypertensive retinopathy, and labile blood pressure
h Includes all hemorrhage terms. Hemorrhage terms that occurred in 1 or more subjects in either treatment group include: Anal hemorrhage, aneurysm ruptured, blood blister, blood loss anemia, blood urine present, 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
i Includes decreased appetite and early satiety
j 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
k Includes palmar erythema, palmar-plantar erythrodysesthesia syndrome and plantar erythema
l Includes hemoglobinuria, nephrotic syndrome, and proteinuria
m 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
n Includes alanine aminotransferase increased, aspartate aminotransferase increased, blood bilirubin increased, drug-induced liver injury, hepatic enzyme increased, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatotoxicity, hyperbilirubinemia, hypertransaminasemia, immune-mediated hepatitis, liver function test increased, liver injury, transaminases increased, and gamma-glutamyltransferase increased

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

Table 6: Laboratory Abnormalities in ≥20% (All Grades) of Patients on LENVIMA plus Pembrolizumab   in CLEAR (RCC)
LENVIMA 20 mg in combination with
Pembrolizumab 200 mg
Sunitinib 50 mg
Laboratory Abnormality a All Grades
% b
Grades 3-4
% b
All Grades
% b
Grade 3-4
% b
Chemistry
Hypertriglyceridemia 80 15 71 15
Hypercholesterolemia 64 5 43 1
Increased lipase 61 34 59 28
Increased creatinine 61 5 61 2
Increased amylase 59 17 41 9
Increased aspartate aminotransferase (AST) 58 7 57 3
Hyperglycemia 55 7 48 3
Increased alanine aminotransferase (ALT) 52 7 49 4
Hyperkalemia 44 9 28 6
Hypoglycemia 44 2 27 1
Hyponatremia 41 12 28 9
Decreased albumin 34 0.3 22 0
Increased alkaline phosphatase 32 4 32 1
Hypocalcemia 30 2 22 1
Hypophosphatemia 29 7 50 8
Hypomagnesemia 25 2 15 3
Increased creatine phosphokinase 24 6 36 5
Hypermagnesemia 23 2 22 3
Hypercalcemia 21 1 11 1
Hematology
Lymphopenia 54 9 66 15
Thrombocytopenia 39 2 73 13
Anemia 38 3 66 8
Leukopenia 34 1 77 8
Neutropenia 31 4 72 16
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/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 patients on rechallenge in patients receiving LENVIMA and 10 patients receiving both LENVIMA and pembrolizumab.

Previously T reated Renal Cell Carcinoma in Combination with Everolimus (Study 205)

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 7 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 7.

Table  7 : 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
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 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 Arm a , 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
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 9 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 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
Sorafenib
800 mg
N=475
Grade 1-4
(%)
Grade 3-4
(%)
Grade 1-4
(%)
Grade 3-4
(%)
Endocrine
Hypothyroidisma 21 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-plant