Lenvima

LENVIMA is a kinase inhibitor that is indicated:   

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

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

• For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). (
  1.3

  Hepatocellular Carcinoma

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

• In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR) or not microsatellite instability-high (MSI-H), as determined by an FDA-approved test, who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation. (
  1.4

  Endometrial Carcinoma

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

  [see Dosage and Administration (

  2.1

  )]

  .
  , 
  2

  DOSAGE AND ADMINISTRATION

  Single Agent Therapy:

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

  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.
    
    
  • 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.
      
      
    • 18 mg orally once daily with everolimus 5 mg orally once daily.

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

  2.1

  Patient

  Selection

  For the pMMR/not MSI-H advanced endometrial carcinoma indication, select patients for treatment with LENVIMA in combination with pembrolizumab based on MMR or MSI status in tumor specimens

  [see Clinical Studies (

  14.4

  )].

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

  2.000000000000000e+00

  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.

  2.000000000000000e+00

  3

  Recommended Dos

  ag

  e

  for

  Differentiated

  Thyroid Cancer (DTC)

  The recommended dosage of LENVIMA is 24 mg orally once daily until disease progression or until unacceptable toxicity.

  2.000000000000000e+00

  4

  Recommended Dosage for Renal Cell Carcinoma (RCC)

  F

  irst-

  L

  ine

  Treatment of Patients with Advanced RCC

  The recommended dosage of LENVIMA is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or until unacceptable toxicity or up to 2 years. After completing 2 years of combination therapy, LENVIMA may be administered as a single agent until disease progression or until unacceptable toxicity.

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

  Previously Treated RCC

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

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

  2.000000000000000e+00

  5

  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.

  2.000000000000000e+00

  6

  Recommended Dosage for Endometrial Carcinoma

  (EC)

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

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

  2.000000000000000e+00

  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.

  2.000000000000000e+00

  8

  Dosage Modifications for Severe Renal Impairment

  The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe renal impairment (creatinine clearance less than 30 mL/min calculated by Cockcroft-Gault equation using actual body weight) is

  [s

  ee Warnings and Precautions (

  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

  2.000000000000000e+00

  9

  Dosage Modifications for Severe Hepatic Impairment

  The recommended dosage of LENVIMA for patients with DTC, RCC, or endometrial carcinoma and severe hepatic impairment (Child-Pugh C) is

  [s

  ee Warnings and Precautions (

  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

  2.000000000000000e+00

  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).
  )

Single Agent Therapy:

• DTC: The recommended dosage is 24 mg orally once daily. (
  2.000000000000000e+00

  3

  Recommended Dos

  ag

  e

  for

  Differentiated

  Thyroid Cancer (DTC)

  The recommended dosage of LENVIMA is 24 mg orally once daily until disease progression or until unacceptable toxicity.
  )
  
  
• 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. (
  2.000000000000000e+00

  5

  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.
  )

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. (
  2.000000000000000e+00

  6

  Recommended Dosage for Endometrial Carcinoma

  (EC)

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

  Refer to the pembrolizumab prescribing information for other pembrolizumab dosing information.
  )
  
  
• 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. (
    2.000000000000000e+00

    4

    Recommended Dosage for Renal Cell Carcinoma (RCC)

    F

    irst-

    L

    ine

    Treatment of Patients with Advanced RCC

    The recommended dosage of LENVIMA is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or until unacceptable toxicity or up to 2 years. After completing 2 years of combination therapy, LENVIMA may be administered as a single agent until disease progression or until unacceptable toxicity.

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

    Previously Treated RCC

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

    Refer to the everolimus prescribing information for recommended everolimus dosing information.
    )
    
    
  • 18 mg orally once daily with everolimus 5 mg orally once daily. (
    2.000000000000000e+00

    4

    Recommended Dosage for Renal Cell Carcinoma (RCC)

    F

    irst-

    L

    ine

    Treatment of Patients with Advanced RCC

    The recommended dosage of LENVIMA is 20 mg orally once daily in combination with pembrolizumab 200 mg administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or until unacceptable toxicity or up to 2 years. After completing 2 years of combination therapy, LENVIMA may be administered as a single agent until disease progression or until unacceptable toxicity.

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

    Previously Treated RCC

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

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

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

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.

• Lactation: Advise not to breastfeed. (
  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 children, advise women to discontinue breastfeeding during treatment with LENVIMA and for 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.
  )