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LENVIMA®
(lenvatinib) Capsules
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:
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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.
LENVIMA is indicated for the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory DTC.
LENVIMA is indicated in combination with everolimus for the treatment of patients with advanced RCC following one prior anti-angiogenic therapy.
The recommended daily dose of LENVIMA is 24 mg (two 10 mg capsules and one 4 mg capsule) orally taken once daily with or without food [see CLINICAL PHARMACOLOGY]. Continue LENVIMA until disease progression or until unacceptable toxicity.
Take LENVIMA at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.
The recommended daily dose of LENVIMA is 18 mg (one 10 mg capsule and two 4 mg capsules) in combination with 5 mg everolimus orally taken once daily with or without food [see CLINICAL PHARMACOLOGY]. Continue LENVIMA plus everolimus until disease progression or until unacceptable toxicity.
Take LENVIMA and everolimus at the same time each day. If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time of administration.
LENVIMA capsules should be swallowed whole. Alternatively, the capsules can be dissolved in a small glass of liquid. Measure 1 tablespoon of water or apple juice and put the capsules into the liquid without breaking or crushing them. Leave the capsules in the liquid for at least 10 minutes. Stir for at least 3 minutes. Drink the mixture. After drinking, add the same amount (1 tablespoon) of water or apple juice to the glass. Swirl the contents a few times and swallow the additional liquid.
Table 1: Adverse Reactions Requiring Dose Modification of LENVIMA in DTC and RCC
| Adverse Reaction | CTCAE Grade | Action | Dose Reduce and Resume LENVIMA |
| Hypertension | Grade 31 | Hold | Resolves to Grade 0, 1, or 2 |
| Grade 4 | Discontinue | Do Not Resume | |
| Cardiac Dysfunction | Grade 3 | Hold | Resolves to Grade 0, 1, or baseline |
| Grade 4 | Discontinue | Do Not Resume | |
| Arterial Thrombotic Event | Any Grade | Discontinue | Do Not Resume |
| Hepatotoxicity | Grade 3 or 4 | Hold OR Discontinue | Consider resuming at reduced dose if resolves to Grade 0-1 or baseline |
| Hepatic Failure | Grade 3 or 4 | Discontinue | Do Not Resume |
| Proteinuria | Greater than or equal to 2 gm/24 hours | Hold | Resolves to less than 2 gm/24 hours |
| Nephrotic Syndrome | - | Discontinue | Do Not Resume |
| Nausea, Vomiting, and Diarrhea2 | Grade 3 | Hold | Resolves to Grade 0, 1, or baseline |
| Vomiting and Diarrhea2 | Grade 4 | Discontinue | Do Not Resume |
| Renal Failure or Impairment | Grade 3 or 4 | Hold OR Discontinue | Consider resuming at reduced dose if resolves to Grade 0-1 or baseline |
| GI Perforation | Any Grade | Discontinue | Do Not Resume |
| Fistula | Grade 3 or 4 | Discontinue | Do Not Resume |
| QTc Prolongation | Greater than 500 ms | Hold | Resolves to less than 480 ms or baseline |
| RPLS | Any Grade | Hold OR Discontinue | Consider resuming at reduced dose if resolves to Grade 0 to 1 |
| Hemorrhage | Grade 3 | Hold | Resolves to Grade 0 to 1 |
| Grade 4 | Discontinue | Do Not Resume | |
| 1 Grade 3 despite optimal anti-hypertensive therapy 2 Initiate prompt medical management for nausea, vomiting or diarrhea. Permanently discontinue for Grade 4 vomiting and diarrhea despite medical management |
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Manage other adverse reactions according to the instructions in Table 2 for DTC or Table 3 for RCC.
Table 2: Dose Modifications for LENVIMA for Persistent and Intolerable Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalities in DTCa
| Adverse Reaction | Modification | Adjusted Doseb |
| First occurrence | Interrupt until resolved to Grade 0-1 or baseline | 20 mg (two 10 mg capsules) orally once daily |
| Second occurrencec | Interrupt until resolved to Grade 0-1 or baseline | 14 mg (one 10 mg capsule plus one 4 mg capsule) orally once daily |
| Third occurrencec | Interrupt until resolved to Grade 0-1 or baseline | 10 mg (one 10 mg capsule) orally once daily |
|
a Initiate medical management for nausea, vomiting, or diarrhea prior to interruption or dose reduction of
LENVIMA b Reduce dose in succession based on the previous dose level (24 mg, 20 mg, or 14 mg per day) c Refers to the same or a different adverse reaction that requires dose modification |
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Severe Renal or Hepatic Impairment in DTC
For patients with DTC, the recommended dose of LENVIMA is 14 mg taken orally once daily in patients with severe renal impairment (creatinine clearance [CLcr] less than 30 mL/min calculated by the Cockcroft-Gault equation) or severe hepatic impairment (Child-Pugh C) [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Table 3: Dose Modifications for LENVIMA for Persistent and Intolerable Grade 2 or Grade 3 Adverse Reactions or Grade 4 Laboratory Abnormalities in RCCa
| Adverse Reaction | Modification | Adjusted Doseb |
| First occurrence | Interrupt until resolved to Grade 0-1 or baseline | 14 mg (one 10 mg capsule plus one 4 mg capsule) orally once daily |
| Second occurrencec | Interrupt until resolved to Grade 0-1 or baseline | 10 mg (one 10 mg capsule) orally once daily |
| Third occurrencec | Interrupt until resolved to Grade 0-1 or baseline | 8 mg (two 4 mg capsules) orally once daily |
|
a Initiate medical management for nausea, vomiting, or diarrhea prior to interruption or dose reduction of
LENVIMA b Reduce dose in succession based on the previous dose level (18 mg, 14 mg, 10 mg, or 8 mg per day) c Refers to the same or a different adverse reaction that requires dose modification |
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Recommendations for Dose Modification of Everolimus in RCC
Review the Full Prescribing Information for everolimus for recommended dose modifications. For toxicities thought to be related to everolimus alone, discontinue, interrupt, or use alternate day dosing. For toxicities thought to be related to both LENVIMA and everolimus, first reduce LENVIMA and then everolimus.
Severe Renal or Hepatic Impairment in RCC
For patients with RCC, the recommended dose of LENVIMA is 10 mg taken orally once daily in patients with severe renal impairment (CLcr less than 30 mL/min calculated by the Cockcroft-Gault equation) or severe hepatic impairment (Child-Pugh C) [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
4 mg hard capsule: A yellowish-red body and yellowish-red cap, marked in black ink with “∈” on the cap and “LENV 4 mg” on the body.
10 mg hard capsule: A yellow body and yellowish-red cap, marked in black ink with “∈” on the cap and “LENV 10 mg” on the body.
LENVIMA 4 mg capsules are supplied as hard hypromellose capsules with yellowish-red body and yellowish-red cap, marked in black ink with “∈” on the cap and “LENV 4 mg” on the body.
LENVIMA 10 mg capsules are supplied as hard hypromellose capsules with yellow body and yellowish-red cap, marked in black ink with “∈” on the cap and “LENV 10 mg” on the body.
LENVIMA capsules are supplied in cartons of 6 cards. Each card is a 5-day blister card as follows:
Store at 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F) [see USP Controlled Room Temperature].
Distributed by: Eisai Inc., Woodcliff Lake, NJ 07677. Revised: June 2018
The following adverse reactions are discussed elsewhere in the label:
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 section reflect exposure to LENVIMA as a single agent in 261 DTC patients (Study 1) and LENVIMA + everolimus in 62 RCC patients (Study 2). Safety data obtained in 1160 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 [see WARNINGS AND PRECAUTIONS]. In the entire single agent population, the median age was 60 years (range 21-89 years), the dose range was 0.2 mg to 32 mg, and the median duration of exposure was 5.5 months.
The safety data described below are derived from Study 1 which randomized (2:1) patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) to LENVIMA (n=261) or placebo (n=131) [see Clinical Studies]. The median treatment duration was 16.1 months for LENVIMA and 3.9 months for placebo. Among 261 patients who received LENVIMA in Study 1, median age was 64 years, 52% were women, 80% were White, 18% were Asian, and 2% were Black; 4% identified themselves as having Hispanic or Latino ethnicity.
In Study 1, the most common adverse reactions observed in LENVIMA-treated patients (greater than or equal to 30%) were, in order of decreasing frequency, hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased appetite, weight decreased, 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 and 5% of patients receiving placebo; 18% of patients discontinued LENVIMA and 5% discontinued placebo 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 4 presents the percentage of patients in Study 1 experiencing adverse reactions at a higher rate in LENVIMA-treated patients than patients receiving placebo in the double-blind phase of the DTC study.
Table 4: Adverse Reactions Occurring in Patients with a Between-Group Difference of Greater than or Equal to 5% in All Grades or Greater than or Equal to 2% in Grades 3 and 4>
| Adverse Reaction | LENVIMA 24 mg N=261 |
Placebo N=131 |
||
| All Grades (%) |
Grades 3-4 (%) |
All Grades (%) |
Grades 3-4 (%) |
|
| Vascular Disorders | ||||
| Hypertensiona | 73 | 44 | 16 | 4 |
| Hypotension | 9 | 2 | 2 | 0 |
| Gastrointestinal Disorders | ||||
| 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 Disorders and Administration Site Conditions | ||||
| Fatiguee | 67 | 11 | 35 | 4 |
| Edema peripheral | 21 | 0.4 | 8 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Arthralgia/Myalgiaf | 62 | 5 | 28 | 3 |
| Metabolism and Nutrition Disorders | ||||
| Weight decreased | 51 | 13 | 15 | 1 |
| Decreased appetite | 54 | 7 | 18 | 1 |
| Dehydration | 9 | 2 | 2 | 1 |
| Nervous System Disorders | ||||
| Headache | 38 | 3 | 11 | 1 |
| Dysgeusia | 18 | 0 | 3 | 0 |
| Dizziness | 15 | 0.4 | 9 | 0 |
| Renal and Urinary Disorders | ||||
| Proteinuria | 34 | 11 | 3 | 0 |
| Skin and Subcutaneous Tissue Disorders | ||||
| 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 Disorders | ||||
| Dysphonia | 31 | 1 | 5 | 0 |
| Cough | 24 | 0 | 18 | 0 |
| Epistaxis | 12 | 0 | 1 | 0 |
| Psychiatric Disorders | ||||
| Insomnia | 12 | 0 | 3 | 0 |
| Infections and Infestations | ||||
| Dental and oral infectionsh | 10 | 1 | 1 | 0 |
| Urinary tract infection | 11 | 1 | 5 | 0 |
| Cardiac Disorders | ||||
| 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 |
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A clinically important adverse reaction occurring more frequently in LENVIMA-treated patients than patients receiving placebo, but with an incidence of less than 5% was pulmonary embolism (3%, including fatal reports vs 2%, respectively).
Table 5: Laboratory Abnormalities with a Difference of at Least ≥2% in Grade 3 - 4 Events and at a Higher Incidence in LENVIMA-Treated Patientsa
| Laboratory Abnormality | LENVIMA 24 mg N=258b |
Placebo N=131b |
| Grades 3-4 (%) | Grades 3-4 (%) | |
| Chemistry | ||
| Creatinine increased | 3 | 0 |
| Alanine aminotransferase (ALT) increased | 4 | 0 |
| Aspartate aminotransferase (AST) increased | 5 | 0 |
| Hypocalcemia | 9 | 2 |
| Hypokalemia | 6 | 1 |
| Lipase increased | 4 | 1 |
| Hematology | ||
| Platelet count decreased | 2 | 0 |
|
a With at least 1 grade increase from baseline b Subject with at least 1 post baseline laboratory value |
||
In addition the following laboratory abnormalities (all Grades) occurred in greater than 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.
The data described below are derived from Study 2 which randomized (1:1:1) patients with unresectable advanced or metastatic renal cell carcinoma (RCC) to LENVIMA 18 mg + everolimus 5 mg (n=51), LENVIMA 24 mg (n=52), or everolimus 10 mg (n=50) once daily [see Clinical Studies]. This data also includes patients on the dose escalation portion of the study who received LENVIMA 18 mg + everolimus 5 mg (n=11). The median treatment duration was 8.1 months for LENVIMA + everolimus and 4.1 months for everolimus. Among 62 patients who received LENVIMA + everolimus in Study 2, the median age was 61 years, 71% were men, and 98% were White.
The most common adverse reactions observed in the LENVIMA + 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, weight decreased, 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 + everolimus and 54% in patients receiving everolimus. The most common adverse reactions (≥ 5%) resulting in dose reductions in the LENVIMA + 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 + everolimus-treated group and 12% of patients in the everolimus-treated group.
Table 6 presents the adverse reactions in > 15% of patients in the LENVIMA + Everolimus arm.
Table 6: Grades 1-4 Adverse Reactions in > 15% of Patients in the LENVIMA + Everolimus Arm
| System Organ Class Preferred Term | LENVIMA 18 mg + Everolimus 5 mg (N=62) |
Everolimus 10 mg (N=50) |
||
| Grade 1-4 (%) |
Grade 3-4 (%) |
Grade 1-4 (%) |
Grade 3-4 (%) |
|
| Endocrine Disorders | ||||
| Hypothyroidism | 24 | 0 | 2 | 0 |
| Gastrointestinal Disorders | ||||
| Constipation | 16 | 0 | 18 | 0 |
| Diarrhea | 81 | 19 | 34 | 2 |
| Dyspepsia/Gastro-esophageal reflux | 21 | 0 | 12 | 0 |
| Abdominal paina | 37 | 3 | 8 | 0 |
| Nausea | 45 | 5 | 16 | 0 |
| Oral painb | 23 | 2 | 4 | 0 |
| Stomatitis/Oral inflammationc | 44 | 2 | 50 | 4 |
| Vomiting | 48 | 7 | 12 | 0 |
| General Disorders and Administration Site Conditions | ||||
| Fatigued | 73 | 18 | 40 | 2 |
| Peripheral edema | 42 | 2 | 20 | 0 |
| Pyrexia/Increased body temperature | 21 | 2 | 10 | 2 |
| Investigations | ||||
| Weight decreased | 34 | 3 | 8 | 0 |
| Metabolism and Nutrition Disorders | ||||
| Decreased appetite | 53 | 5 | 18 | 0 |
| Musculoskeletal and Connective Tissue Disorders | ||||
| Arthralgia/Myalgiae | 55 | 5 | 32 | 0 |
| Musculoskeletal chest pain | 18 | 2 | 4 | 0 |
| Nervous System Disorders | ||||
| Headache | 19 | 2 | 10 | 2 |
| Psychiatric Disorders | ||||
| Insomnia | 16 | 2 | 2 | 0 |
| Renal and Urinary Disorders | ||||
| Proteinuria/Urine protein present | 31 | 8 | 14 | 2 |
| Renal failure eventf | 18 | 10 | 12 | 2 |
| Respiratory, Thoracic and Mediastinal Disorders | ||||
| Cough | 37 | 0 | 30 | 0 |
| Dysphonia | 18 | 0 | 4 | 0 |
| Dyspnea/Exertional dyspnea | 35 | 5 | 28 | 8 |
| Skin and Subcutaneous Tissue Disorders | ||||
| Rashg | 35 | 0 | 40 | 0 |
| Vascular Disorders | ||||
| Hemorrhagic eventsh | 32 | 6 | 26 | 2 |
| Hypertension/Increased blood pressure | 42 | 13 | 10 | 2 |
|
a Includes abdominal discomfort, gastrointestinal pain, lower abdominal pain, and upper abdominal pain b Includes gingival pain, glossodynia, and oropharyngeal pain c Includes aphthous stomatitis, gingival inflammation, glossitis, and mouth ulceration 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 |
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Table 7: Grade 3-4 Laboratory Abnormalities in ≥ 3% of Patients in the LENVIMA + Everolimus Arma,b
| Laboratory Abnormality | LENVIMA 18 mg + Everolimus 5 mg N=62 |
Everolimus 10 mg N=50 |
| Grades 3-4 (%) |
Grades 3-4 (%) |
|
| Chemistry | ||
| Aspartate aminotransferase (AST) increased | 3 | 0 |
| Alanine aminotransferase (ALT) increased | 3 | 2 |
| Alkaline phosphatase increased | 3 | 0 |
| Hyperkalemia | 6 | 2 |
| Hypokalemia | 6 | 2 |
| Hyponatremia | 11 | 6 |
| Hypocalcemia | 6 | 2 |
| Hypophosphatemia | 11 | 6 |
| Hyperglycemia | 3 | 16 |
| Hypertriglyceridemia | 18 | 18 |
| Elevated cholesterol | 11 | 0 |
| Creatine kinase increased | 3 | 4 |
| Lipase increased | 13 | 12 |
| Hematology | ||
| Hemoglobin decreased | 8 | 16 |
| Platelet count decreased | 5 | 0 |
| Lymphocyte count decreased | 10 | 20 |
|
a With at least 1 grade increase from baseline b Subject with at least 1 post baseline laboratory value |
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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 Disorders: pancreatitis, amylase increased
General Disorders: impaired wound healing
Hepatobiliary Disorders: cholecystitis
Musculoskeletal and Connective Tissue Disorders: fistula
Vascular Disorders: aortic dissection
No dose adjustment of LENVIMA is recommended when co-administered with CYP3A, Pglycoprotein (P-gp), and breast cancer resistance protein (BCRP) inhibitors and CYP3A and P-gp inducers [see CLINICAL PHARMACOLOGY].
Included as part of the "PRECAUTIONS" Section
In Study 1 in DTC, hypertension was reported in 73% of LENVIMA-treated patients and 16% of patients in the placebo group [see ADVERSE REACTIONS]. The median time to onset of new or worsening hypertension was 16 days for LENVIMA-treated patients. The incidence of Grade 3 hypertension was 44% as compared to 4% for placebo, and the incidence of Grade 4 hypertension was less than 1% in LENVIMA-treated patients and none in the placebo group.
In Study 2 in RCC, hypertension was reported in 42% of patients in the LENVIMA + everolimus-treated group and 10% of patients in the everolimus-treated group. The median time to onset of new or worsening hypertension was 35 days for LENVIMA + everolimus-treated patients. The incidence of Grade 3 hypertension was 13% in the LENVIMA + everolimus-treated group as compared to 2% in the everolimus-treated group. Systolic blood pressure ≥ 160mmHg occurred in 29% and 21% of patients had a diastolic blood pressure ≥100 in the LENVIMA + everolimus-treated group [see ADVERSE REACTIONS].
Serious complications of poorly controlled hypertension have been reported.
Control blood pressure prior to treatment with LENVIMA. Monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly thereafter during treatment with LENVIMA. Withhold LENVIMA for Grade 3 hypertension despite optimal antihypertensive therapy; resume at a reduced dose when hypertension is controlled at less than or equal to Grade 2. Discontinue LENVIMA for life-threatening hypertension [see DOSAGE AND ADMINISTRATION].
In Study 1 in DTC, cardiac dysfunction, defined as decreased left or right ventricular function, cardiac failure, or pulmonary edema, was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater) and 2% (no Grade 3 or greater) of patients in the placebo group. The majority of these cases in LENVIMA-treated patients (14 of 17 cases) were based on findings of decreased ejection fraction as assessed by echocardiography. Six of 261 (2%) LENVIMA-treated patients in Study 1 had greater than 20% reduction in ejection fraction as measured by echocardiography compared to no patients who received placebo.
In Study 2 in RCC, decreased ejection fraction and cardiac failure were reported in 10% of patients in the LENVIMA + everolimus-treated group and 6% of patients in the everolimustreated group. Grade 3 events occurred in 3% of LENVIMA + everolimus-treated patients and 2% of everolimus-treated patients. In the LENVIMA + everolimus-treated group there were two patients with a Grade 2 to 4 decrease in LVEF as assessed by MUGA.
Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction [see DOSAGE AND ADMINISTRATION].
In Study 1 in DTC, arterial thromboembolic events were reported in 5% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of arterial thromboembolic events of Grade 3 or greater was 3% in LENVIMA-treated patients and 1% in the placebo group.
In Study 2 in RCC, 2% of patients in the LENVIMA + everolimus-treated group and 6% of patients in the everolimus-treated group had arterial thromboembolic events reported. The incidence of arterial thromboembolic events of Grade 3 or greater was 2% with LENVIMA + everolimus-treated patients and 4% in the everolimus-treated group.
Discontinue LENVIMA following an arterial thrombotic event. 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 [see DOSAGE AND ADMINISTRATION].
Across clinical studies in which 1160 patients received LENVIMA monotherapy, hepatic failure (including fatal events) was reported in 3 patients and acute hepatitis was reported in 1 patient.
In Study 1 in DTC, 4% of LENVIMA-treated patients experienced an increase in alanine aminotransferase (ALT) and 5% experienced an increase in aspartate aminotransferase (AST) that was Grade 3 or greater. No patients in the placebo group experienced Grade 3 or greater increases in ALT or AST.
The incidence of ALT and AST elevation was similar in Study 2 in RCC. In Study 2, 3% of LENVIMA + everolimus-treated patients experienced an increase in ALT and 3% experienced an increase in AST that was Grade 3 or greater. Two percent of patients in the everolimus-treated group experienced an increase in ALT and none experienced an increase in AST that was Grade 3 or greater.
Monitor liver function before initiation of LENVIMA, then every 2 weeks for the first 2 months, and at least monthly thereafter during treatment. Withhold LENVIMA for the development of Grade 3 or greater liver impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure [see DOSAGE AND ADMINISTRATION].
In Study 1 in DTC, proteinuria was reported in 34% of LENVIMA-treated patients and 3% of patients in the placebo group [see ADVERSE REACTIONS]. The incidence of Grade 3 proteinuria in LENVIMA-treated patients was 11% compared to none in the placebo group. In Study 2 in RCC, proteinuria was reported in 31% of patients in the LENVIMA + everolimus-treated group and 14% of patients in the everolimus-treated group. The incidence of Grade 3 proteinuria in LENVIMA + everolimus-treated patients was 8% compared to 2% in everolimus-treated patients.
Monitor for proteinuria before initiation of, and periodically throughout treatment. If urine dipstick proteinuria greater than or equal to 2+ is detected, obtain a 24 hour urine protein. Withhold LENVIMA for ≥2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome [see DOSAGE AND ADMINISTRATION].
In Study 2 in RCC, diarrhea was reported in 81% of LENVIMA + everolimus-treated patients and 34% of everolimus-treated patients. Grade 3 or 4 events occurred in 19% of LENVIMA + everolimus-treated patients and 2% of everolimus-treated patients. Diarrhea was the most frequent cause of dose interruption/reduction and recurred despite dose reduction. Diarrhea resulted in discontinuation in one patient [see ADVERSE REACTIONS].
Initiate prompt medical management for the development of diarrhea. Monitor for dehydration. Interrupt LENVIMA for Grade 3 or 4 diarrhea. For Grade 3 diarrhea, resume at a reduced dose of LENVIMA when diarrhea resolves to Grade 1 or baseline. Permanently discontinue LENVIMA for Grade 4 diarrhea despite medical management.
In Study 1 in DTC, events of renal impairment were reported in 14% of LENVIMA-treated patients compared to 2% of patients in the placebo group. The incidence of Grade 3 or greater renal failure or impairment was 3% in LENVIMA-treated patients and 1% in the placebo group.
In Study 2 in RCC, renal impairment was reported in 18% of LENVIMA + everolimustreated group and 12% in the everolimus-treated group. The incidence of Grade 3 or greater renal failure or impairment was 10% in the LENVIMA + everolimus-treated group and 2% in the everolimus-treated group.
One risk factor for severe renal impairment in LENVIMA-treated patients was dehydration/hypovolemia due to diarrhea and vomiting. Active management of diarrhea and any other gastrointestinal symptoms should be initiated for Grade 1 events.
Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment [see DOSAGE AND ADMINISTRATION].
In Study 1 in DTC, events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients and 0.8% of patients in the placebo group.
In Study 2 in RCC, Grade 3 or greater gastrointestinal perforation, abscess or fistula was reported in 2% of patients in the LENVIMA + everolimus-treated group and no patients in the everolimus-treated group. The events resolved in all patients.
Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula [see DOSAGE AND ADMINISTRATION].
In Study 1 in DTC, QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients and 2% of patients in the placebo group. The incidence of QT interval prolongation of greater than 500 ms was 2% in LENVIMA-treated patients compared to no reports in the placebo group.
In Study 2 in RCC, QTc interval increases greater than 60 ms were reported in 11% of patients in the LENVIMA + everolimus-treated group. The incidence of QTc interval greater than 500 ms was 6% in the LENVIMA + everolimus-treated group. No reports of QTc interval prolongation greater than 500 ms or increase greater than 60 ms occurred in the everolimus-treated group.
Monitor and correct electrolyte abnormalities in all patients. 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 LENVIMA for the development of QTc interval prolongation greater than 500 ms. Resume LENVIMA at a reduced dose when QTc prolongation resolves to baseline [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
In Study 1 in DTC, 9% of LENVIMA-treated patients experienced Grade 3 or greater hypocalcemia compared to 2% in the placebo group. In most cases hypocalcemia responded to replacement and dose interruption/dose reduction.
In Study 2 in RCC, 6% of patients in the LENVIMA + everolimus-treated group and 2% of patients in the everolimus-treated group experienced Grade 3 or greater hypocalcemia. No patients discontinued due to hypocalcemia [see ADVERSE REACTIONS].
Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia [see DOSAGE AND ADMINISTRATION].
Across clinical studies in which 1160 patients received LENVIMA monotherapy, there were 4 reported events of reversible posterior leukoencephalopathy syndrome (RPLS). Confirm the diagnosis of RPLS with MRI. Withhold for RPLS until fully resolved. Upon resolution, resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms [see DOSAGE AND ADMINISTRATION].
Across clinical studies in which 1160 patients received LENVIMA monotherapy, Grade 3 or greater hemorrhage was reported in 2% of patients.
In Study 1 in DTC, hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. However, the incidence of Grade 3 to 5 hemorrhage was similar between arms at 2% and 3%, respectively. There was 1 case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA- treated patients.
In Study 2 in RCC, hemorrhagic events occurred in 34% of patients in the LENVIMA + everolimus-treated group and 26% of patients in the everolimus-treated group. The most frequently reported hemorrhagic event was epistaxis (LENVIMA + everolimus 23% and everolimus 24%). Grade 3 or greater events occurred in 8% of LENVIMA + everolimus-treated patients and in 2% of everolimus-treated patients. In the LENVIMA + everolimus-treated patients, this included one fatal cerebral hemorrhage. Discontinuation due to a hemorrhagic event occurred in 3% of patients in the LENVIMA + everolimustreated group.
Serious tumor related bleeds, including fatal hemorrhagic events in LENVIMA-treated patients, have occurred in clinical trials and been reported in post-marketing experience. 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/infiltration of major blood vessels (e.g. carotid artery). Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Either resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage [see DOSAGE AND ADMINISTRATION].
LENVIMA impairs exogenous thyroid suppression. In Study 1 in DTC, 88% of all patients had a baseline thyroid stimulating hormone (TSH) level less than or equal to 0.5 mU/L. In those patients with a normal TSH at baseline, elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients as compared with 14% of patients receiving placebo.
In Study 2 in RCC, Grade 1 or 2 hypothyroidism occurred in 24% of patients in the LENVIMA + everolimus-treated group and 2% of patients in the everolimus-treated group. In those patients with a normal or low TSH at baseline, an elevation of TSH was observed post baseline in 60 % of LENVIMA + everolimus-treated patients as compared with 3% of patients receiving everolimus monotherapy.
Monitor thyroid function before initiation of, and at least monthly throughout, treatment with LENVIMA. Treat hypothyroidism according to standard medical practice to maintain a euthyroid state.
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.
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 human dose 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 2 weeks following completion of therapy [see Use In Specific Populations].
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Advise patients to undergo regular blood pressure monitoring and to contact their health care provider if blood pressure is elevated [see WARNINGS AND PRECAUTIONS].
Advise patients that LENVIMA can cause cardiac dysfunction and to immediately contact their healthcare provider if they experience any clinical symptoms of cardiac dysfunction such as shortness of breath or swelling of ankles [see WARNINGS AND PRECAUTIONS].
Advise patients to seek immediate medical attention for new onset chest pain or acute neurologic symptoms consistent with myocardial infarction or stroke [see WARNINGS AND PRECAUTIONS].
Advise patients that they will need to undergo laboratory tests to monitor for liver function and to report any new symptoms indicating hepatic toxicity or failure [see WARNINGS AND PRECAUTIONS].
Advise patients when to start standard anti-diarrheal therapy and to maintain adequate hydration. Advise patients to contact their healthcare provider if they are unable to maintain adequate hydration [see WARNINGS AND PRECAUTIONS].
Advise patients that they will need to undergo regular laboratory tests to monitor for kidney function and protein in the urine [see WARNINGS AND PRECAUTIONS].
Advise patients that LENVIMA can increase the risk of gastrointestinal perforation or fistula and to seek immediate medical attention for severe abdominal pain [see WARNINGS AND PRECAUTIONS].
QTc Interval Prolongation Advise patients who are at risk for QTc prolongation that they will need to undergo regular ECGs. Advise all patients that they will need to undergo laboratory tests to monitor electrolytes [see WARNINGS AND PRECAUTIONS].
Advise patients that LENVIMA can increase the risk for bleeding and to contact their healthcare provider for bleeding or symptoms of severe bleeding [see WARNINGS AND PRECAUTIONS].
Advise patients that LENVIMA can increase the risk of wound healing complications. Advise patients to inform their healthcare provider of any planned surgical procedure [see WARNINGS AND PRECAUTIONS].
Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy [see WARNINGS AND PRECAUTIONS, Use In Specific Populations].
Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy [see Use In Specific Populations].
Advise nursing women to discontinue breastfeeding during treatment with LENVIMA [see Use In Specific Populations].
Carcinogenicity studies have not been conducted with lenvatinib. Lenvatinib mesylate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay.
No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is a potential for lenvatinib to impair fertility. Male dogs exhibited testicular hypocellularity of the seminiferous epithelium and desquamated seminiferous epithelial cells in the epididymides at lenvatinib exposures approximately 0.02 to 0.09 times the clinical exposure by AUC at the recommended human dose. Follicular atresia of the ovaries was observed in monkeys and rats at exposures 0.2 to 0.8 times and 10 to 44 times the clinical exposure by AUC at the 24 mg clinical dose, respectively. In addition, in monkeys, a decreased incidence of menstruation was reported at lenvatinib exposures lower than those in humans at the 24 mg clinical dose.
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]. In animal reproduction studies, oral administration of lenvatinib during organogenesis at doses below the recommended human dose 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.
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies.
Animal Data
In an embryofetal development study, daily oral administration of lenvatinib mesylate at doses greater than or equal to 0.3 mg/kg [approximately 0.14 times the recommended human dose 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 human dose 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 human dose of 24 mg based on body surface area). At the 0.03 mg/kg dose, increased post-implantation loss, including 1 fetal death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in late abortions in approximately one-third of the rabbits treated at a dose level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose of 24 mg based on BSA).
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 in maternal plasma [see Data]. Because of the potential for serious adverse reactions in nursing infants from LENVIMA, advise women to discontinue breastfeeding during treatment with LENVIMA.
Animal Data
Following administration of radiolabeled lenvatinib to lactating Sprague Dawley rats, lenvatinib-related radioactivity was approximately 2 times higher (based on AUC) in milk compared to maternal plasma.
Based on its mechanism of action, LENVIMA can cause fetal harm when administered to a pregnant woman [see Pregnancy]. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy.
Females
LENVIMA may result in reduced fertility in females of reproductive potential [see Nonclinical Toxicology].
Males
LENVIMA may result in damage to male reproductive tissues leading to reduced fertility of unknown duration [see Nonclinical Toxicology].
The safety and effectiveness of LENVIMA in pediatric patients have not been established.
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 clinical exposure by AUC at the recommended human dose). Decreased length of the femur and tibia persisted following 4 weeks of recovery. In general, the toxicologic profile of lenvatinib was similar between juvenile and adult rats, though toxicities including broken teeth at all dose levels and mortality at the 10 mg/kg/day dose level (attributed to primary duodenal lesions) occurred at earlier treatment time-points in juvenile rats.
Of 261 patients who received LENVIMA in Study 1, 118 (45.2%) were greater than or equal to 65 years of age and 29 (11.1%) were greater than or equal to 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 62 patients who received LENVIMA + everolimus in Study 2, 22 (35.5%) were greater than or equal to 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.
No dose adjustment is recommended in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended dose is 14 mg in the treatment of DTC and 10 mg in the treatment of RCC, either taken orally once daily. Patients with end stage renal disease were not studied [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
No dose adjustment is recommended in patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the recommended dose is 14 mg in the treatment of DTC and 10 mg in the treatment of RCC, either taken orally once daily [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].
There is no specific antidote for overdose with LENVIMA. Due to the high plasma protein binding, lenvatinib is not expected to be dialyzable [see CLINICAL PHARMACOLOGY]. Adverse reactions in patients receiving single doses of LENVIMA as high as 40 mg were similar to the adverse events reported in the clinical studies at the recommended dose for DTC and RCC.
None.
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Lenvatinib also inhibits other RTKs 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; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and RET. The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumor activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signaling in vitro and tumor volume in mouse xenograft models of human renal cell cancer greater than each drug alone.
A single 32 mg dose (1.3 times the recommended daily dose) of lenvatinib did not prolong the QT/QTc interval in a thorough QT study in healthy subjects. However, QT prolongation was observed in clinical studies [see WARNINGS AND PRECAUTIONS].
After oral administration of LENVIMA, time to peak plasma concentration (Tmax) typically occurred from 1 to 4 hours post-dose. Administration with food did not affect the extent of absorption, but decreased the rate of absorption and delayed the median Tmax from 2 hours to 4 hours.
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 to 32 mg with a median accumulation index of 0.96 (20 mg) to 1.54 (6.4 mg).
In vitro binding of lenvatinib to human plasma proteins ranged from 98% to 99% (0.3 – 30 μg/mL). In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 – 10 μg/mL).
Based on in vitro data, lenvatinib is a substrate of P-gp and BCRP but not a substrate for organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, or the bile salt export pump (BSEP).
Plasma concentrations declined bi-exponentially following Cmax. The terminal elimination half-life of lenvatinib was approximately 28 hours.
CYP3A is one of the main metabolic enzymes of lenvatinib. The main metabolic pathways for lenvatinib in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic processes.
Ten days after a single administration of radiolabeled lenvatinib to 6 patients with solid tumors, approximately 64% and 25% of the radiolabel were eliminated in the feces and urine, respectively.
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), and severe (CLcr <30 mL/min) renal impairment, and compared to healthy subjects. Subjects with end stage renal disease were not studied. After a single 24 mg oral dose of LENVIMA, the AUC0-inf for subjects with renal impairment were similar compared to those for healthy subjects [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, Use In Specific Populations].
The pharmacokinetics of lenvatinib following a single 10 mg dose of LENVIMA were evaluated in subjects with mild (Child-Pugh A) and 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 subjects with mild, moderate, and severe hepatic impairment were 119%, 107%, and 180%, respectively [see DOSAGE AND ADMINISTRATION, Use In Specific Populations].
Based on a population PK analysis, weight, age, sex, and race did not have a significant effect on apparent clearance (Cl/F) of lenvatinib.
CYP3A, P-gp, and BCRP Inhibitors:
Ketoconazole (400 mg for 18 days) increased lenvatinib (administered as a single dose on Day 5) AUC by 15% and Cmax by 19% in a dedicated clinical trial.
P-gp Inhibitors:
Rifampicin (600 mg as a single dose) increased lenvatinib (24 mg as a single dose) AUC by 31% and Cmax by 33% in a dedicated clinical trial.
CYP3A and P-gp Inducers:
Rifampicin (600 mg administered daily for 21 days) decreased lenvatinib (a single 24 mg administered on Day 15) AUC by 18% in a dedicated clinical trial. The Cmax was unchanged.
CYP3A4 or CYP2C8 Substrates:
There is no projected significant drug-drug interaction risk between lenvatinib and midazolam (a CYP3A4 substrate) or repaglinide (a CYP2C8 substrate).
In Vitro Studies with CYP or UDP-glucuronosyltransferase (UGT) Substrates:
Lenvatinib inhibits CYP2C8, CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A, but an increase in lenvatinib exposure that impacts safety is unlikely. Lenvatinib does not inhibit CYP2A6 and CYP2E1.
Lenvatinib induces CYP3A, but a decrease in lenvatinib exposure that impacts efficacy is unlikely. Lenvatinib does not induce CYP1A1, CYP1A2, CYP2B6, and CYP2C9. Lenvatinib directly inhibits UGT1A1 and UGT1A4. The clinical implication of this finding is unknown. Lenvatinib shows little or no inhibition on UGT1A6, UGT1A9, UGT2B7, or aldehyde oxidase.
Lenvatinib does not induce UGT1A1, UGT1A4, UGT1A6, UGT1A9, or UGT2B7.
In Vitro Studies with Drug Transporter System Substrates:
Lenvatinib inhibits OAT1, OAT3, OCT1, OCT2, OATP1B1, and BSEP. The clinical implication of this finding is unknown. Lenvatinib shows little or no inhibition on OATP1B3.
A multicenter, randomized (2:1), double-blind, placebo-controlled trial was conducted in 392 patients with locally recurrent or metastatic radioactive iodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within 12 months prior to randomization, confirmed by independent radiologic review. Radioactive iodine-refractory was defined as 1 or more measurable lesions with no iodine uptake on RAI scan, iodine uptake with progression within 12 months of RAI therapy, or having received cumulative RAI activity of >600 mCi (22 GBq) with the last dose administered at least 6 months prior to study entry. Patients were randomized to receive LENVIMA 24 mg once daily (n=261) or placebo (n=131) until disease progression. Randomization was stratified by geographic region, prior VEGF/VEGFR-targeted therapy, and age. The major efficacy outcome measure was progression-free survival as determined by blinded independent radiologic review using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Independent review confirmation of disease progression was required prior to discontinuing patients from the randomization phase of the study. Other efficacy outcome measures included objective response rate and overall survival. Patients in the placebo arm could receive lenvatinib following independent review confirmation of disease progression.
Of the 392 patients randomized, 51% were male, the median age was 63 years, 40% were older than 65 years, 79% were White, 54% had an ECOG performance status of 0, and 24% had received 1 prior VEGF/VEGFR-targeted therapy. Metastases were present in 99% of the patients: lungs in 89%, lymph nodes in 52%, bone in 39%, liver in 18%, and brain in 4%. The histological diagnoses were papillary thyroid cancer (66%) and follicular thyroid cancer (34%); of those with follicular histology, 44% had Hürthle cell and 11% had clear cell subtypes. In the LENVIMA arm, 67% of patients did not demonstrate iodine uptake on any radioiodine scan compared to 77% in the placebo arm. Additionally, 59% of patients on the LENVIMA arm and 61% of patients on placebo arm progressed, according to RECIST 1.1, within 12 months of prior 131I therapy; 19.2% of patients on the LENVIMA arm and 17.6% of patients on placebo arm received prior cumulative activity of >600 mCi or 22 gigabecquerels (GBq) 131I, with the last dose administered at least 6 months prior to study entry. The median cumulative RAI activity administered prior to study entry was 350 mCi (12.95 GBq).
A statistically significant prolongation in PFS was demonstrated in LENVIMA-treated patients compared to those receiving placebo (see Table 8 and Figure 1). Upon confirmation of progression, 109 (83%) patients randomly assigned to placebo crossed over to receive open-label LENVIMA.
Table 8: Efficacy Results for Study 1
| LENVIMA N=261 |
Placebo N=131 |
|
| Progression-free Survivala | ||
| Number of events (%) | 107 (41) | 113 (86) |
| Progressive disease | 93 (36) | 109 (83) |
| Death | 14 (5) | 4 (3) |
| Median PFS in months (95% CI) | 18.3 (15.1, NE) | 3.6 (2.2, 3.7) |
| Hazard ratio (95% CI)b | 0.21 (0.16, 0.28) | |
| P-valuec | <0.001 | |
| Objective Response Ratea | ||
| Objective response rate | 65% | 2% |
| (95% CI) | (59%, 71%) | (0%, 4%) |
| Complete response | 2% | 0% |
| Partial response | 63% | 2% |
| P-valued | <0.001 | |
| Overall Survivale | ||
| Number of deaths (%) | 71 (27) | 47 (36) |
| Median OS in months (95% CI) | NE (22.1, NE) | NE (20.3, NE) |
| Hazard ratio (95% CI)b | 0.73 (0.50, 1.07) | |
| P-valueb | 0.10 | |
|
a Independent radiologic review b Estimated with Cox proportional hazard model stratified by region (Europe vs North America vs other), age group (≤65 years vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1) c Log-rank test stratified by region (Europe vs North America vs other), age group (≤65 years vs >65 years), and previous VEGF/VEGFR-targeted therapy (0 vs 1) d Cochran-Mantel-Haenszel chi-square test e NE = Not estimable |
||
Figure 1: Kaplan-Meier Plot of Progression-Free Survival (Study 1)
 |
A multicenter study (Study 2) randomized 153 patients with advanced or metastatic renal cell carcinoma who have previously received anti-angiogenic therapy 1:1:1 to LENVIMA 18 mg plus everolimus 5 mg, LENVIMA 24 mg monotherapy, or everolimus 10 mg monotherapy. All medications were administered orally once daily. Patients were required to have histological confirmation of clear cell RCC and ECOG Performance Status of 0 or 1. Patients were stratified by hemoglobin level (≤ or > 13 g/dL for males and ≤ or > 11.5 g/dL for females) and corrected serum calcium (≥10 mg/dL vs. <10 mg/dL).
Of the 101 patients randomly allocated to the LENVIMA + everolimus arm and everolimus monotherapy arm, 72% were male, the median age was 60 years, 31% were older than 65 years, 96% were White. Metastases were present in 95% of the patients and unresectable advanced disease was present in 5%. All patients had a baseline ECOG PS of either 0 (54%) or 1 (46%) with similar distribution across the 2 treatment arms. Memorial Sloan Kettering Cancer Center (MSKCC) favorable, intermediate, and poor risk categories were observed respectively, in 24%, 37%, and 39% of patients in the LENVIMA + everolimus arm, and 24%, 38%, and 38% of patients in the everolimus arm.
The major efficacy outcome measure was investigator-assessed PFS evaluated according to RECIST 1.1. Efficacy results from Study 2 are summarized in Table 9 and Figures 2 and 3. The treatment effect of the combination on PFS was supported by a retrospective independent review of radiographs with an observed hazard ratio (HR) of 0.43 (95% CI: 0.24, 0.75) compared with the everolimus arm.
Table 9: Efficacy Results in Renal Cell Carcinoma Per Investigator Assessment (Study 2)
| LENVIMA 18 mg + Everolimus 5 mg (N=51) |
Everolimus 10 mg (N=50) |
|
| Progression-Free Survival (PFS)a | ||
| Number of events, n (%) | 26 (51) | 37 (74) |
| Progressive disease | 21 (41) | 35 (70) |
| Death | 5 (10) | 2 (4) |
| Median PFS in months (95% CI) | 14.6 (5.9, 20.1) | 5.5 (3.5, 7.1) |
| Hazard Ratio (95% CI)b LENVIMA + Everolimus vs Everolimus |
0.37 (0.22, 0.62) | - |
| Overall Survivalc | ||
| Number of deaths, n (%) | 32 (63) | 37 (74) |
| Median OS in months (95% CI) | 25.5 (16.4, 32.1) | 15.4 (11.8, 20.6) |
| Hazard Ratio (95% CI)b LENVIMA + Everolimus vs Everolimus |
0.67 (0.42, 1.08) | - |
| Objective Response Rate (Confirmed) | ||
| Objective response rate, n (%) | 19 (37) | 3 (6) |
| (95% CI) | (24, 52) | (1, 17) |
| Number of complete responses, n (%) | 1 (2) | 0 |
| Number of partial responses (%) | 18 (35) | 3 (6) |
| Tumor assessments were based on RECIST v1.1 criteria for progression but only confirmed responses are included for ORR. Data cutoff date = 13 Jun 2014 CI = confidence interval a Point estimates are based on Kaplan-Meier method and 95% CIs are based on the Greenwood formula using log-log transformation. b Hazard ratio is based on a stratified Cox regression model including treatment as a covariate factor and hemoglobin and corrected serum calcium as strata. c Data cutoff date = 31 Jul 2015 |
||
Figure 2: Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment-Study 2)
 |
Figure 3: Kaplan-Meier Plot of Overall Survival (Study 2)
 |
LENVIMA®
(lehn-veema)
(lenvatinib)
capsules
What is LENVIMA?
LENVIMA is a prescription medicine that is used to treat certain kinds of cancer.
It is not known if LENVIMA is safe and effective in children.
What should I tell my healthcare provider before taking LENVIMA?
Before you take LENVIMA, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and overthe- counter medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of your medicines to show to your healthcare provider and pharmacist when you get a new medicine.
How should I take LENVIMA?
What are the possible side effects of LENVIMA?
LENVIMA may cause serious side effects, including:
The most common side effects of LENVIMA in people treated for thyroid cancer include:
The most common side effects of LENVIMA in people treated for kidney cancer include:
LENVIMA may cause fertility problems in males and females. Talk to your healthcare provider if this is a concern for you.
These are not all the possible side effects of LENVIMA.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800FDA- 1088.
How should I store LENVIMA?
Keep LENVIMA and all medicines out of the reach of children.
General information about the safe and effective use of LENVIMA.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use LENVIMA for a condition for which it was not prescribed. Do not give LENVIMA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about LENVIMA that is written for health professionals.
What are the ingredients in LENVIMA?
Active ingredient: lenvatinib
Inactive ingredients: calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, and talc.
The 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.
This Patient Information has been approved by the U.S. Food and Drug Administration.
