文案整理：Dr.
Jasmine Ding
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to
use LENVIMA® safely and effectively. See full prescribing information for
LENVIMA.
LENVIMA (lenvatinib) capsules, for oral use Initial U.S.
Approval: 2015
---------------------------RECENT MAJOR
CHANGE----------------------------
Warnings and Precautions (5.11) 04/2016
----------------------------INDICATIONS AND
USAGE--------------------------
LENVIMA is a kinase inhibitor indicated for the treatment of
patients with locally recurrent or metastatic, progressive, radioactive
iodine-refractory differentiated thyroid cancer (1).
----------------------DOSAGE AND
ADMINISTRATION----------------------
• Recommended dose: 24 mg orally, once daily (2.1). • In patients with severe renal or hepatic impairment, the
dose is 14 mg once daily (2.1).
---------------------DOSAGE FORMS AND
STRENGTHS---------------------
• Capsules: 4 mg and 10 mg
(3).
-------------------------------CONTRAINDICATIONS------------------------------
None (4).
-----------------------WARNINGS AND
PRECAUTIONS-----------------------
• Hypertension: Control blood pressure prior to treatment with
LENVIMA. Withhold LENVIMA for Grade 3 hypertension despite optimal hypertensive
therapy. Discontinue for life-threatening hypertension (5.1). • Cardiac Failure: Monitor for clinical symptoms or signs of cardiac
decompensation. Withhold LENVIMA for Grade 3 cardiac dysfunction. Discontinue
for Grade 4 cardiac dysfunction (5.2). • Arterial
Thromboembolic Events: Discontinue LENVIMA following an arterial thromboembolic
event (5.3). • Hepatotoxicity: Monitor liver function
tests before initiation of LENVIMA and periodically throughout treatment.
Withhold LENVIMA for Grade 3 or greater liver impairment. Discontinue for
hepatic failure (5.4). • Proteinuria: Monitor for
proteinuria before initiation of, and periodically throughout, treatment with
LENVIMA. Withhold LENVIMA for ≥2 grams of proteinuria
for 24 hours. Discontinue for nephrotic syndrome (5.5). • Renal Failure and Impairment: Withhold LENVIMA for Grade 3 or 4 renal
failure/impairment (5.6). • Gastrointestinal
Perforation and Fistula Formation: Discontinue LENVIMA in patients who develop
gastrointestinal perforation or lifethreatening fistula (5.7). • QT Interval Prolongation: Monitor and correct electrolyte
abnormalities in all patients. Withhold LENVIMA for the development of Grade 3
or greater QT interval prolongation (5.8). • Hypocalcemia: Monitor blood calcium levels at least monthly and replace calcium
as necessary (5.9). • Reversible Posterior
Leukoencephalopathy Syndrome (RPLS): Withhold LENVIMA for RPLS until fully
resolved (5.10). • Hemorrhagic Events: Withhold LENVIMA
for Grade 3 hemorrhage. Discontinue for Grade 4 hemorrhage (5.11). • Impairment of Thyroid Stimulating Hormone Suppression:
Monitor TSH levels monthly and adjust thyroid replacement medication as needed
in patients with DTC (5.12). • Embryofetal Toxicity:
Can cause fetal harm. Advise of potential risk to a fetus and use of effective
contraception (5.13, 8.1, 8.3).
------------------------------ADVERSE
REACTIONS------------------------------
The most common adverse reactions (incidence greater than or
equal to 30%) for LENVIMA are hypertension, fatigue, diarrhea, arthralgia/myalgia,
decreased appetite, weight decreased, nausea, stomatitis, headache, vomiting,
proteinuria, palmar-plantar erythrodysesthesia syndrome, abdominal pain, and
dysphonia (6). To report SUSPECTED ADVERSE REACTIONS, contact Eisai Inc. at
1-877-873-4724 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
-------------------------USE IN SPECIFIC
POPULATIONS--------------------- Lactation: Discontinue breastfeeding (8.2).
See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised:
04/2016
FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE
LENVIMA is indicated for the treatment of patients with
locally recurrent or metastatic, progressive, radioactive iodine-refractory
differentiated thyroid cancer (DTC).
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose 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 (12.3)]. Continue LENVIMA until disease
progression or until unacceptable toxicity occurs. 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. Severe
Renal or Hepatic Impairment 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 Warning and Precaution
(5.4, 5.6), Use in Specific Populations (8.6, 8.7)].
2.2 Dose Modifications Hypertension Assess blood pressure prior to and periodically during treatment. Initiate or
adjust medical management to control blood pressure prior to and during
treatment. Withhold LENVIMA for Grade 3 hypertension
that persists despite optimal antihypertensive therapy; resume at a reduced
dose (see Table 1) when hypertension is controlled at less than or equal to
Grade 2. Discontinue LENVIMA for life-threatening
hypertension. Cardiac dysfunction or hemorrhage Discontinue for a Grade 4 event. Withhold LENVIMA for
development of Grade 3 event until improved to Grade 0 or 1 or baseline. Either resume at a reduced dose (see Table 1) or
discontinue LENVIMA depending on the severity and persistence of the adverse
event. Arterial thrombotic event Discontinue LENVIMA
following an arterial thrombotic event. Renal failure and impairment or
hepatotoxicity Withhold LENVIMA for development of
Grade 3 or 4 renal failure/impairment or hepatotoxicity until resolved to Grade
0 to 1 or baseline. Reference ID: 3921411 Either
resume at a reduced dose (see Table 1) or discontinue LENVIMA depending on the
severity and persistence of renal impairment or hepatotoxicity. Discontinue LENVIMA for hepatic failure. Proteinuria Withhold LENVIMA for ≥2 grams of
proteinuria/24 hours. Resume at a reduced dose (see
Table 1) when proteinuria is <2 gm/24 hours. Discontinue LENVIMA for nephrotic syndrome. Gastrointestinal perforation or
fistula formation Discontinue LENVIMA in patients who
develop gastrointestinal perforation or lifethreatening fistula. QT
prolongation Withhold LENVIMA for the development of
Grade 3 or greater QT interval prolongation. Resume
LENVIMA at a reduced dose (see Table 1) when QT prolongation resolves to Grade
0 or 1 or baseline. Reversible posterior leukoencephalopathy syndrome (RPLS) 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. Manage other adverse
reactions according to the instructions in Table 1. Based on the absence of
clinical experience, there are no recommendations on resumption of dosing in
patients with Grade 4 clinical adverse reactions that resolve. Table 1
Recommended Dose Modifications for Persistent and Intolerable Grade 2 or Grade
3 Adverse Reactions or Grade 4 Laboratory Abnormalitiesa 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 Reference ID: 3921411
3 DOSAGE FORMS AND STRENGTHS
4 mg hard capsule: A yellowish-red body and yellowish-red cap,
marked in black ink with “Є” 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 “Є” on the cap and “LENV 10 mg” on the body. 4 CONTRAINDICATIONS None.
5 WARNINGS AND PRECAUTIONS 5.1 Hypertension In Study 1
hypertension was reported in 73% of LENVIMA-treated patients and 16% of
patients in the placebo group [see Adverse Reactions (6.1)]. 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. 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
(2.2)]. 5.2 Cardiac Dysfunction In Study 1, 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. 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 (2.2)]. 5.3 Arterial Thromboembolic Events In Study 1,
arterial thromboembolic events were reported in 5% of LENVIMA-treated patients
and 2% of patients in the placebo group. The incidence of arterial
thromboembolic Reference ID: 3921411 events of Grade 3 or greater was 3% in
LENVIMA-treated patients and 1% in the placebo 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 (2.2)]. 5.4 Hepatotoxicity In
Study 1, 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. Across clinical
studies in which 1108 patients received LENVIMA, hepatic failure (including
fatal events) was reported in 3 patients and acute hepatitis was reported in 1
patient. 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 (2.2)]. 5.5 Proteinuria In Study 1, proteinuria was reported in
34% of LENVIMA-treated patients and 3% of patients in the placebo group [see
Adverse Reactions (6.1)]. The incidence of Grade 3 proteinuria in
LENVIMA-treated patients was 11% compared to none in the placebo group. 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 (2.2)]. 5.6 Renal Failure and Impairment In Study 1, 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. The primary risk factor for severe renal impairment in LENVIMA-treated
patients was dehydration/hypovolemia due to diarrhea and vomiting. 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 (2.2)].
5.7 Gastrointestinal Perforation and Fistula Formation In Study
1, events of gastrointestinal perforation or fistula were reported in 2% of
LENVIMA-treated patients and 0.8% of patients in the placebo group. Discontinue
LENVIMA in patients who develop gastrointestinal perforation or lifethreatening
fistula [see Dosage and Administration (2.2)]. 5.8 QT Interval Prolongation In
Study 1, 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 Grade 3 or greater was 2% in LENVIMA-treated patients compared
to no reports in the placebo group. 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. Monitor and correct electrolyte abnormalities in all
patients. Withhold LENVIMA for the development of Grade 3 or greater QT
interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation
resolves to Grade 0 or 1 or baseline [see Dosage and Administration (2.2),
Clinical Pharmacology (12.2)]. 5.9 Hypocalcemia In Study 1, 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 [see Adverse Reactions (6.1)]. 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 (2.2)]. 5.10 Reversible Posterior Leukoencephalopathy
Syndrome Across clinical studies in which 1108 patients received LENVIMA, there
were 3 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 (2.2)]. 5.11 Hemorrhagic Events In Study 1, hemorrhagic
events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group.
However, the incidence of Grade 3-5 hemorrhage was similar between arms at 2%
and 3%, respectively. 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. Reference ID: 3921411 Across
clinical studies in which 1108 patients received LENVIMA, Grade 3 or greater
hemorrhage was reported in 2% of patients. In Study 1, there was 1 case of
fatal intracranial hemorrhage among 16 patients who received lenvatinib and had
CNS metastases at baseline. 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 (2.2)]. 5.12 Impairment of Thyroid Stimulating Hormone Suppression
LENVIMA impairs exogenous thyroid suppression. In Study 1, 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. Monitor TSH levels
monthly and adjust thyroid replacement medication as needed in patients with
DTC. 5.13 Embryofetal 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 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 (8.1, 8.3)]. 6 ADVERSE REACTIONS The following adverse
reactions are discussed elsewhere in the label: 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)] Proteinuria [see Warnings and Precautions (5.5)] Reference
ID: 3921411 Renal Failure and Impairment [see
Warnings and Precautions (5.6)] Gastrointestinal
Perforation and Fistula Formation [see Warnings and Precautions (5.7)] QT Interval Prolongation [see Warnings and Precautions
(5.8)] Hypocalcemia [see Warnings and Precautions
(5.9)] Reversible Posterior Leukoencephalopathy
Syndrome [see Warnings and Precautions (5.10)] Hemorrhagic Events [see Warnings and Precautions (5.11)] Impairment of Thyroid Stimulating Hormone Suppression [see Warnings and
Precautions (5.12)] 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. Safety data obtained in 1108 patients with advanced solid tumors who
received LENVIMA as a single agent across multiple clinical studies was used to
further characterize risks of serious adverse drug reactions [see Warnings and
Precautions (5.4, 5.10, 5.11)]. The median age was 60 years (range 21-89
years). The dose range was 0.2 mg to 32 mg. The median duration of exposure in
the entire population 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 (14)]. 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 2
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.
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. Reference ID: 3921411
7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on Lenvatinib 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 (12.3)].
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy Risk Summary Based on its mechanism of action and
data from animal reproduction studies, LENVIMA can cause fetal harm when
administered to a pregnant woman [see Clinical Pharmacology (12.1)]. In animal
reproduction studies, oral administration of lenvatinib during organogenesis at
doses below the recommended human 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. Data 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 doserelated 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 postimplantation loss, including 1 fetal
death, was also observed. Lenvatinib was abortifacient in rabbits, resulting in
late abortions in approximately one-third of the rabbits treated at a dose
level of 0.5 mg/kg/day (approximately 0.5 times the recommended clinical dose
of 24 mg based on BSA). Reference ID: 3921411 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 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. Data 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. 8.3 Females and Males of Reproductive Potential Contraception Based on
its mechanism of action, LENVIMA can cause fetal harm when administered to a
pregnant woman [see Use in Specific Populations (8.1)]. Advise females of
reproductive potential to use effective contraception during treatment with
LENVIMA and for at least 2 weeks following completion of therapy. Infertility
Females LENVIMA may result in reduced fertility in females of reproductive
potential [see Nonclinical Toxicology (13.1)]. Males LENVIMA may result in
damage to male reproductive tissues leading to reduced fertility of unknown
duration [see Nonclinical Toxicology (13.1)].
8.4 Pediatric Use The safety and effectiveness of LENVIMA in
pediatric patients have not been established. Juvenile Animal Data Daily oral
administration of lenvatinib mesylate to juvenile rats for 8 weeks starting on
postnatal day 21 (approximately equal to a human pediatric age of 2 years)
resulted in growth retardation (decreased body weight gain, decreased food
consumption, and decreases in the width and/or length of the femur and tibia)
and secondary delays in physical development and reproductive organ immaturity
at doses greater than or equal to 2 mg/kg (approximately 1.2 to 5 times the
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. Reference ID: 3921411
8.5 Geriatric Use 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.
8.6 Renal Impairment 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 taken once daily. Patients with end stage
renal disease were not studied [see Dosage and Administration (2.1), Warnings
and Precautions (5.6), Clinical Pharmacology (12.3)].
8.7 Hepatic Impairment 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 taken once daily [see Dosage
and Administration (2.1), Clinical Pharmacology (12.3)].
10 OVERDOSAGE
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 (12.3)].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.
11 DESCRIPTION LENVIMA, a kinase inhibitor, is the mesylate salt
of lenvatinib. Its chemical name is 4-[3 chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide
methanesulfonate. The molecular formula is C21H19ClN4O4 • CH4O3S, and the molecular weight of the mesylate salt is 522.96. The chemical
structure of lenvatinib mesylate is: Lenvatinib mesylate is a white to pale
reddish yellow powder. It is slightly soluble in water and practically
insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of
lenvatinib mesylate is 5.05 at 25°C. The partition
coefficient (log P value) is 3.30. Each LENVIMA capsule contains lenvatinib
mesylate equivalent to 4 mg or 10 mg of lenvatinib, and the following inactive
ingredients: calcium carbonate, mannitol, microcrystalline cellulose,
hydroxypropylcellulose, hydroxypropyl cellulose (type H), and Reference ID:
3921411 talc. The hypromellose capsule shell contains titanium dioxide, ferric
oxide yellow, and ferric oxide red. The printing ink contains shellac, black
iron oxide, potassium hydroxide, and propylene glycol.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Lenvatinib is a 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.
12.2 Pharmacodynamics Cardiac Electrophysiology 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 Study 1 [see Warnings and Precautions
(5.8)].
12.3 Pharmacokinetics Absorption: 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). Distribution: 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). Elimination: Plasma concentrations declined bi-exponentially
following Cmax. The terminal elimination half-life of lenvatinib was
approximately 28 hours. Reference ID: 3921411 Metabolism: 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. Excretion: 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.
Specific Populations: Renal Impairment The pharmacokinetics of lenvatinib
following a single 24 mg dose were evaluated in subjects with mild (CLcr 60-89
mL/min), moderate (CLcr 30-59 mL/min), 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 (2.1), Warnings and Precautions
(5.6), Use in Specific Populations (8.6)]. Hepatic Impairment 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 (2.1), Use in Specific
Populations (8.7)]. Effects of Age, Sex, and Race Based on a population PK
analysis, age, sex, and race did not have a significant effect on apparent
clearance (Cl/F) of lenvatinib. Drug Interaction Studies Effect of Other Drugs
on 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. Reference ID: 3921411 Effect of Lenvatinib on Other
Drugs 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.
13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis,
Impairment of Fertility Carcinogenicity studies have not been conducted with
lenvatinib. Lenvatinib mesylate was not mutagenic in the in vitro bacterial
reverse mutation (Ames) assay. Lenvatinib was not clastogenic in the in vitro
mouse lymphoma thymidine kinase assay or the in vivo rat micronucleus assay. No
specific studies with lenvatinib have been conducted in animals to evaluate the
effect on fertility; however, results from general toxicology studies in rats,
monkeys, and dogs suggest there is a potential for lenvatinib to impair
fertility. Male dogs exhibited testicular hypocellularity of the seminiferous
epithelium and desquamated seminiferous epithelial cells in the epididymides at
lenvatinib exposures approximately 0.02 to 0.09 times the 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.
14 CLINICAL STUDIES
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
Reference ID: 3921411 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 4 and
Figure 1). Upon confirmation of progression, 109 (83%) patients randomly
assigned to placebo crossed over to receive open-label LENVIMA.
16 HOW SUPPLIED/STORAGE AND HANDLING
LENVIMA 4 mg capsules are supplied as hard hypromellose capsules
with yellowish-red body and yellowish-red cap, marked in black ink with “Є” on the cap and “LENV 4 mg” on the body. LENVIMA 10 mg capsules are supplied as hard
hypromellose capsules with yellow body and yellowish-red cap, marked in black
ink with “Є” 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: NDC 62856-724-30:
24 mg, carton with 6 cards NDC 62856-724-05 (ten 10 mg capsules and five 4 mg
capsules per card). NDC 62856-720-30: 20 mg, carton
with 6 cards NDC 62856-720-05 (ten 10 mg capsules per card). NDC 62856-714-30: 14 mg, carton with 6 cards NDC 62856-714-05 (five 10 mg
capsules and five 4 mg capsules per card). NDC
62856-710-30: 10 mg, carton with 6 cards NDC 62856-710-05 (five 10 mg capsules
per card). Store at 25°C (77°F);
excursions permitted to 15–30°C
(59–86°F) [see USP Controlled
Room Temperature]. Reference ID: 3921411
17 PATIENT COUNSELING INFORMATION Advise the patient to read the
FDA-approved patient labeling (Patient Information). Hypertension: Advise
patients to undergo regular blood pressure monitoring and to contact their
health care provider if blood pressure is elevated [see Warnings and
Precautions (5.1)]. Cardiac Dysfunction: Advise patients that LENVIMA can cause
cardiac dysfunction and to immediately contact their healthcare provider if
they experience any clinical symptoms of cardiac dysfunction such as shortness
of breath or swelling of ankles [see Warnings and Precautions (5.2)]. Arterial
Thrombotic Events 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 (5.3)]. Hepatotoxicity:
Advise patients that they will need to undergo lab tests to monitor for liver
function and to report any new symptoms indicating hepatic toxicity or failure
[see Warnings and Precautions (5.4)]. Proteinuria and Renal Failure/Impairment:
Advise patients that they will need to undergo regular lab tests to monitor for
kidney function and protein in the urine [see Warnings and Precautions (5.5,
5.6)]. Gastrointestinal perforation or fistula formation: 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 (5.7)]. Hemorrhagic Events: Advise patients that LENVIMA can
increase the risk for bleeding and to contact their health care provider for
bleeding or symptoms of severe bleeding [see Warnings and Precautions (5.11)].
Embryofetal Toxicity: 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 (5.13), Use in Specific Populations
(8.1)]. 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 (8.3)]. Reference ID: 3921411
Lactation: Advise nursing women to discontinue breastfeeding during treatment
with LENVIMA [see Use in Specific Populations (8.2)].
