Lenvaxen 4 mg
Lenvaxen 4 mg Details:
COMPOSITION
LENVAXEN 4 capsules: Each capsule contains Lenvatinib
Mesylate INN equivalent to Lenvatinib 4 mg.
INDICATIONS AND USAGE
Lenvatinib is indicated as monotherapy for the treatment of
adult patients with progressive, locally advanced or metastatic,
differentiated (papillary/follicular/Hirthle cell) thyroid carcino-
ma (DTC), refractory to radioactive iodine (RAI). Lenvatinib is
indicated as monotherapy for the treatment of adult patients
with advanced or unresectable hepatocellular carcinoma
(HCC) who have received no prior systemic therapy.
DOSAGE AND ADMINISTRATION
Recommended Dosage for Differentiated Thyroid Cancer
(DTC)
The recommended dosage of lenvatinib is 24 mg orally once
daily until disease progression or until unacceptable toxicity.
Recommended Dosage for Renal Cell Carcinoma (RCC)
The recommended dosage of lenvatinib is 18 mg in combina-
tion with 5 mg everolimus orally once daily until disease
progression or until unacceptable toxicity.
Refer to everolimus prescribing information for recommended
everolimus dosing information.
Recommended Dosage for Hepatocellular Carcinoma
(HCC)
The recommended dosage of lenvatinio is based on actual
body weight, 12 mg for patients greater than or equal to 60 kg
or 8 mg for patients less than 60 kg. Take lenvatinib orally once
daily until disease progression or until unacceptable toxicity.
Reduce the dose for certain patients with renal or hepatic
impairment. Take lenvatinib once daily, with or without food, 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.
DOSAGE MODIFICATION
Management of some adverse reactions may require dose
interruption, adjustment, or discontinuation of lenvatinib
therapy. Mild to moderate adverse reactions (e.g., Grade 1 or
2) generally do not warrant interruption of lenvatinib, unless
intolerable to the patient despite optimal management. Details
for monitoring, dose adjustment and discontinuation are provid-
ed in Table 1 & 2.
Table 1 Dose modifications from recommended lenvatinib
daily dose in DTC patients*
Dose level Dally dose Number of capsules
Recommended | 24 mg orally once daily | Two 10 mg capsules
daily dose plus one 4 mg capsule
First dose 20 mg orally once daily | Two 10 mg capsules
reduction
Second dose | 14 mg orally once daily | One 10 mg capsule
reduction plus one 4 mg capsule
Third dose 10 mg orally once daily* | One 10 mg capsule
reduction
* Further dose reductions should be considered on an individual
patient basis as limited data are available for doses below 10 mg.
Table 2 Dose modifications from recommended lenvatinib
daily dose in HCC patients
260 kg BW <60 kg BW
12 mg (three 4 8 mg (two 4 mg
Starting Dose mg capsules capsules orally
orally once daily} | once daily)
Persistent and Intolerable Grade 2 or Grade 3 Toxicitles*
Adverse Modification | Adjusted Dose | Adjusted Dose?
Reaction (260 kg BW) (<60 kg BW)
First Interrupt until] 8 mg (two4mg_ | 4mg (one 4 mg
occurrence’ | resolvedto | capsules) orally | capsule) orally
Grade 0-1 or | once daily once daily
baselined
Second Interrupt until] 4 mg (one 4mg_ | 4 mg (one 4 mg
occurrence | resolvedto | capsule) orally | capsule) orally
(same Grade 0-1 or | once daily every other day
reaction or | baseline’
new reaction)
Third Interrupt until! 4 mg (one 4mg_ | Discontinue
occurrence | resolvedto | capsule) orally
(same Grade 0-1 or | every other day
reaction or | baseline®
new reaction)
Life-threatening toxicities (Grade 4): Discontinue®
a. Initiate medical management for nausea, vomiting, or diarrhoea
prior to interruption or dose reduction.
b. Reduce dose in succession based on the previous dose level
(12 mg, 8 mg, 4 mg or 4 mg every other day).
c, Haematologic toxicity or proteinuria-no dose adjustment
required for first occurrence.
d. For haematologic toxicity, dosing can restart when resolved to
Grade 2; proteinuria, resume when resolves to less than 29/24
hours
e. Excluding laboratory abnormalities judged to be nonlife-threat
ening, which should be managed as Grade 3.
Elderly population
DTC
Patients of age >75 years, of Asian race, with comorbidities
(such as hypertension, and hepatic or renal impairment), or
body weight below 60 kg appear to have reduced tolerability to
lenvatinib. All patients other than those with severe hepatic or
renal impairment should initiate treatment at the recommended
24 mg dose, following which the dose should be further
adjusted on the basis of individual tolerability.
HCC
Patients 275 years, of white race or female sex or those with
worse baseline hepatic impairment (Child-Pugh A score of 6
compared to score of 5) appear to have reduced tolerability to
lenvatinib.
HCC patients other than those with moderate and severe
hepatic impairment or severe renal impairment should initiate
treatment at the recommended starting dose of 8 mg (two 4mg
capsules) for body weight < 60 kg and 12 mg (three 4 mg
capsules) for body weight 2 60 kg, following which the dose
should be further adjusted on the basis of individual tolerability.
Patlents with hypertension
Blood pressure should be well controlled prior to treatment with
lenvatinib and should be regularly monitored during treatment.
Patlents with hepatic Impairment
DTC
No adjustment of starting dose is required on the basis of
hepatic function in patients with mild (Child-Pugh A) or moder-
ate (Child-Pugh B) hepatic impairment. In patients with severe
(Child-Pugh C) hepatic impairment, the recommended starting
dose is 14 mg taken once daily. Further dose adjustments may
be necessary on the basis of individual tolerability.
HCC
In the patient populations enrolled in the HCC study no dose
adjustments were required on the basis of hepatic function in
those patients who had mild hepatic impairment (Child-Pugh
A). The available very limited data are not sufficient to allow for
a dosing recommendation for HCC patients with moderate
hepatic impairment (Child-Pugh B). Close monitoring of overall
safety is recommended in these patients. Lenvatinib has not
been studied in patients with severe hepatic imparement
(Child-Pugh C) and is not recommended for use in these
patients.
Svereot
Patlents with renal Impairment
DTC
No adjustment of starting dose is required on the basis of renal
function in patients with mild or moderate renal impairment. In
patients with severe renal impairment, the recommended
starting dose is 14 mg taken once daily. Further dose
adjustments may be necessary based on individual tolerability.
Patients with end-stage renal disease were not studied,
therefore the use of lenvatinib in these patients is not recom-
mended.
HCC
No dose adjustments are required on the basis of renal function
in patients with mild or moderate renal impairment. The
available data do not allow for a dosing recommendation for
patients with HCC and severe renal impairment.
CONTRAINDICATION
Hypersensitivity to the active substance or to any of the
excipients.
WARNINGS AND PRECAUTIONS
Hypertension
Hypertension has been reported in patients treated with lenvati-
nib, usually occurring early in the course of treatment. Blood
pressure (BP) should be well controlled prior to treatment with
lenvatinib and if patients are known to be hypertensive, they
should be on a stable dose of antihypertensive therapy for at
least 1 week prior to treatment with lenvatinib. Serious compli-
cations of poorly controlled hypertension, including aortic
dissection, have been reported. The early detection and
effective management of hypertension are important to
minimise the need for lenvatinib dose interruptions and
reductions. Antihypertensive agents should be started as soon
as elevated BP is confirmed. BP should be monitored after 1
week of treatment with lenvatinib, then every 2 weeks for the
first 2 months, and monthly thereafter.
Cardiac Dysfunction
Serious and fatal cardiac dysfunction can occur with lenvatinib.
Across clinical trials in 799 patients with DTC, RCC or HCC,
Grade 3 or higher cardiac dysfunction (including cardiomyopa-
thy, left or right ventricular dysfunction, congestive heart failure,
cardiac failure, ventricular hypokinesia, or decrease in left or
right ventricular ejection fraction of more than 20% from
baseline) occurred in 3% of lenvatinib-treated patients. Monitor
patients for clinical symptoms or signs of cardiac dysfunction.
Withhold and resume at a reduced dose upon recovery or
permanently discontinue lenvatinib based on severity.
Arterlal Thromboembollc Events
Among patients receiving lenvatinib or lenvatinib with everolim-
us, arterial thromboembolic events of any severity occurred in
2% of patients in Study 205 (RCC), 2% of patients in REFLECT
{HCC) and 5% of patients in SELECT (DTC). Grade 3 to 5
arterial thromboembolic events ranged from 2% to 3% across
all clinical trials. Permanently discontinue lenvatinib following
an arterial thrombotic event. The safety of resuming lenvatinib
after an arterial thromboembolic event has not been
established and lenvatinib has not been studied in patients who
have had an arterial thromboembolic event within the previous
6 months.
Hepatotoxicity
Across clinical studies enrolling 1327 lenvatinib-treated
patients with malignancies other than HCC, serious hepatic
adverse reactions occurred in 1.4% of patients. Fatal events,
including hepatic failure, acute hepatitis and hepatorenal
syndrome, occurred in 0.5% of patients. In REFLECT (HCC),
hepatic encephalopathy (including hepatic encephalopathy,
encephalopathy, metabolic encephalopathy, and hepatic
coma) occurred in 8% of lenvatinib-treated patients and 3% of
sorafenib-treated patients. Grade 3 to 5 hepatic encephalopa-
thy occurred in 5% of lenvatinib-treated patients and 2% of
sorafenib-treated patients. Grade 3 to 5 hepatic failure
occurred in 3% of lenvatinib-treated patients and 3% of
sorafenib-treated patients. Two percent of patients discontin-
ued lenvatinib and 0.2% discontinued sorafenib due to hepatic
encephalopathy and 1% of patients discontinued lenvatinib or
sorafenib due to hepatic failure. Monitor liver function prior to
initiating lenvatinib, then every 2 weeks for the first 2 months,
and at least monthly thereafter during treatment.
Renal Failure or Impairment
Serious including fatal renal failure or impairment can occur
with lenvatinib. Renal impairment occurred in 14% of patients
receiving lenvatinib in SELECT (DTC) and in 7% of patients
receiving lenvatinib in REFLECT (HCC). Grade 3 to 5 renal
failure or impairment occurred in 3% (DTC) and 2% (HCC) of
patients, including 1 fatality in each study. In Study 205 (RCC),
renal impairment or renal failure occurred in 18% of patients
receiving lenvatinib with everolimus, including Grade 3 in 10%
of patients. Initiate prompt management of diarrhea or dehydra-
tion/hypovolemia. Withhold and resume at a reduced dose
upon recovery or permanently discontinue lenvatinib for renal
failure or impairment based on severity.
Proteinuria
Proteinuria occurred in 34% of lenvatinib-treated patients in
SELECT (DTC) and in 26% of lenvatinib-treated patients in
REFLECT (HCC). Grade 3 proteinuria occurred in 11% and 6%
in SELECT and REFLECT, respectively. In Study 205 (RCC),
proteinuria occurred in 31% of patients receiving lenvatinib with
everolimus and 14% of patients receiving everolimus. Grade 3
proteinuria occurred in 8% of patients receiving lenvatinib with
everolimus compared to 2% of patients receiving everolimus.
Monitor for proteinuria prior to initiating lenvatinib and periodi-
cally during treatrnent. If urine dipstick proteinuria greater than
or equal to 2+ is detected, obtain a 24-hour urine protein.
Withhold and resume at a reduced dose upon recovery or
permanently discontinue lenvatinib based on severity.
Diarrhea
Of the 737 patients treated with lenvatinib in SELECT (DTC) and
REFLECT (HCC), diarrhea occurred in 49% of patients,
including Grade 3 in 6%. In Study 205 (RCC), diarrhea
occurred in 81% of patients receiving lenvatinib with everolim-
us, including Grade 3 in 19%. Diarrhea was the most frequent
cause of dose interruption/reduction and diarrhea recurred
despite dose reduction. Promptly initiate management of
diarrhea. Withhold and resume at a reduced dose upon
recovery or permanently discontinue lenvatinidb based on
severity.
Fistula Formation and Gastrointestinal Perforation
Of 799 patients treated with lenvatinib or lenvatinib with everoli-
mus in select (DTC), Study 205 (RCC) and REFLECT (HCC),
fistula or gastrointestinal perforation occurred in 2%. Perma-
nently discontinue lenvatinib in patients who develop gastroin-
testinal perforation of any severity or Grade 3 or 4 fistula.
QT Interval Prolongation
In SELECT (DTC), QT/QTc interval prolongation occurred in 9%
of lenvatinib-treated patients and QT interval prolongation of
>500 ms occurred in 2%. In Study 205 (RCC), QTc interval
increases of >60 ms occurred in 11% of patients receiving
lenvatinib with everolimus and QTc interval >500 ms occurred
in 6%. In REFLECT (HCC), QTc interval increases of >60 ms
occurred in 8% of lenvatinib-treated patients and QTc interval
>500 ms occurred in 2%. Monitor and correct electrolyte
abnormalities at baseline and periodically during treatment.
Hypocalcemia
In SELECT {DTC), Grade 3 to 4 hypocalcemia occurred in 9%
of patients receiving lenvatinib. In 65% of cases, hypocalcemia
improved or resolved following calcium supplementation, with
or without dose interruption or dose reduction. In Study 205
(RCC), Grade 3 to 4 hypocalcemia occurred in 6% of patients
treated with lenvatinib with everolimus. In REFLECT (HCC),
Grade 3 hypocalcemia occurred in 0.8% of lenvatinib-treated
patients Monitor blood calcium levels at least monthly and
replace calcium as necessary during treatment. Withhold and
resume at reduced dose upon recovery or permanently discon-
tinue lenvatinib depending on severity.
——?
Lenvaxen
Lenvatinib 4 mg & 10 mg
Reversible Posterlor Leukoencephalopathy Syndrome
Across clinical studies of 1823 patients who received lenvatinib
as a single age, reversible posterior leukoencephalopathy
syndrome (RPLS) occurred in 0.3%. Confirm the diagnosis of
RPLS with magnetic resonance imaging. Withnold and resume at
a reduced dose upon recovery or permanently discontinue
lenvatinib depending on severity and persistence of neurologic
symptoms.
Hemorrhagle Events
Serious including fatal hemorrhagic events can occur with
lenvatinib. Across SELECT (DTC), Study 205 (RCC) and
REFLECT (HCC), hemorrhagic events of any grade occurred in
29% of the 799 patients treated with lenvatinib as a single agent
or in combination with everolimus. The most frequently reported
hemorrhagic events (all grades and occurring in at least 5% of
patients) were epistaxis and hematuria. In SELECT, Grade 3 to 5
hemorrhage occurred in 2% of patients receiving lenvatinib,
including 1 fatal intracranial hemorrhage among 16 patients who
received lenvatinio and had CNS metastases at baseline. In
Study 205, Grade 3 to 5 hemorrhage occurred in 8% of patients
receiving lenvatinib with everolimus, including 1 fatal cerebral
hemorrhage. In REFLECT, Grade 3 to 5 hemorrhage occurred in
5% of patients receiving lenvatinib, including 7 fatal hemorrhagic
evens.
Impalrment of Thyrold Stimulating Hormone Suppression/
Thyroid Dysfunction
Lenvatinib impairs exogenous thyroid suppression. In SELECT
(DTC), 88% of all patients had a baseline thyroid stimulating
hormone (TSH) level <0.5 mU/L. In those patients with a normal
TSH at baseline, elevation of TSH level >0.5 mU/L was observed
post baseline in 57% of lenvatinib-treated patients. Grade 1 or 2
hypothyroidism occurred in 24% of patients receiving lenvatinib
with everolimus in Study 205 (RCC) and in 21% of patients
receiving lenvatinib in REFLECT (HCC).
Wound Heallng Complications
Wound healing complications, including fistula formation and
wound dehiscence, can occur with lenvatinib. Withhold
lenvatinib for at least 6 days prior to scheduled surgery. Resume
lenvatinib after surgery based on clinical judgment of adequate
wound healing. Permanently discontinue lenvatinib in patients
with wound healing complications.
Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal
reproduction studies, lenvatinib can cause fetal harm when
administered to a pregnant woman. In animal reproduction
studies, oral administration of lenvatinib during organogenesis at
doses below the recommended clinical doses resulted in
embryotoxicity, fetotoxicity, and teratogenicity in rats and
rabbits. Advise pregnant women of the potential risk to a fetus.
Advise females of reproductive potential to use effective
contraception during treatment with lenvatinib and for at least 30
days after the last dose.
SIDE EFFECTS
Hypertension, Cardiac Dysfunction, Arterial Thromboembolic
Events, Hepatotoxicity, Renal Failure and Impairment Protein-
uria, Diarrhea, Fistula Formation and Gastrointestinal Perforation,
QT Interval Prolongation, Hypocalcemia, Reversible Posterior
Leukoencephalopathy Syndrome Hemorrhagic Events,
Impairment of Thyroid Stimulating Hormone Suppression/Thy-
roid Dysfunction, Wound Healing Complications.
DRUG INTERACTIONS
Chemotherapeutic agents
Concomitant administration of lenvatinib, carboplatin, and
paclitaxel has no significant impact on the pharmacokinetics of
any of these 3 substances.
Effect of Lenvatinib on other medicine
A clinical drug-drug interaction (DDI) study in cancer patients
showed that plasma concentrations of midazolam (a sensitive
CYP3A and Pgp substrate) were not altered in the presence of
lenvatinib. No significant drug-drug interaction is therefore
expected between lenvatinib and other CYP3A4/Pgp substrates.
Oral contraceptives
It is currently unknown whether lenvatinib may reduce the
effectiveness of hormonal contraceptives, and therefore women
using oral hormonal contraceptives should add a barrier method.
USE IN SPECIFIC POPULATION
Women of childbearing potential
Women of childbearing potential should avoid becoming pregnant
and use highly effective contraception while on treatment with
lenvatiniob and for at least one month after finishing treatment. It is
currently unknown whether lenvatinib may reduce the effective-
ness of hormonal contraceptives, and therefore women using oral
hormonal contraceptives should add a barrier method.
Pregnancy
There are no data on the use of lenvatinib in pregnant women.
Lenvatinib was embryotoxic and teratogenic when administered
to rats and rabbits. Lenvatinib should not be used during
pregnancy unless clearly necessary and after a careful consid-
eration of the needs of the mother and the risk to the foetus.
Breast-feeding
It is not known whether lenvatinib is excreted in human milk.
Lenvatinib and its metabolites are excreted in rat milk. A risk to
newborns or infants cannot be excluded and, therefore,
lenvatinib is contraindicated during breast-feeding.
Fertility
Effects in humans are unknown. However, testicular and ovarian
toxicity has been observed in rats, dogs, and monkeys.
Patients with Renal Impairment
The pharmacokinetics of lenvatinib following a single 24 mg
dose were evaluated in subjects with mild (CLer 60-89 mL/min),
moderate (CLer 30-59 mL/min), or severe (CLer <30 mL/min}
renal impairment, and compared to healthy subjects. Subjects
with end stage renal disease were not studied. The AUC(oinf) for
subjects with renal impairment were similar compared to those
for healthy subjects.
Patients with Hepatic Impairment
The pharmacokinetics of lenvatinib following a single 10 mg
dose were evaluated in subjects with mild (Child-Pugh A} or
moderate (Child-Pugh B) hepatic impairment. The pharmacoki-
netics 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
AUC(oini) of lenvatinib for subjects with mild, moderate, and
severe hepatic impairment were 119%, 107%, and 180%,
respectively. Apparent oral clearance of lenvatinib in patients
with HCC and mild hepatic impairment was similar to patients
with HCC and moderate hepatic impairment.
Paediatric Population
Paediatric patients have not been studied.
OVERDOSE
The highest doses of lenvatinib studied clinically were 32 mg
and 40 mg per day. Accidental medication errors resulting in
single doses of 40 to 48 mg have occurred in clinical trials. The
most frequently observed adverse drug reactions at these doses
were hypertension, nausea, diarrhoea, fatigue, stomatitis,
proteinuria, headache, and aggravation of PPE. There have also
been reports of overdose with lenvatinib involving single
administrations of 6 to 10 times the recommended daily dose.
These cases were associated with adverse reactions consistent
with the known safety profile of lenvatinib (i.e., renal and cardiac
failure), or were without adverse reactions.
DESCRIPTION
Lenvatinib, a kinase inhibitor, is the mesylate salt of lenvatinib. Its
chemical name is 4-[3chloro-4-(N’-cyclopropylureido) phenoxy]
Svereot
-7-methoxyquinoline-6-carboxamide methanesulfonate. The
molecular formula is C2iH1gCIN4O4.CH403S, and the molecular
weight of the mesylate salt is 522.96. The chemical structure of
lenvatinib mesylate is:
H3CO. Ny
ea
ie)
CA
c) HH
Lenvatinib mesylate is a white to pale reddish yellow powder. It
is slightly soluble in water & 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.
H2N
- HgC-SOsH
CLINICAL PHARMACOLOGY
Mechanism of Action
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that
selectively inhibits the kinase activities of vascular endothelial
growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR),
and VEGFR3 (FLT4), in addition to other proangiogenic and
oncogenic pathway-related RTKs including fibroblast growth
factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived
growth factor (PDGF) receptor PDGFRa, KIT, and RET.
In addition, lenvatinib had selective, direct antiproliferative
activity in hepatocellular cell lines dependent on activated FGFR
signalling, which is attributed to the inhibition of FGFR signalling
by lenvatinib.
Although not studied directly with lenvatinib, the mechanism of
action (MOA) for hypertension is postulated to be mediated by
the inhibition of VEGFR2 in vascular endothelial cells. Similarly,
although not studied directly, the MOA for proteinuria is postulat-
ed to be mediated by downregulation of VEGFR1 and VEGFR2 in
the podocytes of the glomerulus.
The mechanism of action for hypothyroidism is not fully elucidated.
Pharmacokinetic properties
Pharmacokinetic parameters of lenvatinib have been studied in
healthy adult subjects, adult subjects with hepatic impairment,
renal impairment, and solid tumours.
Absorption
Lenvatinib is rapidly absorbed after oral administration with Tmax
typically observed from 1 to 4 hours postdose. Food does not
affect the extent of absorption but slows the rate of absorption.
When administered with food to healthy subjects, peak plasma
concentrations are delayed by 2 hours. Absolute bioavailability
has not been determined in humans; however, data from a
mass-balance study suggest that it is in the order of 85%.
Lenvatinib exhibited good oral bioavailability in dogs (70.4%)
and monkeys (78.4%).
Distribution
{n vitro binding of lenvatinib to human plasma proteins is high
and ranged from 98% to 99% (0.3 - 30 yg/mL, mesylate). This
binding was mainly to aloumin with minor binding to at-acid
glycoprotein and y-globulin.
n_ vitro, the lenvatinib blood-to-plasma concentration ratio
ranged from 0.589 to 0.608 (0.1 — 10 g/mL, mesylate).
Lenvatinib is a substrate for P-gp and BCRP. Lenvatinib is not a
substrate for OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2,
MATE1, MATE2-K or the bile salt export pump BSEP.
In patients, the median apparent volume of distribution (Vz/F) of
the first dose ranged from 50.5 L to 92 L and was generally
consistent across the dose groups from 3.2 mg to 32 mg. The
analogous median apparent volume of distribution at
steady-state (Vz/Fss) was also generally consistent and ranged
from 43.2 L to 121L.
Biotransformation
In vitro, cytochrome P450 3A4 was demonstrated as the
predominant (>80%) isoform involved in the P450-mediated
metabolism of lenvatinib. However, in vivo data indicated that
non-P450-mediated pathways contributed to a_ significant
portion of the overall metabolism of lenvatinib. Consequently, in
vivo, inducers and inhibitors of CYP 3A4 had a minimal effect on
lenvatinib exposure.
In human liver microsomes, the demethylated form of lenvatinib
(M2) was identified as the main metabolite. M2' and M3’, the
major metabolites in human faeces, were formed from M2 and
lenvatinib, respectively, by aldehyde oxidase.
In plasma samples collected up to 24 hours after administration,
lenvatinib constituted 97% of the radioactivity in plasma
radiochromatograms while the M2 metabolite accounted for an
additional 2.5%. Based on AUCo - in), lenvatinib accounted for
60% and 64% of the total radioactivity in plasma and blood,
respectively.
Elimination
Plasma concentrations decline bi-exponentially following Cmax.
The mean terminal exponential half-life of lenvatinib is approxi-
mately 28 hours.
Following administration of radiolabelled lenvatinib to 6 patients
with solid tumours, approximately two-thirds and one-quarter of
the radiolabel were eliminated in the faeces and urine, respec-
tively. The M3 metabolite was the predominant analyte in excreta
(~17% of the dose), followed by M2' (~11% of the dose) and M2
(~4.4 of the dose)
NONCLINICAL TOXICOLOGY
Carcinogenesis, mutagenesis, impairment of fertility carcinoge-
nicity studies have not been conducted with lenvatinib. Lenvati-
nib 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 AUC at the recommended
clinical dose of 24 mg once daily. 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 AUC at the recommended clinical dose of
24 mg once daily, respectively. In addition, in monkeys, a
decreased incidence of menstruation was reported at lenvatinib
exposures lower than those observed in humans at the
recommended clinical dose of 24 mg once daily.
PHARMACEUTICAL INFORMATION
Storage Conditions
Store in a cool and dry place. Do not store above 30°C. Do not
take LENVAXEN if it is suspected of having been exposed to
temperatures greater than 40° C or 104° F.
Keep LENVAXEN out of reach and sight of the children.
Dispended only in original container.
HOW SUPPLIED
LENVAXEN 4 capsules: Each Child-resistant HDPE container
contains 30 capsules (each capsule contains Lenvatinib
Mesylate INN equivalent to Lenvatinib 4 mg).
LENVAXEN 10 capsules: Each Child-resistant HDPE container
contains 30 capsules (each capsule contains Lenvatinib
Mesylate INN equivalent to Lenvatinib 10 mg).
Manufactured By
Everest Pharmaceuticals Ltd.
BSCIC, Kanchpur, Narayanganj, Bangladesh
www.everestpharmabd.com