LENVAXEN 10 (LENVATINIB)

LENVAXEN 10 (LENVATINIB)

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Description

Lenvaxen
Lenvatinib 4 mg & 10 mg

COMPOSITION
LENVAXEN 4 capsules: Each capsule contains Lenvatinib Mesylate INN equivalent to Lenvatinib 4 mg.

LENVAXEN 10 capsules Each capsule conlains Lenvatinib Mesylate INN equivalent to Lenvatinib 10 mg.

INDICATIONS AND USAGE
Lenvatinib is indicated as monotherapy for the treatment of adult patients with progressive, IocaIIy advanced or metastatic, differenliated (papillary/foIIicuIar/Hürthle cell) thyroid carcino- ma (DTC), refractory to radioactiva 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 Ditferentiated 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 wilh 5 mg everolimus orally once daily until disease progression or until inacceptable toxicity.

Refer to everolimus prescribing information for recommended everolimus dosing intormation.

Recommended Dosage for Hepatocellular Carcinoma
(Hcc)
The recommended dosage of lenvatinib 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, ad]ustment, or discontinuation of lenvatinib therapy. Mild to moderate adverse reactions (e.g., Grade 1 or
2) generalIy 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 Daily dose Number of capsules
Recommended daily dose 24 mg orally once daily Two 10 mg capsules plus one 4 mg capsule
First dose reduclion 20 mg orally once daily Two 10 mg capsules
Second dose
reduction 14 mg orally once daily One 10 mg capsule
plus one 4 mg capsule
Third dose reduction 10 mg orally once daily’ One 10 mg capsule
’ Furlher 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 MCC patients

z60 kg BW
12 mg tthree 4 mg zapsvles orally once daily) ‹6g kg BW
8 mg (two 4 mg zaysvles «rally once daily)
Intolerable tiiade 2 or tiiade 3 ioiiiiIiis•

Modilicalion Adjusled Dose° fidjusled Oose°
First occurrence• Interrupt unïil resolved ïo Grade 0-1 or baselined 8 mg (two 4 mg capsules) orally once daily 4 mg (one 4 mg capsule) orally once daily
8econd occurrence (same reaction or new reaction) Interrupt until resolved to Grade 0-1 or baseline” 4 mg (one 4 mg capsule) orally once daily 4 mg (one 4 mg capsule) orally every other day
Third occurrence (same reaction or new reaction) Interrupt until resolved to Grade 0-1 or baseline° 4 mg (one 4 mg capsule) orally every other day Discontinue
Life-thieatening toxicities (Grade 4): Discontinue°
⦁ lnitiate medical managemenï for nausea, vomiting, or diarrhoea prior to interruption or dose reduction.
⦁ Reduce dose in succession based on the previous dose level
(12 mg, 8 mg, 4 mg or 4 mg every other day).
⦁ Haemaïologic toxicity or proïeinuria-no dose adjustmenï
required for first occurrence.
⦁ For haem6tologic toxicity, dosing can restart when resolved to Grade 2; proïeinuria, resume when resolves to less Khan 2g/24 hours
⦁ Excluding labor6tory abnormaliïies judged ïo be nonlife-threat ening, which should be managed as Gr6de 3.
Elderïy 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. AII patients other lhan those with severe hepatic or renal impairment should initiate treatment at the recommended
24 mg dose, followTng which the dose should be further adjusted on the basis of individual tolerability.

HCC
Patients 75 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 impaTrment should initiate treatment at the recommended starling dose of 8 mg (two 4 mg capsules) for body weight‹ 60 kg and 12 mg (three 4 mg capsules) for body weTghl 60 kg, following which the dose should be further ad¡usted on the basis of individual tolerability

Patients with hypertension
Blood pressure should be well controlled prior to treatment with lenvatinib and should be regularly monitored during treatment.

Patients 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- ats (Child-Pugh B) hepatic impairment In patients with severe (Child-Pugh C) hepatic impairmenl, Ihe recommended starting dose is 14 mg taken once daily. Further dose adjustments may be necessari on the basis of individual tolerability.

HCC
In Ihe patient populations enrolled in the HC:C 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 moderats hepatic impairment (Child-Pugh B). Close monitoring of overall
Patients with renal impairment DTC
No adjustment of starting dose is required on the basis of renal function in palients wilh 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 nol 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 uctive to any of

WARNING s AND PRECAUTIONS
Hypertension
Hypertension has been in with Ienvati- nib usually ing early in the course of treatment. Blood should be controlled to treatment with
if are to be hypertensive, they
be a stable antihypertensive therapy at least week to with lenvatinib Ser ious
Nations controlled aortic dissection, have been reported. early detection effective are
minimise the need for lunvatinib dose interrupcions and reductions Antihypertensive agents should be as soon as elevated BP is be monitored
week of with lenvatinib , every 2 weeks the 2 months, and

Cardiao Dysfunction
Serious dysfunction occur with
Across trials in 799 with DTC, RCC or HCC,
Gradu 3 higher cardiac (including
thy left failure,
ventricular or in
e]ecfion of more 20% occurred in patients
pacients clinical or of
and at a reduced dose upon based on

Arterial Thromboembolic Events
lenvatinib lenvatinib with
us, arterial events of severity in
2% of patients in 2°ü of REFLECT in SELECT to
drterial 2% to 3% across
all clinical trials Permanently discontinue lenvatinib lollowing
thrombotic event The safety of
after arterial thromboembolic has not ustublished and lunvatinib has not studied in who have had an lat within the previous 6 months.

Hepatotoxicity

pacients with olher lhan serious
adverse reactions in 1.4% of patients events, including acute hepatitis hepatorenal
síndrome, of In PEFLECT hepatic encephalopathy (including hepatic

in patients of
to 5
thy 5% of lenvalinib-treated palients 2% of Grade 3 5 failure
patients

ued lenvalinib 0 2% due to encephalopathy and % of
due to liver to then every 2 weeks for the first 2
al least

Renal Failure or Impairment
Serious impairment
impairment occurred
lenvatinib in SELECT in 7% of
in REFLECT Grade 3 to 5 renal or impairment occurred in 3% 2% ot
patients, including falality in each study In Study renal or failure occurred in
lenvatinib with everolimus, including Gradu 3 in of lnitiate or
at a reduced dose
on or permanently lenvatinib for
or based on

Proteinuria
F in 349a in
SELECT and in of pacients in
REFLECT Grade 3 proteinuria occurred in and 6% SELECT and Study 205
319a of patients with
of receiving
in pacients receiving with
everolimus to 2% of pacients Monitor for proteinuria prior to
cally If dipstick proteinuria
e to 2+ is obtain a 24-hour nono Withfiold and rusume at a reduced dose upon rucovery permaaently disconlinue lenvdtiaib based on severity.

Diarrhea
Of patients with in SELECT and REFLECT occurred 49% of
Grade 3 in 6% In Sludy 205 occurred in 81% of receiving
us, including in Diarrhea was
cause of dose and recurred despile dose reduction Promptly initiate of
and at a reduced dose recovery permanenlly discontinue on

Fistula Formation and Gastrointestinal Perforation
799 treated lenvatinib with everoli- mus in select 205 REFLECT
or perforation occurred in Perma- nently discontinue lenvatinib in patients who develop gastroin- testinal of any severity or de 3 4 listula.

0T lnterval Prolongation
In SELECT OT/QTc interval in 9% of and OT prolongation of
›500 ms in 2% In Study 205 QTc
of ms in 11% receiving
everolimus and QTc ms occurred 6°s In REFLECT OTc interval increases ›60 ms
occurred 89a
in 2% Monitor corrent electrolyte at and periodically

Hypocalcemia
In SELECT Grade 3 to 4 hypocalcemia 9% of patients receiving lenvatinib 65% of cases,
or supplementation, with
or without dose dose reduction In Study 205 (RCC), Grade 3 to 4 6% of
treated lenvatinib with (HCC),
Gra hypocalcemia in of
patients blood at least and
Reversible Posterior Leukoencephelopathy
Across ot who lenvalinib as a single age, posterior leukoencephalopalhy occurred in 0.3% mm the ol
PPLS with imaging resume at
a reduced dose upon or permanently discontinue
on severity and neurologic

ïdemorrhagic Events
Serious latal hemorrhagic can occur with lenvatinib Across SELECT (DTC), Study 205 and PEFLECT hemorrhagic events of any de occurred in 29% 799 patients treated wilh Ienv8tinib es a single
everolimus.
hemorrhagic grades occurring at
de 3 to 5
hemorrhage in receiving lenvatinib, intracranial hemorrhage
rece›veó lenvatinib and had CNS metastases at baseline In Study 3 5 hemorrhage in 8% of
with everolimus, including 1 fatal hemorrhage. In Gra to occurred in 5% pacients 7

lmpairment of Thyroid Stimulating Hormone Suppression/
Thyroid Dysfunction
suppression.
of all a thyroid stimulating hormone level s0.5 mU/L. In those patients with a
at baseline elevation TSH ›0 5 mU/L was
post baseline in 57% of lenvatinib-treated pacients Grade or 2
occurred in 24°à of receiving lenvatinib with everolimus in Study 205 and in 21% of pacients
in PEFLECT

Wound Healing Complicacions
listula and
wound dehiscence, occur Withhold lenvatinib lor at least 6 days prior to sCheduled Resume lenvutinib after surgery basud clinicul judgment ol adequate
Permanently in
with wound

Embryo-Fetal Toxicity
Based on its of action and data animal studies, lenvatinib can cause fetal harm when to a In
oral at
doses in
embryotoxicity, and in rals and rabbits. Advise pregnant women of potential risk to a fetus. Advise ol to use contraception during with and for at least 30 days after the last

SIDE
Dystunction,
Events, Penal Failure and Protein-
uria Fistula and
OT I Prolongat ion, Peversible
Leukoencephalopathy Hemorrhagic Events,
Impairment of Thyroid
ro›

DRUG INTERACTIONS
Chemotherapeutic agents
Concomitant administration of lenyatinib, 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 pacients showed that plasma concentracions 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 subslrates.

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 ol childbearing potenlial should avoid becoming pregnanl and use highly effeclive contraception while on treatment with lenvatinib and for at least one month alter linishing treatment It is currently unknown whether lenvatinib may reduce the effective- ness of hormonal contraceptives, and therelore women using oral hormonal contraceptives should add a barrier melhod

Pregnancy
There are no data on the use ot 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 nol 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, therelore, IenvatTnib is contraindicated during breast-feeding.

Fertility
Eflects in humans are unknown. However, testicular and ovarian
toxicity has been observed in raÏs, dogs, and monkeys.

Patients with Renal lmpairment
The pharmacokinetics of lenvatinib lollowing a single 24 mg dose were evaluated in sub ects with mild (CLcr 60-89 mL/mín), moderats (CLcr 30-59 mL/min), or severe (CLcr x30 mL/min) renal impairment, and compared to healthy subjects. Subjecta with end stage renal disease were not studied. The AUC(‹’ .rï) for subjects with renal impairment were similar compared to those for healthy subjecta.

Patients with Hepetic lmpairment
The pharmacokinetics of lenvatinib following a single 10 mg dose were evaluated in subjecta with mild (Child-Pugh A) or moderats (Child-Pugh B) hepatic impairment. The pharmacoki- netics of a single 5 mg dose were evaluated in sub]ects wilh severe (Child-Pugh C) hepatic impairment. Compared to subjects with normal hepatic function, the dose-adjusted AUC(‹’ .r ) of lenvatinib for subjecta with mild, moderate, and severe hepatic impairment were 119P•, 107°ü, 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 mials. 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. Ihese cases were associated with adverse reactions consistenl with the known safety profile of lenvatinib (i.e., renal and cardiac failure), or were without adyerse reactions.

DESCRIPTION
Lenvatinib, a kinase inhibitor, is the mesylate salt of lenvatinib Its chemical name is 4-[3chIoro-4-(N’-cyclopropylureido) phenoxy]
-7-methoxyquinoIine-6-carboxamide methanesulfonate. The molecular formula is CzJ HJaCIN4O4 CH4OzS, and the molecular weight of the mesylale salt is 522.96. The chemical structure ot lenvatinib mesylate is

HAN
O O HCC – SOaH

Lenvatinib mesylate is a white to pale reddish yellow powder. It is slighlly soluble in water & insoluble in ethanol (dehydrated). The dissociation constant (pKa value) of lenvatinib mesylate is
5.05 at 25°C. The panition coefficient (log P value) is 3.3.

CLINICAL PHARMACOLOGY
Mech8niam of Action
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vasc ular 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, Ihe 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 arributed to the inhibition of FGFR signalling by lenvatinib

Although not studied directly wilh lenvatinib, Ihe mechanism of action (MOA) for hypertension is postulated to be mediated by the inhibition of VEGFP2 in vascular endothelial cells. Similarly, although not studied directly, the MOA Ïor proteinuria is postulat- ed to be mediated by downregulalion of VEGFR1 and VEGFR2 in the podocytes of the glomerulus.

The mechanism of action for hypothyr

Pharmacokinetic properties
Pharmacokinetic parameters of lenvatinib have been studied in healthy adult subjecta, adult subjecta with hepatic impairment, renal impairment, and solid tumours.

Absorption
Lenvatinib is rapidly absorbed after oral administration with Tram lypically observed from 1 to 4 hours postdose. Food does nol affect the extent of absorption but slows the rate of absorption. When administered wilh food to healthy subjecta, peak plasma concentracions 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 (70.4R ) and monkeys (78.4%).

Dlstrlbutlon
in vitro binding of lenvatinib to human plasma proteins is high and ranged Irom 98°ü to 99% (0.3 – 30 pg/mL, mesylate). This binding was mainly to albumin with minor binding to a1-acid glycoprotein and y-globulin.

In vitro, the lenvatinib blood-lo-plasma concenlration ratio ranged from 0.589 to 0.608 (0.1— 10 Ag/mL, mesylate).

Lenvatinib is a substrate lor 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 trom 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 yoIume of distribution at steady-state (Vz/Fss) was also generally consistent and ranged from 43 2 L to 121 L

Biotransformation
in vitro, cytochrome P450 3A4 was demonstrated as lhe predominant (›80%) isoform involved in the P450-mediated metabolism of lenyatinib. However, in aivo data indicated that non-P450-mediated pathways conlrTbuted to a significant porlion of Ihe overall metabolism of lenvatinib Consequently, in vivo, inducers and inhibitors ol CYP 3A4 had a minimal effect on lenvatinib exposure.

In human liver microsomes, lhe demethylated form ot lenvatinib (M2) was identified as the main metabolite. M2’ and M3′, the ma or metabolites in human faeces, were formed from M2 and lenvatinib, respectively, by aldehyde oxidase

In plasma samp les collected up to 24 hours after adminislration, lenvatinib constiÏuted 97% oÏ the radioactivity in plasma radiochromatograms while the M2 metabolite accounted for an addicional 2.5%. Based on AUC‹— »‹›, lenvatinib accounted for 60% and 64″ó ol the total radioactiyity in plasma and blood, respectively.

Elimination
Plasma concentrations decline bi-exponentially following Com. Ihe mean terminal exponenlial half-life of lenvatinib is approxi- mately 28 hours.

Following administration of radiolabelled lenvatinib to 6 patients wilh solid tumours, approximately two-thirds and one-quarter of the radiolabel were eliminated in lhe faeces and urine, respec- tively The M3 metabolite was the predominant analyte in excrela (-17% of the dose), lollowed by M2′ (-11R ot 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 Lenvali- nib mesylate was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. Lenvatinib was not clasïogenic in the n vitro mouse lymphoma thymidine kinase assay or the n v/vo rat micronucleus assay. No specific studTes with lenvatinib haye been conducted in animals to evaluate the effect on ferlility; however, results from general toxicology studies in rats, monkeys, and dogs suggest there is a potential for lenvatinib lo impair fertility. Male dogs exhibiled 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 INFOPMATION
Storage Conditione
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 lo temperalures greater than 40º C or 104º 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 conlainer contains 30 capsules (each capsule contains Lenvatinib Mesylate INN equivalent to Lenyatinib 4 mg).

LENVAXEN 10 capsules: Each Child-resistant HDPE container contains 30 capsules (each capsule contains Lenvatinib Mesylale INN equivalent to Lenvatinib 10 mg).

safety is recommended in these patients Lenvatinib has not been studied in patients wilh severe hepatic imparement (Child-Pugh C) and is not recommended for use in these patients.
replace calcium as necessQfy during Withhold and resume at reduced dose up permanently
tinue lenvatinib on
Manufactured By
Everest Pharmaceuticals Ltd.

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