CABOXEN 20 MG

CABOXEN
CABOZANTINIB

GABOXEN 20 cspsule: Eech cegsule conains Ceboa?nib (S/malate INN equivalent to 20 mg Cabozantinib.

CABOXEN 80 capsule: Each capsule contains Cabozantinib tS)-malate INN equivaleM to 80 mg Cabozantinib.

CLINICAL PHARMACOLOGY
Mechanism of Action
In Vida biochemical and/or cellular assays have shown that Cabozantinib inhibits the tyrosine kinase activity of MET, VEGFR-1, -2 and -3, AXL, FiET, PO’21, TYRO3, MeFi, KIT, TFiKB,
FLT-3, and TIE-2. These receptor tyrosine kinases are involved in both normal cellular function and pathologic processors such as oncogenesia, metastasis, tumor angiogeneais, drug resistance, and maintenance of the tumor microenvironment.

NONCLINICAL TOXICOLOGY
Cemlnogenesl¥, Mutagenesle, impelrmeM of 6eniiKy
The carcinogenic potential of Cabozantinib has been evaluated in two species rasHP transgenic mice snd Sprsgue-Dswïey rate. In the 2-year rat carcinogenicity study, once-daily oral administration of Cebozant!nib tesulted in e satirically significant increase in the incidence ol malignant/complex malignsnt pheochromocjrlome in combination with benign pheochromocytoma or in benign pheochromocytoma alone in male rats at a dose of mg/kg (approximately 5 times the
baseline or resolution to Grade ), reduce the dose as follows:

II previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg snd one 2Omg capsule)
II previously receiving 100 mg daily dose, resume treatment al 60 mg daily (three 20-mg capsules)
If previously receiving 60 mg daily dose, resume at 6Q mg il tolerated, otherwise, discontinue Cabozantinib PermaneMly discontinue Cabozentinib for any of the following:
Development of v!scetel perforation or f!stuls information
¥ Severe hemorrhage
Serious arterial thromboembolic event (e g., myocardial infarction, cerebral infarction)
Nephroiio síndrome
ueiignant hypertension, hypenensive ctisis, pemieent uncontrolted hypertension despite optimal medical manage-

Osteonecrosis of the ¡aw
Reversible posterior leukoenoephalopaihy síndrome
In Petlents Concurrently T¥klng ¥ Strong CYRsA4 Inhlbhor
Reduce the daily Cabozantinib dose by 40 mg (for exemple, from J 4o mg to J a mg daily or from J00 mg to 60 mg daily).
Osteonecrosk of tI+e Jr
ol Ihe jaw in 0
palienls. as yak osteomYeiilis, erosion, tooth toothache,
ulceralion jaw healing of jaw atter dental fo+
en orei initialion Csbozentinib
periodically Cabozantinib patienls good oral hygiene For
procedures. Oubozantinib tr for at ?8 days scfieduied possible.
Pslrr•ar-Plsntar Eryth sesthesia 8yn6rorr e
occurred in 60m
treated with Cebozantinib and cas zï in
13d pacients Withhold
Grade 2 or 3 lo Grade al a +educed dose
Protelnurta
was observed in 4 oJ pacients 0abozan- linib, including one with es ed lo none of
receiving placebo. urine
Cabozantinib treatment. Cabozanlinib pacients

RsverslbN Posterior Lo+ikosnoaphelopathy rome
Reversible Leukoencephalopathy a
OOE l8 S9ECIFN 909ULATTON
Pregnancy
Based on lindings hom enimel Mudies gnd its mechanism of aclion, cabozanlinib can cause felal harm when adminislered to a pregnant woman. There are no available dala in pregnant women to inform Ihe drug-asaociated +isk. In animal dweloprrieMal and +eproductive toxicoiogy Mudies edministtetion d lzenànio o pregnant rate and rabbils during organogenesis resulted in embryotetal letfiality and structural anomalies at exposures Prat were below tfiose occu+ring olinically at the +ecommended dose. 4dfise pregnant women or women ol chilooegring potencial ol the potentiel hazard to a fetus

Tt›e eslimeled bacXg+ound risc of major binh defects and miscarriage for the indicsted population is unkr+aún.
gpg. |#g
There is no inlomation rega+ding the pteaence ol Cabozanlinib o+ its meteooiites in fiuman milk, or treif elÏects on the breactled inlent, or milk production. Because ol the potencial lar serious adverse reaccions in a breastled inlant Irom Cabozantinib, advlse a lactating woman not to b+eastIeed during tfeatrrerr tr cabozantinib and lor 4 monlhs alter the final dose Fenilijy There are no dala on fiuman feitility Based on non-clinical satety lindings, male and lemale feitility may be compromised by tieatment with cabozantinib. Both men and women should be advised to seek a0Yioe and considet feitiiity presexation belore treatment.

human exposure by AUC at the recommended 60 mg dose).
Cabozantinib was not carcinogenic in a 26-week carcinogenici- ty study in rasH2 transgenic mice at a slightly higher exposure than the intended Human therapeutic exposure

Cabozantinib was not mutagenic in vitro in the bacterial reverse
Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation ol the strong inhibitor. In Pacients Concurrently Taking a Strong CYP3A4 lnducer lncrease the daily cabozantinib dose by 40 mg (for exemple, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily)
ho
RPLS in
edema diagnosed by
(‹16)

conlusion altered menlal in who PPLS
an Cmtraception
Females Csbozantinib csn oeuce fetai hem wfien sdminiMered to a pregnant woman. Advise lernales of reproductive potencial to use eflectiYe cc+itraception during treatrrieM wilh Cabozantinib and for 4

muation (Ames) aasay and was not clastogenic in both the in

B86d Of ÜO0uIiÜiFBI fiÜdi0g9. rTl8lB 80d fBW8l6 fB0ility T8y DB
impaired by treatment with Cabc’zantinib. In a fertility study in wnicn Oabozaniinib was aominisiereo to ma+e ano lema+e rars at doses of , 2.5, and 5 mg/kg/day, male fenility was significentiy compromised at doses eguei to or greeter than z.s mg/kg/day (approximately 3-Iold ol human AUC at the recommended dose), w!th e decrease in sperm counts end reproductive orgar weigho In females, leniiity was signilicantly reduced at doses equel to or greater than mg/kg/day (5-foid of human AUC at the recommended dose) with a significant decrease in the number ol live embryos ond e signilicent increase in pre- and post-implantation losses.

Observacions of etfects on reproductive tract tissues in general tox!cology studies were supponive of effects noted in the dedicated fenility sludy and included hyposperrrlia and absence of corpora lutea in male cd female dogs in a 6-month repeat dose sludy al plasma exposures (AUC) approximately 0 5-fold (males) and ‹0.1-fold (females) of those expected in humana at the recommended dose. In addition. female rate adm!nistered 5 mg/kg/day for 14 days tapproximately 9-fold of human AUC et the rocornmendod dose) exhibíted ovarian necrosis.

CABOXEN is indicated for the treatment of patients with
as tolerated. Resume the dose that was used prior to initiating the CYF8 4 inducer 2 to 3 deys atter discontinuation ot the slrong inducer. The daily dose of Caóozantinib should not exceed 180 mg.

CONTRATNDICATTON

WARMIMG8 AND PRECAUTION8
8erforatlons and Flatulaa
perfo+ations and were
396 and J 98 of All
end one ci wes 1 Non-Gi
tracheal/esophageal were reported ol
-Ira8lad Two tha3a

patients d perlorstions and
Yrho
a a

and
The incidence Gfade z 3 fhagic
was -treated palieno
J

Do adm!nister pat!ents a recent hislory of or

in an incidence of
Embry’e.fietal yoxjc|jy
on mechanism of
can cause fetal when to a edminiMration lo
ofganoqenesis fesuiled in embryoiethality at
at in
ol and visceral
in pregnanl women nsk
a

of reproductive to use
lion wlh and for + laM

FIDE EFFEOTS
adverse +eaotions treated
is
(PPES), decreased appetite,
nausea, faligue, color dysgeusia,
sion, snd Tte most
increased incfeased nia, increased ALP, hypocalcemia,
Md
reaccions laboralory hich occu!red in z 5B of
mare lrequently in
a diflerence 26 included, in
decreasing
hypocalcemie. hypenension.
decfeased appetite hypenension
nausea.

Females and Males Based on findings in animals, Cabozantinib rmy impai+ feit:iity in females and males of reptoducdve potencial

Tt›e safety and effecliveness al Cabozandnib in pediabic pacients have rot been Mudied.

Clinical sMdies of Cat›ozantinib did not include sutficient numbers of patienls aged 65 yeate and over to dete+mine whether they +espond diflerenlly from younger pacients

lncreesed exposure to Cabozantinib cas been obseryed in patients with mild to rrodefate hepaic impaiment Reduce the Maning dose al cabozantinib in patieriB nitfi mild (Child-Pugh score (C-P) A) or moderate (C-P B) hepatic impaiment. Cabozantinib is r›ot
fWorrlN60d8d fOt ug6 in g8ti0Mg with 90vBr6 h8 liv iN rrrl60t.

fiena7 /m¡oai r
DPsBge adjustment is not required in pacients with mild or rroderate fenai impai+ment. nefe is no exper:ence •:tf’ Cabozarrinib in patients with seYere Penal impairmeM.

OYfiROOW
One case ol oye+0oeage was +eported in a palienl who inedyenently took fiYice the intended dose (CO mg daiÇ) lar nir›e days. ïhe patient suftered Grade 3 memoy impairment, Grade 8 mental status efianges, Grade 3 cognilive distu+bance, Grade 2 weight loss, and G+ade increase in BUN. The extent of recoyeiy mes not documeMed

progressive, metaststic meduiisiy thyroid cancer (MCC)

OOGAGE AND DOMINI TION
The recommended daily dose of Cabozantinib is 140 mg (one
events
36
29s 096
Administiation ol a Mrong CYP3A4 inhibitor, ketoconazole to hedtfiy subjects increased singledose plasma Cabozantinib exposure by
386. Avoid taking 8 3bong CYP3A+ inhibitor (e g . ketoconazole,

CabozBnIinib is the (S)-malate sal ol Cabozandnib. Cabozantinib
‹sï- aiat is dxc+’bed «reu:raiiy as N-ï+¥s,z-diaa•Yr ino-

8o-mg end tfiree @-mg capsules).

Do not administer Cabozantinib with food. lnstrucl patients not to eat lar at least 2 hours belore and at least hour alter taking Cabozantinib. Continue treatment until disease progression or unacceptable toxicity occurs

Do NOT substitute Cabozantinib capsules with Cebozantinib tablets.

Swallow Cabozantinib capsules whole. Do not open

Do not rate a misseo òose within 4 z fioum or the neu dose.
Do not ingest foods te.g., grapelruit, grepelruit juice) or nutritionel supplements that are knorrn to inhibit cytochrome
P45O whi te taking Ga0ozantinib.
Cebozantinib who deveiop an scute or other clinically

Wound Complicacions

Stop with Cabozantinib at
Pesume Cabozantinib surgery

Withhold Cabozantinib in or healing complications ing intervention.

treatment resulta in an of Joint Nstionai
Evaluation, and Treatment of
Blood Ptessute JNC cr Gage 1 or 2 hyparten-
itraconazole, clarithrorriycin, atazanayir, indinayir, nefazcdone, nellinavir, ritonavir, saguinavir, telithromycin, voriconazole) while td‹ing Cabozandnib o +educe the dosage d Cabozaetinib if concom- uee filh Glrong CYP2A+ infiibitors cannol be ayoided. Avoid ingestion ol foods (e g., grapeftuit, grapefruit juice) or nutricional supplements Ihat ae km to inhibit cytochro+ne P450 while taking
Cabozantinib.
Bflest of Oyp Indus
Administiation of a strong CYB3A4 inducer, r4ampin to hedtfiy subjects decreased single-dose plasma Cabozanlinib exposu+e by es. Avoid chronic oo-adminiMretion of el+ong cYw4 inducers (e g., pheriytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbilal, si. John’s won) ciii Cabozantinib or increase the dosage of Cabozantinib if COncoTtTBOl UW XIX 8Trong CYP3A4 indoceis cenrot be evoided.
Eftest ol MRP2 lnhlbltors
Conoorrdaut administialion of MqP2 inhibito+s may increBse the
lin4yloxy)phenyl/N -(4 Iluorophenyl) cyclopropane1 , J-dicarboxam- ide, (2g) fiydroxybutanedioate The molecular lomula is CgHyFNs0s•CxgOs and the rr+olecular eight is 635.6 Daltons as malete eaii. ne cfiemicai n«Jctu+e al cabozarrinib (S)-maiate sait is

0 0
0

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PHARMOEWCAL IkFORMATlON
Store bebw 25°C. Keep oul al the agM 6 reach of children Protect from

Ijgw euppl¥e
CABOXEN z0 capsule Each HDPE container contains 90 capsules

In Pacients with Hepetic lmpsirment: The recommended Narting dose of Cabozantinib for patieno with mild to moderate hepatic impairment is 80 mg.
Docage ModTflcztlons for Adveree Reacdons
Withfiold Cebozantinib for NCI CTCAE Grede 4 fiemetologic

aa d piacebo-treated
ized trial blood to and
treatment.

Witfihold is
pacients randorn-
expoeute to Cebozananib. Monao paieMs lat incteased toxicíty hen MRP2 inhibilors (e g., abacm’ir, adefoYir, cidofoyir, furosemide,
IamiYudine, neYiragine, rito+iavir, probenecid, saquinavir, and tenofoYir) are coBdTinistered with CabozaMinib
each of which contains zantinib 20 mg

cxBoxEn so cepsule ra«h HDPE containet comainsü capsoles each of which corilains lzantinib 80 mg

adverse reactions, Grade 3 or greater non-hematologic adverse reaccions or intolerable Grade 2 adver8e reactions. upon resolutionfimprovement of the adverse reaction ti.e., return to

Cabozanlinib at a Cabozantinib caonol be cim
Manufactured By
Everest Pharmaceuticals Ltd./*54745756836*/