Rx Thuc bn theo n

Xarelto
Vin nn bao phim

Bayer Pharma AG

Thnh phn
Hot cht:
Xarelto 15 mg: Mi vin nn bao phim c cha 15 mg rivaroxaban.
Xarelto 20 mg: Mi vin nn bao phim c cha 20 mg rivaroxaban.
T dc: Cellulose vi tinh th, croscarmellose sodium, hypromellose 5 cP, lactose monohydrat,
magnesium stearate, sodium lauryl sulfate. Bao phim: Oxyd st , hypromellose 15 cP,
macrogol 3350, titanium dioxid
M t sn phm
Xarelto 15 mg: Vin nn bao phim 15 mg hnh trn, mu , hai mt li, c hnh tam gic ch
xung pha trn s 15 c khc trn mt mt v Xa trn mt kia.
Xarelto 20 mg: Vin nn bao phim 20 mg hnh trn, mu , hai mt li, c hnh tam gic ch
xung pha trn s 20 c khc trn mt mt v Xa trn mt kia
Ch nh
Xarelto c ch nh d phng t qu v thuyn tc mch ton thn cc bnh nhn b rung
nh khng do bnh l van tim c mt yu t nguy c hoc nhiu hn nh: suy tim, tng huyt p,
75 tui, i tho ng, tin s t qu hoc cn thiu mu hoi t cc b thong qua.
Xarelto c ch nh iu tr huyt khi tnh mch su (DVT) v d phng ti pht huyt
khi tnh mch su v thuyn tc mch phi (PE).
Liu lng v cch dng
1. D phng t qu bnh nhn rung nh (SPAF)
SPAF: Cch dng
S dng theo ng ung
SPAF: Liu thng dng c khuyn co
Liu c khuyn co l 20 mg ngy 1 ln.
bnh nhn suy thn mc trung bnh ( thanh thi creatinin (CrC): <50-30 mL/pht), liu
c khuyn co l 15 mg ngy 1 ln.
SPAF: Thi gian iu tr
Cn tip tc iu tr ko di chng no m nhng nguy c gy t qu v thuyn tc mch ton
thn vn cn.
SPAF: Cch dng v tn sut s dng thuc
Ung 1 vin Xarelto 20 mg 1 ln trong ngy.
bnh nhn suy thn mc trung bnh ( thanh thi creatinin (CrC): <50-30 mL/pht), ung
1 vin Xarelto 15 mg 1 ln trong ngy.
Vin Xarelto 20 mg v Xarelto 15 mg nn c ung c ng v i thc n.
SPAF: Qun ung thuc
Nu bnh nhn qun ung mt liu thuc th nn ung Xarelto ngay khi nh ra v tip tc ung
ngy 1 ln theo khuyn co vo ngy tip theo.

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 1

Khng nn d ng liu gp i trong c ng mt ngy b cho liu thuc qun khng ung.
SPAF: Liu ti a hng ngy
Liu ti a hng ngy c khuyn co l 20 mg.
SPAF: Chuyn t cc thuc i khng vitamin K (VKA) sang Xarelto
Cn ngng iu tr bng VKA v bt u s dng Xarelto khi ch s INR 3,0 .
Khi chuyn bnh nhn t s dng cc thuc VKA sang Xarelto, cc gi tr INR s tng gi sau khi
d ng Xarelto. Ch s INR khng c gi tr nh gi hot tnh chng ng ca Xarelto v do ,
khng nn s dng ch s ny (xem phn Tng tc vi thuc khc v cc dng tng tc
khc).
SPAF: Chuyn t Xarelto sang cc thuc khng vitamin K (VKA)
C kh nng chng ng khng y trong thi gian chuyn tip t Xarelto sang s dng VKA.
Cn m bo tc dng chng ng lin tc khi chuyn tip sang mt thuc chng ng thay th
khc. Lu rng Xarelto c th gp phn lm tng ch s INR.
bnh nhn chuyn t Xarelto sang VKA, nn s dng ng thi Xarelto v VKA cho t i khi ch
s INR 2,0. Trong hai ngy u tin ca giai on chuyn i thuc, liu VKA iu chnh theo
test INR c s dng sau liu chun VKA. Khi bnh nhn s dng ng thi Xarelto v VKA,
khng nn kim tra ch s INR tr c 24 gi (sau liu tr c nhng tr c liu k tip ca Xarelto).
Khi ngng s dng Xarelto, th c th tin hnh test INR 24 gi sau liu cui c ng c kt qu
ng tin cy (xem phn Tng tc vi thuc khc v cc dng tng tc khc v Liu dng v
cch dng).
SPAF: Chuyn t cc thuc chng ng dng ng tim sang Xarelto
bnh nhn ang s dng thuc chng ng ng tim, nn bt u ung Xarelto 0 n 2 gi
tr c ln d ng d kin tip theo ca thuc tim (v d: LMWH) hoc ti thi im ngng cc
thuc truyn tnh mch lin tc (v d: heparin khng phn on truyn tnh mch).
SPAF: Chuyn t Xarelto sang cc thuc chng ng ng tim
Ngng ung Xarelto v a liu u tin ca thuc chng ng ng tim vo thi im d ng
liu Xarelto tip theo.
SPAF: Thng tin b sung cho cc dn s c bit
SPAF: Bnh nhn suy gim chc nng gan
Chng ch nh Xarelto cc bnh nhn mc bnh gan i km v i bnh ng mu, v nguy c
chy mu c lin quan v mt lm sng k c nhng bnh nhn x gan v i xp loi Child Pugh B
v C (xem phn Chng ch nh).
SPAF: Bnh nhn suy gim chc nng thn
Khng cn hiu chnh liu Xarelto bnh nhn suy gim chc nng thn mc nh. V i bnh
nhn suy gim chc nng thn trung bnh, liu c khuyn co l 15 mg ngy 1 ln.
Cc d liu lm sng cn hn ch trn bnh nhn suy gim chc nng thn nng cho thy nng
rivaroxaban trong huyt tng tng ln ng k dn s bnh nhn ny. Do , cn thn trng khi
s dng Xarelto 15 mg cc bnh nhn ny.
Khng khuyn co s dng Xarelto bnh nhn c CrC <15 mL/pht (xem phn Cnh bo c
bit v thn trng khi s dng).
SPAF: Tr em v thanh thiu nin
(t lc sinh n 16 hoc 18 tui ty theo lut ca nc s ti)
an ton v hiu qu ca thuc cha c thit lp tr em v thanh thiu nin d i 18 tui.
SPAF: Bnh nhn lo khoa
Khng cn chnh liu theo tui.
SPAF: Gii
Khng cn chnh liu theo gi i.

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 2

 SPAF: Cn nng c th
Khng cn chnh liu theo cn nng c th.
SPAF: Cc dn tc khc nhau
Khng cn chnh liu theo s khc nhau v dn tc.
2. iu tr huyt khi thuyn tc tnh mch (VTE)
iu tr VTE: ng dng
S dng theo ng ung
iu tr VTE: Liu thng dng c khuyn co
Liu khuyn co khi u iu tr DVT cp tnh l 15 mg Xarelto 2 ln mi ngy trong 3 tun u,
sau d ng liu Xarelto 20 mg ngy 1 ln cho iu tr lin tc v d phng ti pht DVT v PE.
iu tr VTE: Thi gian iu tr
Cn tip tc iu tr chng no vn cn c nguy c VTE.
iu tr VTE: Cch dng v tn sut s dng thuc
Trong 3 tun u tin iu tr cp tnh, s dng 15 mg Xarelto 2 ln mi ngy
Sau 3 tun u tin, tip tc iu tr bng Xarelto liu 20 mg mi ngy 1 ln.
Vin Xarelto 15 mg v vin Xarelto 20 mg nn c ung c ng v i thc n.
iu tr VTE: Qun dng thuc
Cn thit phi tun th theo liu lng d kin.
Nu qun d ng thuc trong giai on iu tr liu 15 mg 2 ln mi ngy th nn ung Xarelto ngay
khi nh ra m bo s dng 30 mg Xarelto mi ngy. Trong trng hp ny, c th ung 2
vin 15 mg mt lc. Bnh nhn cn tip tc ung u n 15 mg 2 ln ngy theo khuyn co vo
hm sau.
Nu qun d ng thuc trong giai on iu tr liu 20 mg 1 ln mi ngy th nn d ng Xarelto ngay
khi nh ra m bo s dng 20 mg mi ngy. Bnh nhn cn tip tc ung u n 20 mg 1
ln mi ngy theo khuyn co vo hm sau.
iu tr VTE: Liu ti a hng ngy
Liu ti a hng ngy c khuyn co l 30 mg trong 3 tun u iu tr. Trong giai on tip
theo, liu ti a hng ngy c khuyn co l 20 mg.
iu tr VTE: Chuyn t cc thuc i khng vitamin K sang Xarelto
Cn ngng iu tr bng VKA v bt u s dng Xarelto khi ch s INR 2,5 .
Khi chuyn bnh nhn t s dng cc thuc VKA sang Xarelto, cc gi tr INR c th tng gi sau
khi d ng Xarelto. INR khng c gi tr nh gi hot tnh chng ng ca Xarelto v do ,
khng nn s dng ch s ny (xem phn Tng tc vi thuc khc v cc dng tng tc
khc).
iu tr VTE: Chuyn t Xarelto sang cc thuc khng vitamin K (VKA)
C kh nng chng ng khng y trong thi gian chuyn tip t Xarelto sang VKA. Cn
m bo chng ng y lin tc trong bt k thi gian chuyn tip sang mt thuc chng
ng thay th khc. Cn lu rng Xarelto c th gp phn lm tng ch s INR.
bnh nhn chuyn t Xarelto sang VKA, nn s dng ng thi Xarelto v VKA cho t i khi ch
s INR 2,0. Trong hai ngy u tin ca giai on chuyn i thuc, liu VKA iu chnh theo
test INR c s dng sau liu chun VKA. Khi bnh nhn s dng ng thi Xarelto v VKA,
khng nn kim tra ch s INR tr c 24 gi (sau liu tr c nhng tr c liu k tip ca Xarelto).
Khi ngng s dng Xarelto, tin hnh xt nghim INR 24 gi sau liu cui c ng c kt qu tin
cy (xem phn Tng tc vi thuc khc v cc dng tng tc khc v Liu dng v cch
dng).

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 3

 iu tr VTE: Chuyn t cc thuc chng ng ng tim sang Xarelto
bnh nhn hin ang s dng thuc chng ng ng tim, nn bt u ung Xarelto 0 n 2
gi tr c ln d ng tip theo ca thuc tim (v d: LMWH) hoc thi im ngng cc thuc
truyn tnh mch lin tc (v d: heparin khng phn on truyn tnh mch).
iu tr VTE: Chuyn t Xarelto sang cc thuc chng ng ng tim
Ngng ung Xarelto v cho liu u tin ca thuc chng ng ng tim vo thi im d ng
liu Xarelto tip theo.
iu tr VTE: Thng tin thm cho cc dn s c bit
iu tr VTE: Bnh nhn suy gim chc nng gan
Chng ch nh Xarelto cc bnh nhn mc bnh gan i km v i bnh ng mu, v nguy c
chy mu c lin quan v mt lm sng k c nhng bnh nhn x gan v i xp loi Child Pugh B
v C (xem phn Chng ch nh).
iu tr VTE: Bnh nhn suy gim chc nng thn
Khng cn chnh liu Xarelto bnh nhn suy gim chc nng thn mc nh hoc trung bnh.
Cc d liu lm sng cn hn ch trn bnh nhn suy gim chc nng thn nng cho thy nng
rivaroxaban trong huyt tng tng ln ng k bnh nhn ny. Do , cn thn trng khi s
dng Xarelto cho cc bnh nhn ny.
Khng khuyn co s dng Xarelto bnh nhn c CrC <15 mL/pht (xem phn Cnh bo c
bit v thn trng khi s dng).
iu tr VTE: Tr em v thanh thiu nin
(t lc sinh n 16 n 18 tui ty theo lut ca nc s ti)
an ton v hiu qu ca thuc tr em v thanh thiu nin d i 18 tui cha c thit lp.
iu tr VTE: Bnh nhn lo khoa
Khng cn chnh liu theo tui.
iu tr VTE: Gii
Khng cn chnh liu theo gi i.
iu tr VTE: Cn nng c th
Khng cn chnh liu theo cn nng c th.
iu tr VTE: Cc dn tc khc nhau
Khng cn chnh liu theo s khc nhau v dn tc.
Chng ch nh
Chng ch nh Xarelto bnh nhn mn cm v i rivaroxaban hoc bt k thnh phn no ca
thuc (xem phn Cc c tnh dc hc).
Chng ch nh Xarelto bnh nhn ang chy mu lin quan lm sng (nh chy mu ni s,
xut huyt tiu ha)
Chng ch nh Xarelto cc bnh nhn mc bnh gan i km v i ri lon ng mu v nguy c
chy mu c lin quan v mt lm sng k c nhng bnh nhn x gan v i xp loi Child Pugh B
v C.
an ton v hiu qu ca Xarelto trn ph n c thai cha c thit lp. Cc d liu trn ng
vt cho thy rivaroxaban qua c hng ro nhau thai. Do , chng ch nh Xarelto trong sut
thi gian mang thai (xem phn Ph n c thai v cho con b).
an ton v hiu qu ca Xarelto trn ph n cho con b cha c thit lp. Cc d liu trn
ng vt cho thy rivaroxaban c bi tit vo sa m. Do , ngi m ch s dng Xarelto khi
ngng cho con b (xem phn Ph n c thai v cho con b).

Cnh bo v thn trng

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 4

 Nguy c xut huyt
Cng nh v i cc thuc chng ng khc, nhng bnh nhn s dng Xarelto phi c quan st
cn thn i v i cc du hiu chy mu. Khuyn co nn s dng thn trng trong nhng chng
bnh c gia tng nguy c xut huyt. Phi ngng d ng Xarelto nu c xut huyt xy ra.
Trong nhng nghin cu lm sng, nhng chy mu nim mc (nh chy mu cam, li, tiu ha,
niu sinh dc) v thiu mu thng c thy nhiu hn trong thi gian iu tr rivaroxaban lu
di so v i iu tr VKA. V vy, ngoi theo di lm sng y , th cc test xt nghim
haemoglobin/ haematocrit c th c gi tr pht hin chy mu b che lp, khi c nh gi thch
ng.
Vi phn nhm bnh nhn, nh c trnh by chi tit d i y, c nguy c chy mu gia tng.
Nhng bnh nhn ny phi c theo di cc du hiu v triu chng ca cc bin chng chy
mu v thiu mu mt cch cn thn sau khi bt u iu tr (xem phn Nhng Tc Dng Khng
Mong Mun).
Bt k s tt gim haemoglobin hay huyt p khng gii thch c phi tm kim v tr chy mu.
Mc d iu tr v i rivaroxaban khng cn phi theo di thng quy s phi nhim thuc, nhng
nng rivaroxaban c o lng v i xt nghim nh lng khng Yu T Xa c chun
nh c th c ch li trong nhng trng hp ngoi l m s am hiu v phi nhim rivaroxaban
c th gip cho nhng quyt nh v lm sng, v.d, qu liu v phu thut cp cu (xem phn
c im Dc Lc Hc v Dc ng Hc)
Bnh nhn thay van tim nhn to
an ton v hiu qu ca Xarelto cha c nghin cu bnh nhn thay van tim nhn to; do
, khng c d liu cho thy Xarelto 20 mg (15 mg bnh nhn suy gim chc nng thn va)
em li s chng ng y nhng bnh nhn ny.
Nhng bnh nhn b thuyn tc phi (PE) c huyt ng hc khng n nh hoc bnh
nhn cn lm tan huyt khi hay th thut ly b vt nghn mch phi
Xarelto khng khuyn co iu tr thay th cho heparin khng phn on trn bnh nhn c thuyn
tc phi c huyt ng hc khng n nh hoc c th iu tr tan huyt khi hay lm th thut ly
b vt nghn mch phi do an ton v hiu qu ca Xarelto cha c chng minh trong
nhng tnh hung lm sng ny.
Thuc dng ng thi
Khng khuyn co s dng ng thi Xarelto v thuc chng nm nhm azol d ng ng ton
thn (nh ketoconazol) hoc cc thuc c ch protease HIV (nh ritonavir). Nhng thuc ny l
cc cht c ch mnh c CYP 3A4 ln P-gp. Do , cc thuc ny lm tng nng rivaroxaban
trong huyt tng n mc c lin quan n lm sng (trung bnh gp 2,6 ln) c th dn n
tng nguy c chy mu.
Tuy nhin, thuc chng nm nhm azol nh fluconazol l mt cht c ch CYP 3A4 mc
trung bnh, t c nh hng ln s phi nhim ca rivaroxaban hn v c th c d ng ng thi
(xem phn Tng tc vi thuc khc v cc dng tng tc khc).
iu tr VTE: Suy gim chc nng thn
bnh nhn suy gim chc nng thn mc trung bnh, nn thn trng khi s dng Xarelto
ng thi v i cc thuc khc lm tng nng rivaroxaban trong huyt tng (xem phn Tng
tc vi thuc khc v cc dng tng tc khc).
Suy gim chc nng thn
bnh nhn suy gim chc nng thn nng, nng rivaroxaban c th tng ln ng k (trung
bnh gp 1,6 ln) c th dn n tng nguy c chy mu.
Do cc d liu lm sng cn hn ch, nn thn trng khi s dng Xarelto cc bnh nhn c
CrC <30-15 mL/pht.

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 5

Khng c cc d liu lm sng i v i bnh nhn suy gim chc nng thn nng. Do , khng
khuyn co s dng Xarelto cc bnh nhn ny (xem phn Liu dng v cch dng).
Cn theo di cht ch cc du hiu ca bin chng chy mu sau khi bt u iu tr bnh nhn
suy gim chc nng thn nng hoc tng nguy c chy mu v bnh nhn s dng ng thi thuc
chng nm nhm azole d ng ng ton thn hoc cc thuc c ch protease HIV.
Nguy c chy mu
Tng t nh cc thuc chng huyt khi khc, cn thn trng khi s dng Xarelto cc bnh
nhn c nguy c cao chy mu nh:
Ri lon chy mu bm sinh hoc mc phi
Tng huyt p ng mch nghim trng khng kim sot c
Bnh lot ng tiu ha ang tin trin
Lot ng tiu ha gn y
Bnh l vng mc do mch mu
Chy mu ni s hoc chy mu no gn y
Bt thng mch mu trong ty sng hoc trong no
Phu thut no, ty sng hoc nhn khoa gn y
Gin ph qun hoc tin s chy mu phi
Cn theo di bnh nhn nu bnh nhn ang d ng ng thi v i cc thuc nh hng n qu
trnh cm mu ng mu nh cc thuc chng vim khng phi steroid (NSAID), thuc c ch
kt tp tiu cu hoc cc thuc chng huyt khi khc.
Xem xt iu tr d phng chy mu trn bnh nhn c nguy c lot ng tiu ha (xem phn
Tng tc vi thuc khc v cc dng tng tc khc).
Phi tm v tr xut huyt khi hemoglobin hoc huyt p gim khng gii thch c.
Phu thut v can thip
Khi cn tin hnh cc th thut xm ln hoc can thip phu thut, nn ngng iu tr bng
Xarelto ti thiu 24 gi tr c khi thc hin can thip nu c th v da trn s nh gi lm sng
ca bc s.
Nu khng th tr hon vic thc hin th thut, th nn nh gi s tng nguy c chy mu v i
tnh cp thit ca can thip.
Sau khi tin hnh cc th thut xm ln hoc can thip phu thut, nn bt u s dng li Xarelto
ngay khi c th min l tnh trng lm sng cho php v qu trnh cm mu y c thit
lp.
Ph n tui sinh sn
Ch nn s dng Xarelto ph n tui sinh sn khi c bin php trnh thai hiu qu.
Ko di khong QTc
Xarelto khng c tc dng ko di khong QTc.
Thng tin v cc t dc
Do thuc c cha lactose, nn bnh nhn cc vn v khng dung np lactose hoc galactose
mang tnh di truyn him (nh khim khuyt Lapp lactase hoc km hp thu glucose galactose)
khng nn d ng ch phm ny.
Tng tc vi cc thuc khc v cc dng tng tc khc
Tng tc dc ng hc
Rivaroxaban thi tr ch yu qua chuyn ha gan nh trung gian cytocrom P450 (CYP 3A4,
CYP 2J2) v bi tit qua thn d i dng khng i, lin quan n h thng vn chuyn P-
glycoprotein (P-gp) / protein khng ung th v (Bcrp).

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 6

 c ch CYP
Rivaroxaban khng c ch CYP 3A4 hoc bt k CYP ng dng (isoform) ch yu no khc
CYP Induction
Rivaroxaban khng cm ng CYP 3A4 hoc bt k CYP ng dng ch yu no khc
nh hng ln rivaroxaban
Vic s dng ng thi Xarelto v i cc cht c ch CYP 3A4 v P-gp mnh, c th dn n s
gim thanh thi qua c gan ln thn v do , lm tng ng k s phi nhim ca thuc trong
c th.
D ng ng thi Xarelto v thuc chng nm nhm azole nh ketoconazol (400 mg ngy 1 ln)
mt cht c ch CYP 3A4 v P-gp mnh, dn n AUC trung bnh ca rivaroxaban trng thi n
nh tng gp 2,6 ln v Cmax trung bnh rivaroxaban tng gp 1,7 ln c ng v i s tng ng k tc
dng dc lc hc ca thuc.
D ng ng thi Xarelto v thuc c ch protease HIV nh ritonavir (600 mg ngy 2 ln) - mt
cht c ch CYP 3A4 v P-gp mnh, dn n AUC trung bnh ca rivaroxaban trng thi n
nh tng gp 2,5 ln v Cmax trung bnh ca rivaroxaban tng gp 1,6 ln c ng v i s tng ng
k tc dng dc lc hc ca thuc.
V vy, khng khuyn co s dng Xarelto ng thi v i cc thuc khng nm nhm azole d ng
ng ton thn nh ketoconazole, itraconazole, voriconazole v posaconazole hoc cc thuc c
ch protease HIV (xem phn Cnh bo c bit v thn trng khi s dng).
Clarithromycin (500 mg ngy 2 ln), c xem l mt cht c ch CYP 3A4 mnh v c ch P-gp
trung bnh, khi s dng ng thi dn n AUC trung bnh ca rivaroxaban tng gp 1,5 ln v
Cmax tng gp 1,4 ln. S tng ln gn v i tm bin thin bnh thng ca AUC v C max c coi
l khng lin quan v mt lm sng.
Erythromycin (500 mg 3 ln/ngy), c ch CYP 3A4 v P-gp mc va phi, khi s dng ng
thi, dn n AUC v Cmax trung bnh ca rivaroxaban tng gp 1,3 ln. S tng ln ny nm trong
tm bin thin bnh thng ca AUC v Cmax v c coi l khng lin quan v lm sng.
D ng ng thi Xarelto v i cht cm ng CYP 3A4 v P-gp mnh nh rifampicin dn n AUC
trung bnh ca rivaroxaban gim khong 50% song song v i gim tc dng dc lc hc ca
thuc. D ng ng thi Xarelto v i cc cht cm ng CYP 3A4 mnh khc (nh phenytoin,
carbamazepin, phenobarbitone hoc St. Johns Wort) c th cng dn n gim nng
rivaroxaban trong huyt tng. Nn thn trng khi s dng ng thi v i cc cht cm ng CYP
3A4 mnh.
Tng tc dc lc hc
Cc thuc chng ng
Sau khi s dng phi hp enoxaparin (40 mg n liu) v Xarelto (10 mg n liu), ghi nhn c
tc dng cng thm trn hot tnh c ch yu t Xa nhng khng c bt k tc ng cng thm
test ng mu (PT, aPTT). Enoxaparin khng tc ng n dc ng hc ca rivaroxaban (xem
phn Cnh bo c bit v thn trng khi s dng).
Do nguy c chy mu gia tng, nn cn ch bnh nhn nu iu tr ng thi v i bt k cc
thuc chng ng khc. (xem phn Cnh Bo v Thn Trng khi S Dng).
NSAIDs/ Cc thuc c ch kt tp tiu cu
Clopidogrel (liu ti 300 mg, sau d ng liu duy tr 75 mg) khng thy c tng tc dc ng
hc (v i Xarelto 15 mg) nhng mt nhm nh bnh nhn ghi nhn c s tng lin quan n
thi gian chy mu, m khng c tng quan n s kt tp tiu cu, P-selectin hoc nng ca
th th GPIIb / IIIa (xem phn Cnh bo c bit v thn trng khi s dng).
Sau khi s dng ng thi Xarelto (15 mg) v naproxen 500 mg, khng thy c s ko di lin
quan n thi gian chy mu v mt lm sng. Tuy nhin, p ng dc lc hc trn mt s bnh
nhn c th r rt hn (xem phn Cnh bo c bit v thn trng khi s dng).

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 7

Cha thy c cc tng tc dc ng hc v dc lc hc ng k v mt lm sng khi
rivaroxaban c d ng ng thi v i 500 mg acetylsalicylic acid.
Cn ch bnh nhn nu iu tr bnh nhn ng thi v i NSAIDs (bao gm acetylsalicylic acid)
V cc thuc c ch kt tp tiu cu v cc thuc ny lm tng nguy c chy mu mt cch c
trng (xem phn Cnh Bo v Thn Trng khi S Dng).
Warfarin
Vic chuyn i cho bnh nhn t warfarin (INR 2,0 3,0) sang Xarelto (20 mg) hoc t Xarelto
(20 mg) sang warfarin (INR 2,0 3,0) lm thi gian prothrombin/INR (Neoplastin) tng thm
nhiu hn mc cng hp (c th quan st gi tr INR tng ln n 12), trong khi tc dng ln trn
aPTT, hot tnh c ch yu t Xa v thrombin ni sinh c kh nng cng hp.
Nu mun kim tra tc dng dc lc hc ca Xarelto trong giai on chuyn i thuc, c th s
dng cc test v hot tnh c ch yu t Xa, PiCT v HepTest do nhng xt nghim ny khng b
tc ng bi warfarin. T ngy th 4 sau khi dng warfarin tr i, tt c cc test (bao gm PT,
aPTT, c ch hot tnh yu t Xa v ETP) ch phn nh tc dng ca Xarelto (xem phn Liu
dng v cch dng).
Nu mun kim tra tc dng dc lc hc ca Xarelto trong giai on chuyn i thuc, c th o
lng ch s INR thi im rivaroxaban t nng y (24 gi sau khi ung liu rivaroxaban
tr c) do thi im , rivaroxaban nh hng n xt nghim mc nh nht.
Khng ghi nhn tng tc dc ng hc gia warfarin v Xarelto.
Thc n v thc phm t sa
Vin nn Xarelto 15 mg v Xarelto 20 mg c th ung c ng v i thc n.
Tng tc vi cc thng s xt nghim
Cc thng s xt nghim ng mu (PT, aPTT, HepTest) c cho l c b nh hng do
phng thc tc dng ca Xarelto.
S dng ph n c thai v cho con b
Ph n tui sinh sn / Trnh thai
Ch s dng Xarelto cho ph n tui sinh sn c p dng cc phng php trnh thai hiu
qu.
Ph n c thai
an ton v hiu qu ca Xarelto ph n c thai cha c thit lp.
Trn chut v th, rivaroxaban th hin c tnh r rt trn ng vt m v i nhng s thay i v
nhau thai lin quan t i tc dng dc l hc ca thuc (nh bin chng chy mu), dn n c
tnh trn sinh sn. Khng nhn dng c kh nng gy qui thai ch yu no. Do nguy c chy
mu ni sinh v bng chng l rivaroxaban qua c hng ro nhau thai, chng ch nh Xarelto
ph n c thai (xem phn Chng ch nh).
Ph n cho con b
an ton v hiu qu ca Xarelto ph n cho con b cha c thit lp. chut, rivaroxaban
c bi tit vo sa m.
Do , Xarelto chng ch nh trong thi gian nui con bng sa m (xem phn Chng ch nh).
Cn phi quyt nh ngng cho b hoc ngng thuc iu tr.
Tc dng trn kh nng li xe v vn hnh my mc
c bo co v cc trng hp ngt v chong vng v c th nh hng ln kh nng li xe v
vn hnh my mc (xem phn Tc dng khng mong mun). Bnh nhn gp phi cc phn ng
c hi ny khng nn li xe hoc s dng my mc.
Tc dng khng mong mun
Tm lc d liu v an ton

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 8

Tnh an ton ca Xarelto c nh gi trong bn nghin cu pha III bao gm 6097 bnh nhn
d ng Xarelto 10 mg phu thut chnh hnh chi d i (thay ton b kh p hng hay kh p gi ) trn
3997 bnh nhn bnh ni khoa nhp vin c iu tr t i 39 ngy, v trong ba th nghim pha
III iu tr VTE v i 4556 bnh nhn d ng hoc 15 mg Xarelto 2 ln mi ngy trong 3 tun tip
theo 20 mg mt ln/ngy hoc 20 mg mt ln mi ngy iu tr n 21 thng.
Hn na tnh an ton ca Xarelto cng c nh gi trn 7750 bnh nhn b rung nh khng
do van tim t hai nghin cu pha III v i t nht mt liu Xarelto cng nh trn 10,225 bnh nhn
ACS v i t nht mt liu hoc 2.5 mg (hai ln/ngy) hoc 5 mg (hai ln mi ngy) Xarelto thm
vo hoc ASA hoc ASA c ng v i clopidogrel hay ticlopidine.
Do phng thc tc dng dc l hc, Xarelto c th i km v i tng nguy c chy mu su hoc
nng t bt k m hoc c quan no trong c th, c th dn n thiu mu sau xut huyt. Nguy
c chy mu tng ln mt s nhm bnh nhn, nh bnh nhn tng huyt p ng mch nghim
trng khng kim sot c v/hoc d ng ng thi cc thuc nh hng n qu trnh cm mu
(xem phn Cnh bo c bit v thn trng khi s dng).
Cc du hiu, triu chng v mc nng (bao gm c t vong) thay i t y theo v tr v mc
hoc phm vi chy mu v/hoc thiu mu (xem phn Qu liu/ X tr thiu mu).
Bin chng xut huyt thng c biu hin nh yu c, ti nht, chong vng, au u hoc
sng khng gii thch c, kh th v sc khng gii thch c. Trong mt vi trng hp, ghi
nhn c cc triu chng thiu mu cc b tim nh au ngc hoc cn au tht ngc, c th l
hu qu ca thiu mu.
Cc bin chng t th yu n chy mu nghim trng nh hi chng chn p khoang v suy thn
do gim t i mu cng c bo co cho Xarelto. Do , cn cn nhc kh nng xut huyt
trong vic nh gi tnh trng bnh bt k cc bnh nhn c iu tr chng ng.
Bng lit k cc phn ng c hi
Tn sut gp cc ADR ca Xarelto c tm tt trong bng d i y. Trong mi nhm phn loi
theo tn sut, cc tc dng khng mong mun c sp xp theo th t mc nghim trng
gim dn. Cc nhm phn loi tn sut c quy c nh sau:
Rt hay gp ( 1/10),
Hay gp ( 1/100 t i < 1/10),
t gp ( 1/1.000 t i < 1/100),
Him gp ( 1/10.000 t i < 1/1.000),

Bng 1: Tt c cc phn ng c hi ca thuc trong qu trnh iu tr c bo co trn

cc bnh nhn trong th nghim lm sng pha III (RECORD 1-4 gp, ROCKET,
J-ROCKET, MAGELLAN, ATLAS v EINSTEIN (DVT/PE/Extension))
Nhm h c quan
Hay gp t gp Him gp
(MedDRA)
Cc ri lon trn mu v Thiu mu (bao gm c Tng tiu cu nguyn pht
h bch huyt thng s xt nghim tng (bao gm tng s lng
ng) tiu cu) A
Cc ri lon trn tim Nhp tim nhanh
Cc ri lon trn mt Chy mu mt (bao gm
xut huyt mng kt mc)

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 9

 Bng 1: Tt c cc phn ng c hi ca thuc trong qu trnh iu tr c bo co trn
cc bnh nhn trong th nghim lm sng pha III (RECORD 1-4 gp, ROCKET,
J-ROCKET, MAGELLAN, ATLAS v EINSTEIN (DVT/PE/Extension))
Nhm h c quan
Hay gp t gp Him gp
(MedDRA)
Cc ri lon tiu ha Chy mu n u rng Kh ming
Xut huyt tiu ha (bao
gm c xut huyt trc
trng)
au d dy rut v au
bng
Kh tiu
Bun nn
To bn A
Tiu chy
Nn A
Cc ri lon chung v St A Cm gic khng khe Ph ti ch A
cc phn ng xy ra ti Ph ngoi vi (bao gm kh chu)
v tr a thuc Gim sc lc v nng
lng chung (bao gm c
mt mi v suy nhc)
Cc ri lon gan-mt Bt thng chc nng gan Vng da
Cc ri lon h min Phn ng d ng
dch Vim da d ng
Tn thng, c tnh v Chy mu hu phu (bao Vt thng xut tit A Gi phnh mch
bin chng hu phu gm c thiu mu hu
phu v xut huyt vt
m)
ng dp
Cc xt nghim Tng nng cc Tng nng bilirubin Tng nng bilirubin
transaminase Tng nng phosphatase lin hp (c ng hoc
kim trong mu A khng c ng v i tng
Tng LDH A ALT)
Tng lipase A
Tng amylase A
Tng GGT A
Cc ri lon trn h c au chi A T mu kh p Xut huyt c
xng v m lin kt
Cc ri lon thn kinh Chong vng Chy mu no v ni s
trung ng au u Ngt

Cc ri lon thn v tit Xut huyt ng niu-

niu sinh dc (bao gm i
mu v rong kinh B)
Suy thn (bao gm c tng
creatinin mu, tng ur
mu A)

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 10

 Bng 1: Tt c cc phn ng c hi ca thuc trong qu trnh iu tr c bo co trn
cc bnh nhn trong th nghim lm sng pha III (RECORD 1-4 gp, ROCKET,
J-ROCKET, MAGELLAN, ATLAS v EINSTEIN (DVT/PE/Extension))
Nhm h c quan
Hay gp t gp Him gp
(MedDRA)
Cc ri lon ng h Chy mu cam
hp Ho ra mu
Cc ri lon da v m Nga (bao gm c nhng My ay
d i da trng hp nga ton thn
t gp)
Pht ban
Bm tm
Xut huyt ti da v d i
da
Cc ri lon trn mch H huyt p
T mu
A
quan st sau phu thut chnh hnh chi d i
B
c ghi nhn trong iu tr VTE, hay gp ph n < 55 tui
C
quan st khng thng xuyn trong tr liu ACS (sau khi can thip qua da)
< Cch trnh by cc thut ng ADR da trn MedDRA phin bn 14.1 >

Cc kho st sau khi thuc a ra th trng

Ph mch v ph do d ng c bo co sau khi thuc a ra th trng i km theo thi gian
v i s dng Xarelto.
Thng bo cho bc s nhng tc dng khng mong mun gp phi khi s dng thuc.
Qu liu v cch x l
Cc trng hp qu liu him ln n 600 mg c bo co, khng c cc bin chng chy mu
hoc cc phn ng c hi khc. Do s hp thu b gi i hn, nn tc dng trn khng tng thm s
phi nhim huyt tng trung bnh c mong i mc liu trn liu iu tr t 50 mg tr ln,.
Hin cha c cht gii c c hiu i khng tc dng dc lc hc ca rivaroxaban. S dng
than hot gim hp thu trong trng hp qu liu Xarelto c xem xt. Do rivaroxaban gn
kt v i protein trong huyt tng cao nn ngi ta cho rng khng th thm tch c.
X tr chy mu
Trn bnh nhn ung rivaroxaban nu xy ra bin chng chy mu, th nn tm ngng liu iu tr
tip theo hoc ngng hn iu tr nu thch hp. Rivaroxaban c thi gian bn thi khong 5 n
13 gi. Vic x tr cho ring tng c nhn t y theo mc nng v v tr xut huyt. C th s
dng cc bin php iu tr triu chng nu cn thit, nh s dng thit b p c hc (nh v i chy
mu cam nng), s cm mu trong phu thut v i cc quy trnh kim sot chy mu, truyn dch
v cc bin php h tr huyt ng, cc sn phm mu (hng cu lng hoc huyt tng ng lnh
ti t y thuc vo tnh trng thiu mu hoc bnh ng mu i km) v tiu cu.
Nu khng th kim sot tnh trng chy mu bng cc bin php trn, nn xem xt s dng thuc
c hiu o chiu cht tin ng mu nh phc hp prothrombin c c (PCC), phc hp
prothrombin hot ha c c (APCC) hoc yu t VIIa ti t hp (r-FVIIa). Tuy nhin, hin gi c
rt t kinh nghim lm sng v vic s dng nhng ch phm ny trn nhng bnh nhn d ng
Xarelto.
Protamin sulfat v vitamin K khng c cho l c nh hng ln hot tnh chng ng ca
rivaroxaban.

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 11

Khng c kinh nghim v vic s dng cc thuc chng s phn hy si fibrin (acid tranxenamic,
acid aminocaproic) trn cc bnh nhn d ng Xarelto. Khng c ly do li ch v mt khoa hc cng
nh khng c kinh nghim s dng v i cc cht cm mu ton thn desmopressin v aprotinin
cc bnh nhn d ng Xarelto.
c im dc l hc
1. c tnh dc lc hc
Nhm thuc tr liu: thuc chng huyt khi
M ATC: B01AX06
C ch tc dng
Rivaroxaban l mt cht c ch trc tip chn lc cao i v i yu t Xa v i sinh kh dng qua
ng ung.
S hot ha yu t X thnh yu t Xa (FXa) qua con ng ni sinh v ngoi sinh ng vai tr
trung tm trong dng thc ng mu. FXa trc tip bin i prothrombin thnh thrombin thng
qua phc hp prothrombinase v cui c ng, dn n s hnh thnh cc mu ng fibrin v hot
ha tiu cu bi thrombin. Mt phn t FXa c kh nng to ra trn 1000 phn t thrombin do bn
cht khuch i ca dng thc ng mu. Ngoi ra, t l phn ng ca prothrombinase-gn FXa
tng ln gp 300.000 ln so v i FXa dng t do v dn n s b ng n to thrombin. Cc cht
c ch chn lc FXa c th km hm qu trnh b ng n khuch i to thrombin. Kt qu l mt s
test chung v c hiu v to cc mu ng b nh hng bi rivaroxaban. S c ch hot tnh
yu t Xa ph thuc liu d ng c ghi nhn trn ngi.
Tc dng dc lc hc
S c ch yu t Xa ph thuc liu d ng c ghi nhn trn ngi. Thi gian prothrombin (PT) b
nh hng bi rivaroxaban theo cch ph thuc liu v i mi tng quan gn v i nng thuc
trong huyt tng (gi tr r bng 0,98) nu s dng Neoplastin. Cc thuc th khc s cho kt qu
khc nhau. Kt qu ca PT c biu th theo giy, bi ch s INR (International Normalized
Ratio) ch c nh c v c gi tr cho coumarin v khng c s dng cho bt k thuc chng
ng no khc.
bnh nhn s dng rivaroxaban iu tr DVT v d phng ti pht DVT v PE, bch phn v
5/95 ca PT (Neoplastin) 2-4 gi sau khi ung thuc (ngha l thi im thuc c tc dng ti
a) ln lt trong gi i hn t 16 giy n 33 giy cho liu 15 mg ngy 2 ln hoc t 15 giy n
30 giy cho liu 20 mg ngy 1 ln.
bnh nhn rung nh khng do bnh l van tim s dng rivaroxaban d phng t qu v
thuyn tc mch ton thn, bch phn v 5/95 cho PT (Neoplastin) 1-4 gi sau khi ung vin thuc
(ngha l thi im thuc c tc dng ti a) ln lt trong gi i hn t 14 giy n 40 giy cho
liu 20 mg ngy 1 ln hoc t 10 giy n 50 giy bnh nhn suy gim chc nng thn mc
trung bnh c iu tr v i 15 mg ngy 1 ln.
Thi gian prothrombin c hot ha tng phn (aPTT) v HepTest cng b ko di ph thuc
liu d ng; tuy nhin, cc xt nghim ny khng c khuyn co nh gi tc dng dc lc
hc ca rivaroxaban. Rivaroxaban cng nh hng n hot tnh khng v i yu t Xa; tuy nhin,
hin cha c chun nh gi.
Khng cn theo di cc thng s ng mu trong thi gian iu tr bng Xarelto.
SPAF: Hiu qu lm sng v an ton
Cc chng trnh th nghim lm sng c thit k chng minh hiu qu ca Xarelto trong d
phng t qu v thuyn tc ton thn bnh nhn rung nh (AF) khng do bnh l van tim.
Trong nghin cu m i then cht ROCKET-AF, 14264 bnh nhn c s dng hoc Xarelto
20 mg d ng ng ung ngy 1 ln (15 mg d ng ng ung ngy 1 ln bnh nhn suy gim
chc nng thn mc trung bnh (CrC: <50-30 mL/pht) hoc warfarin chun t i mc tiu

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 12

INR 2,5 (khong iu tr 2,0-3,0). Thi gian iu tr trung bnh l 19 thng v tng ton b thi
gian iu tr l 41 thng.
34,9% bnh nhn ang iu tr bng ASA v 11,4% dng thuc chng lon nhp tim nhm III bao
gm amiodaron.
Tng t nh warfarin, Xarelto lm gim ng k kt cc chnh hn hp t qu v thuyn tc
ton thn ngoi h thn kinh trung ng. Ngoi ra, cc kt cc ph th yu (hn hp t qu,
thuyn tc ton thn ngoi h thn kinh trung ng v t vong do bnh mch mu v hn hp t
qu, thuyn tc ton thn ngoi h thn kinh trung ng, nhi mu c tim v t vong do bnh
mch mu) cng gim r rt. (xem Bng 2). T l xut hin i v i kt qu chnh v an ton (bin
c chy mu lin quan lm sng nng hoc khng nng) tng t nhau c hai nhm iu tr (xem
Bng 3).
Bng 2: Kt qu v hiu qu t th nghim pha III ROCKET AF
Phn tch ITT v hiu qu trn bnh nhn rung nh khng do bnh
Dn s nghin cu
l van tim
Xarelto Warfarin
20 mg ung ngy 1 ln chun n mc tiu T s ri ro
(15 mg ung ngy 1 ln INR 2,5 (gi i hn tr (khong tin cy
Liu iu tr bnh nhn c liu 2,0 n 3,0) 95%)
CrC: <50-30 mL/pht) gi tr p, test cho
T l bin c T l bin c tnh tri hn
(100 bnh nhn-nm) (100 bnh nhn-nm)
t qu, thuyn tc ton
306 0.88 (0.74 1.03)
thn ngoi h thn kinh 269 (2.12)
(2.42) 0.117
trung ng
t qu, thuyn tc ton
thn ngoi h thn kinh 572 (4.51) 609 0.94 (0.84 1.05)
trung ng, t vong do (4.81) 0.265
bnh mch mu
t qu, thuyn tc ton
thn ngoi h thn kinh
0.93 (0.83 1.03)
trung ng, t vong do 659 (5.24) 709 (5.65)
0.158
bnh mch mu, nhi
mu c tim
0.90 (0.76 1.07)
t qu 253 (1.99) 281(2.22)
0.221
Thuyn tc ngoi h 20 27 0.74 (0.42 -1.32)
thn kinh trung ng (0.16) (0.21) 0.308
0.91 (0.72 1.16)
Nhi mu c tim 130 (1.02) 142 (1.11)
0.464

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 13

 Bng 3: Kt qu v an ton t th nghim pha III ROCKET AF
Dn s nghin cu Bnh nhn rung nh khng do bnh l van tim a)
Warfarin
Xarelto chun n mc tiu
20 mg ung ngy 1 ln INR 2,5 (gi i hn tr
(15 mg ung ngy 1 ln liu 2,0 n 3,0) T s ri ro
bnh nhn c (khong tin cy
Liu iu tr CrC: <50-30 mL/pht) 95%)
N=7061 gi tr p
T l bin c N=7082
(100 bnh nhn-nm) T l bin c
(100 bnh nhn-nm)
Cc bin c chy mu
1475 1449 1,03 (0,96 1,11)
lin quan lm sng nng
(14,91) (14,52) 0,442
hoc khng nng
Cc bin c chy mu 395 386 1,04 (0,90 1,20)
nng (3,60) (3,45) 0,576
27 55 0,50 (0,31 0,79)
T vong ** (0,24) (0,48) 0,003
Chy mu c 91 133 0,69 (0,53 0,91)
quan quan trng (0,82) (1,18) 0,007
**
Chy mu ni s 55 84 0,67 (0,47 0,93)
** (0,49) (0,74) 0.019
Gim nng 305 254 1,22 (1,03 1,44)
hemoglobin** (2,77) (2,26) 0,019
Truyn 2 hoc 183 149 1,25 (1,01 1,55)
nhiu hn 2 n v (1,65) (1,32) 0,044
hng cu lng hoc
mu ton phn **
Bin c chy mu lin
1185 1151 1,04 (0,96 1,13)
quan lm sng khng
(11,80) (11,37) 0,345
nng
a) dn s an ton, trong iu tr
** t c ngha
iu tr VTE: Hiu qu lm sng v an ton
Chng trnh nghin cu lm sng Xarelto c thit k chng minh hiu qu ca Xarelto
trong iu tr khi u v iu tr lin tc DVT cp tnh v d phng DVT v PE.
Cc nghin cu lm sng pha III ngu nhin c i chng (Einstein DVT v Einstein m rng)
trn 4600 bnh nhn tham gia.
Thi gian iu tr c kt hp ni chung trn c 2 nghin cu l 21 thng.
Trong nghin cu Einstein DVT, 3449 bnh nhn c DVT cp tnh c nghin cu iu tr
DVT v d phng ti pht DVT v PE . Thi gian iu tr ln n 12 thng t y theo nh gi lm
sng ca ngi nghin cu.
Trong 3 tun u tin iu tr DVT cp tnh, Xarelto 15 mg c ch nh ngy 2 ln. Sau , s
dng liu Xarelto 20 mg ngy 1 ln.
Phc iu tr v i thuc so snh gm enoxaparin c ch nh t nht 5 ngy kt hp v i thuc

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 14

khng vitamin K cho t i khi PT/INR nm trong gi i hn iu tr (2,0). iu tr tip tc bng
thuc khng vitamin K v i liu c chnh duy tr cc gi tr PT/INR nm trong khong iu tr
2,0-3,0.
Trong nghin cu Einstein m rng 1.197 bnh nhn mc DVT v PE c nghin cu d
phng ti pht DVT v PE. Thi gian iu tr ln n 12 thng t y theo nh gi lm sng ca
ngi nghin cu. Xarelto 20 mg ngy 1 ln c so snh v i placebo.
C hai nghin cu pha III c ng s dng cc tiu ch nh gi hiu qu iu tr c xc nh
tr c. Tiu ch chnh nh gi hiu qu iu tr l VTE ti pht c triu chng c nh ngha l
hn hp DVT ti pht hay PE gy t vong hoc khng gy t vong. Tiu ch ph nh gi hiu
qu iu tr c nh ngha l DVT ti pht, PE khng gy t vong v t vong do mi nguyn
nhn.
Trong nghin cu EINSTEIN DVT (xem bng 4), i v i tiu ch chnh nh gi hiu qu, Xarelto
cho thy khng km hn enoxaparin/VKA. NCB c nh tr c (tiu ch nh gi hiu qu
chnh kt hp cc bin c chy mu nng) c bo cov i HR l 0,67 ((khong tin cy 95% =
0,47-0,95), gi tr p nh (p 0.027) thun li cho rivaroxaban. T l xut hin cho tiu ch nh
gi an ton chnh(cc bin c chy mu nng hoc khng nng v lm sng) cng nh tiu ch ph
nh gi an ton (bin c chy mu nng) tng t nhau c hai nhm iu tr.
Trong nghin cu EINSTEIN M RNG (xem Bng 5), Xarelto hiu qu hn so v i placebo c
tiu ch nh gi hiu qu chnh v ph. i v i tiu ch chnh nh gi an ton (cc bin c
chy mu nng), t l xut hin cao hn khng c ngha v s lng cho bnh nhn iu tr bng
Xarelto 20 mg ngy 1 ln so v i nhm d ng placebo. Tiu ch ph nh gi an ton (cc bin
c chy mu nng hoc khng nng lin quan v lm sng) cho thy t l cao hn i v i bnh
nhn iu tr bng Xarelto 20 mg ngy 1 ln so v i placebo.
Bng 4: Kt qu v hiu qu v an ton t nghin cu pha III EINSTEIN DVT
3449 bnh nhn b huyt khi tnh mch su cp tnh c
Dn s nghin cu
triu chng
Enoxaparin/ VKAb
a
Xarelto trong 5 ngy
Liu dng v thi gian iu 3, 6 hoc 12 thng sau d ng VKA
tr 3, 6 hoc 12 thng
N=1731
N=1718
36 51
VTE ti pht c triu chng* (2,1%) (3,0%)
20 18
PE ti pht c triu chng
(1,2%) (1,0%)
Triu chng ti pht DVT ti 14 28
pht c triu chng (0,8%) (1,6%)
1
PE v DVTc triu chng 0
(0,1%)
T vong do PE/T vong 4 6
trong khng loi tr PE (0,2%) (0,3%)
Chy mu nng hay chy
mu khng nng c lin quan 139 (8.1%) 138 (8.1%)
v lm sng
14 20
Cc bin c chy mu nng
(0,8%) (1,2%)
a) Rivaroxaban 15 mg ngy hai ln trong 3 tun sau 20 mg ngy mt ln.
b) Enoxaparin trong t nht 5 ngy, c chng cho nhau v i VKA v tip theo VKA
* p < 0.0001 (tnh khng km hn i v i hazard ratio c nh r tr c l 2.0); hazard ratio: 0.680

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 15

 (0.443 - 1.042), p 0.076 (tnh tri hn)

Bng 5: Kt qu v hiu qu v an ton t nghin cu pha III EINSTEIN M

RNG
119 bnh nhn tip tc iu tr v d phng ti pht thuyn
Dn s nghin cu
tc huyt khi tnh mch
Xarelto 20 mg ngy 1 ln Placebo
Liu dng v thi gian iu trong 6 hoc 12 thng trong 6 hoc 12 thng
tr
N=602 N=594
8 42
VTE ti pht c triu chng* (1,3%) (7,1%)
2 13
PE ti pht c triu chng
(0,3%) (2,2%)
5 31
DVT ti pht c triu chng
(0,8%) (5,2%)
T vong do PE/T vong 1 1
trong khng loi tr PE (0,2%) (0,2%)
4 0
Cc bin c chy mu nng
(0,7%) (0,0%)
* p: < 0,0001 (tri hn)
HR: 0,185 (0,087 0,393)
nh hng ln khong QTc
Khng ghi nhn tc dng ko di khong QTc nam v n gi i khe mnh trn 50 tui.
2. c tnh dc ng hc
Hp thu v sinh kh dng
Rivaroxaban c hp thu nhanh, v i nng ti a (Cmax) sau 2-4 gi ung thuc.
Rivaroxaban hp thu hu nh hon ton qua ng ung v sinh kh dng ng ung cao (80
100%) v i vin 10 mg, bt k ung thuc tnh trng i/no. Vic s dng thuc c ng v i thc n
khng lm nh hng n AUC hoc Cmax ca rivaroxaban liu 10 mg. Xarelto vin 10 mg c
th dng cng hoc khng c ng v i thc n (xem phn Liu dng v cch dng).
Do mc hp thu gim, sinh kh dng ng ung ca vin Xarelto 20 mg ung lc i ch t
66%. Khi ung Xarelto 20 mg c ng v i thc n lm tng AUC trung bnh 39% so v i khi ung
thuc vo lc i, cho thy thuc hp thu hu nh hon ton v c sinh kh dng ng ung cao
(xem phn Liu dng v cch dng).
tnh trng no, s hp thu ca vin Xarelto 10 mg, 15 mg, 20 mg t l thun v i liu dng.
Tnh bin thin trong dc ng hc ca rivaroxaban va phi v i tnh bin thin gia cc c th
(CV%) trong gi i hn t 30% n 40%.
Phn b
Gn kt protein trong huyt tng ngi cao, xp x khong 92% n 95% v i albumin huyt
tng l thnh phn gn kt chnh. Th tch phn b mc trung bnh v i Vss khong 50L.
Chuyn ha v thi tr
Trong liu rivaroxaban ung vo c khong 2/3 liu b thoi bin theo chuyn ha, v i mt na
sau c thi tr qua thn v mt na kia b thi tr qua ng phn. 1/3 liu d ng cn li thi
tr trc tip qua thn d i dng hot cht khng i trong n c tiu, phn l n qua s bi tit ch
ng ca thn.

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 16

Rivaroxaban c chuyn ha qua cc c ch CYP 3A4, CYP 2J2 v c ch khng ph thuc
CYP. S thoi bin do oxyd ha nhm morpholinone v thy phn cc lin kt amid l cc v tr
ch yu ca s bin i sinh hc. Theo cc nghin cu in vitro th rivaroxaban l mt cht nn ca
cc protein vn chuyn P-gp (P-glycoprotein) v B crp (protein khng ung th v).
Rivaroxaban dng khng i l hp cht quan trng nht trong huyt tng ngi v i s c mt
ca cc cht chuyn ha khng quan trng hoc c hot tnh ang lu hnh. thanh thi ton
phn ca rivaroxaban l khong 10 L/h, c xp vo nhm thuc c thanh thi thp. S thi
tr rivaroxaban khi huyt tng xy ra v i thi gian bn thi khong 5-9 gi ngi tr v
khong 11-13 gi ngi gi.
Bnh nhn lo khoa
bnh nhn cao tui, nng thuc trong huyt tng cao hn ngi tr tui v i gi tr AUC
trung bnh cao hn xp x gp 1,5 ln, phn l n do gim (r rng) thanh thi ton phn v
thanh thi qua thn (xem phn Liu dng v cch dng).
Gii
Gia bnh nhn nam v n khng c s khc bit v dc ng hc trn lm sng (xem phn
Liu dng v cch dng).
S khc bit v cc loi cn nng
Cc mc thi cc ca cn nng c th (< 50 kg so v i 120 kg) ch c nh hng nh ln nng
rivaroxaban trong huyt tng (d i 25%) (xem phn Liu dng v cch dng).
Tr em v thanh thiu nin
an ton v hiu qu ca thuc tr em v thanh thiu nin d i 18 tui cha c thit lp
(xem phn Liu dng v cch dng).
S khc nhau gia cc dn tc
Khng c s khc nhau v dc ng hc v dc lc hc lin quan lm sng gia cc bnh nhn
da trng, ngi M gc Phi, Ty Ba Nha hoc B o Nha, Nht bn v Trung Quc (xem phn
Liu dng v cch dng).
Suy gim chc nng gan
nh hng ca s suy gim chc nng gan ln dc ng hc ca rivaroxaban c nghin cu
trn cc i tng c phn nhm theo h thng xp loi Child Pugh, mt quy trnh chun trong
pht trin lm sng. Mc ch ban u ca xp loi Child Pugh l nh gi tin lng bnh gan
mn tnh, ch yu l x gan. bnh nhn d nh d ng thuc chng ng, iu quan trng ca
suy gim chc nng gan l gim tng hp cc yu t ng mu bnh thng gan. V iu ny ch
o c nh mt trong nm o lng lm sng/ha sinh trong h thng phn loi Child Pugh, nn
khng c mi tng quan r rng gia nguy c chy mu bnh nhn v i s sp xp phn loi
ca h thng ny. Do , quyt nh iu tr thuc chng ng cho bnh nhn phi c lp v i xp
loi Child Pugh.
Chng ch nh Xarelto cc bnh nhn mc bnh gan i km v i bnh ng mu, dn n nguy
c chy mu lin quan lm sng (xem phn Chng ch nh).
bnh nhn x gan suy gim chc nng gan mc nh (c xp loi Child Pugh A) dc
ng hc ca rivaroxaban ch thay i nh (trung bnh AUC ca rivaroxaban tng 1,2 ln), gn
nh tng ng v i mc t c nhm i chng khe mnh. Khng ghi nhn thy s khc
bit c lin quan v c tnh dc lc hc gia cc nhm ny.
bnh nhn x gan suy gim chc nng gan mc trung bnh (c xp loi Child Pugh B),
AUC trung bnh ca rivaroxaban tng ng k, gp 2,3 ln so v i ngi tnh nguyn khe mnh
do s thanh thi thuc gim i ng k th hin bnh gan r rt. AUC khng gn kt tng gp 2,6
ln. Khng c d liu bnh nhn suy gim chc nng gan nng. S c ch hot ng ca yu t
Xa tng gp 2,6 ln so v i trn ngi tnh nguyn khe mnh; s ko di PT tng t tng gp 2,1
ln. PT trong xt nghim ng mu ton b nh gi con ng ngoi sinh bao gm cc yu t

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 17

ng mu VII, X, V, II v I c tng hp gan. Bnh nhn suy gim chc nng gan mc
trung bnh thng nhy cm hn v i rivaroxaban, dn n th biu din mi quan h Dc
ng hc/Dc lc hc (PK/PD) gia nng v PT tr nn dc ng hn.
Hin khng c d liu v cc bnh nhn Child Pugh C (xem phn Liu dng v cch dng
Chng ch nh).
Suy gim chc nng thn
S phi nhim ca rivaroxaban tng ln ngc li v i s gim chc nng thn c nh gi qua
thanh thi creatinin.
bnh nhn suy gim chc nng thn mc nh (CrC: <80-50 mL/pht), trung bnh (CrC:
<50-30 mL/pht) v nng (CrC: <30-15 mL/pht), nng rivaroxaban trong huyt thanh (AUC)
ln lt tng gp 1,4, 1,5 v 1,6 ln so v i ngi tnh nguyn khe mnh (xem phn Liu dng
v cch dng, Cnh bo c bit v thn trng khi s dng).
S tng tc dng dc lc hc tng ng r rt hn (xem phn Liu dng v cch dng, Cnh
bo c bit v thn trng khi s dng)..
bnh nhn suy gim chc nng thn mc nh, trung bnh v nng, s c ch hot ng ca
yu t Xa ni chung tng ln lt gp 1,5, 1,9 v 2,0 ln so v i ngi tnh nguyn khe mnh,
s ko di PT tng t tng tng ng l gp 1,3, 2,2 v 2,4 ln. Khng c d liu v bnh nhn
c CrC <15 mL/pht.
Khuyn co khng s dng thuc bnh nhn c thanh thi creatinin <15 mL/pht. Nn thn
trng khi s dng Xarelto bnh nhn suy gim chc nng thn nng c thanh thi creatinin
15-30 mL/pht. (xem phn Liu dng v cch dng, Cnh bo c bit v thn trng khi s
dng).
Do bi bnh nn, nn nhng bnh nhn c suy gim chc nng thn nng c nguy c tng c chy
mu v huyt khi.
3. D liu an ton tin lm sng
D liu khng phi lm sng cho thy khng c nguy c c bit cho ngi da trn cc nghin
cu quy c v dc l hc an ton, c tnh v i mt liu duy nht, c tnh v i nh sng, c
tnh v di truyn, kh nng sinh ung th v c tnh sinh sn.
Cc tc dng c quan st thy trong nhng nghin cu c tnh liu lp li u ch yu l do
hot tnh v dc lc hc tng qu mc ca rivaroxaban. Trn chut, nng IgG v IgA trong
huyt tng gia tng c thy nng phi nhim c lin quan v lm sng.
Trn chut, khng thy c nh hng ln kh nng sinh sn ca chut c v chut ci. Cc
nghin cu trn ng vt cho thy c tnh sinh sn lin quan n phng thc tc dng dc l
hc ca rivaroxaban (chng hn cc bin chng xut huyt). c tnh trn phi thai (mt phi thai
sau khi cy, s ha xng chm/tin trin, nhiu m sng mu sc trn gan) v tn sut xut hin
(incidence) cc d tt thng gp cng nh cc thay i ca nhau thai c quan st thy nhng
nng huyt tng c lin quan v lm sng. Trong nghin cu tr c v sau sinh chut, kh
nng sng ca chut con gim c quan st thy nhng liu lng c i v i chut m.
Tnh tng k
Khng r
Hn dng
36 thng
iu kin bo qun
Khng thuc nhit trn 30oC.
Quy cch ng gi
Hp thuc bao gm 1 v x 14 vin

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 18

Hng dn s dng/ x l
Khng

xa tm tay tr em
c k hng dn s dng trc khi dng
Nu cn thm thng tin, xin hi kin bc s

Sn xut bi: Bayer Pharma AG,

D-51368 Leverkusen, CHLB c

Ngy duyt ni dung tm tt sn phm: 15/01/2013

Xarelto 15mg, 20mg/CCDS 4/150113/PI VN01

Xarelto 15mg, 20mg/CCDS 4/15012013/PI VN01 19