31ilIPEH II3BEIIITAJ 3A OCOlilIHIITE HA JIEKOT

1. MME HA ME)J;lIIJ:lIHCKlIOT IIPOH3BO)J;

TeMo;::i:aJI, 5 mg, rnp;::i:H KancynH

TeMo;::i:aJI, 20 mg, rnp;::i:H KancynH
TeMo;::i:aJI, 100 mg, rnp;::i:H Kancyn11
TeMo;::i:aJI, 250 mg, rnp;::i:H KancynH

2. KBAJilIT ATlIBEH lI KBAHTlITATlIBEH COCT AB

CeKoja rnp.na Kancyna co.np)lnI 5 mg, 20 mg, 100 mg HJIH 250 mg TeMo30JIOMHJJ:.

EKcu11n11eHCH co no3HaT e<}?eKT:

CeKoja Tsp.na Kancyna o.n 5 mg co;::i:p)l{H 132,8 mg 6e3so;::i:tta naKTo3a.
CeKoja Tsp;::i:a Kancyna o.n 20 mg co.np)l{H 182,2 mg 6e3so.ntta naKT03a.
CeKoja rnp.na Kancyna o.n 100 mg co.np)l{H 175; 7 mg 6e3so;::i:Ha naKT03a.
CeKoja Tsp.na Kancyna o.n 250 mg co.np)l{H 154,3 mg 6e3so.ntta JiaKT03a.

3a uenocHa JIHCTa Ha eKcummeHCH, BH.JJ,eTe ;::i:en 6.1.

3. <l>APMAIJ:EBTCKA <l>OPMA

Tsp.na Kancyna (Kancyna).

TeMO.ll,aJI 5 mg, Tsp;::i:11 KancynH HMaaT 6eno, HenposH.JJ,HO Teno H 3eJieHa HenposH;::i:Ha Kana H ce 11cneYaTeHH co
upHo MaCTHJIO. KanaTa e HcneYaTeHa co " Temodal". TenoTo e 11cneYaTeHo co " 5 mg", noroTo Ha WepHHr-
ITnay H .nse neHTH.
T eMO.[f,aJI 20mg, TBp.ll,H KancyJIH HMaaT 6eno HenpOBHJJ:HO TeJIO H )l{OJITa HenpOBH;::J:Ha Kana 11 ce Hcne4aTeHH co
upHo MaCTHJIO. KanaTa e HcneYaTeHa co "Temodal". TenoTo e HcneYaTeHo co " 20 mg", JioroTo Ha Wep11Hr-
flnay H .nse neHTH.
TeMO.ll,aJI 1OOmg, TBPJJ:H Kancyn11 HMaaT 6eno HenpoBHJJ:HO Teno H po3eBa HenpoBH.[f,Ha Kana H ce 11cneYaTeH11
co upHo MaCTHJIO. KanaTa e 11cneYaTeHa co " Temodal" . TeJioTo e 11cneYaTeHo co "100 mg", noroTo Ha
Wep11Hr-ITJ1ay H ;::i:se neHTH.
T eMO.[f,aJI 250 mg, TBp.ll,H KancyJIH HMaaT 6eJTO HenpOBH.[f,HO TeJIO H 6ena Kana H ce Hcne4aTeHH co UPHO
MaCTHJTO. KanaTa e HcneYaTeHa co "Temodal". TenoTo e 11cneYaTeHo co "250 mg", noroTo Ha Wep11Hr-ITnay H
.nse JieHTH.

4. KJilIHliqKlI OCOI>EHOCTlI

4.1 TepaneBTCKH HHJJ:HKaQHH

TeMo.naJI Kancym1Te ce HHA,!1UHpaHH 3a Tepan11ja Ha:

B03pacHH rrautteHTH co HOBOOTKptteH MYJITHcpOpMeH rJIH06JTaCTOM HCTOBpeMeHO co pa.ll,HOTepanHJa
(RT) 11 no;::i:ouHa KaKo MOH0Tepan11ja .
.neua Ha.n TPH ro;::i:HHH, a.nonecueHTH 11 so3pacHH rrau11eHTH co MaJIHrtteH rnHoM , KaKo MYJITHcpopMeH
rJIH06JiaCTOM HJIH aHanJiaCTH4eH acTpOUHTOM, KOj CC'- nOBTOpysa HJIH Harrpe;::i:ysa nocne CTaH.ll,ap.nHa
TepanHJa.
4.2 ,[(o3ttpalbe H uaquu ua ynoTpe6a

TeMO,ll,aJI Tpe6a ,ll,a npem1wyBaaT caMO JieKap.11 co HCKYCTBO BO OHKOJIOWKHOT TpeTMaH Ha M0304Hl1 TYMOpH .

Mo)Ke ,ll,a ce ,ll,a,ll,e 11 aHrn-eMeTH4Ha Tepan11ja (B.11,ll,eTe ,ll,eJI 4.4).

B03pQCHu nQyueHmu co HoeooujQZHocmuyupQH MW1murjJopMeH 2J1uo6J1QcmoM

TeMo,ll,aJI ce ,ll,aBa Bo KOM611Hau,11ja co <t>oKaJIHa pa,ll,.110Tepan11ja (KoHKOMHTaHTHa <Pa3a), npocne,ll,eHa co

MOHOTeparmja Ha TeM030JIOM.11,ll, (TMZ) ,ll,O 6 LJ,HKJiyca (MOHOTepanHCKa <Pa3a).

KoHKOMUmQHmHQ cjJQJQ

TMZ ce ,ll,aBa nepopa11Ho BO ,ll,03a O,ll, 75 mg/m 2 ,ll,HeBHO BO TeK Ha 42 ,ll,eHa npH,ll,py)KeHo co <t>oKaJIHa
pa,ll,110Tepan.11ja (60 Gy ,ll,a,ll,eH.11 BO 30 <t>paKu,11.11). He ce npenopa4yBa HaManyBaH>e Ha ,ll,03aTa, HO 3a
0,ll,JIO)KyBalbe HJIH npeK.HH Ha ,ll,aBalbeTO Ha TeM030JIOM.11,ll, ce O,ll,JIY4YBa He,l],eJIHO, BO cornaCHOCT co
xeMaTOJIOWKHTe .11 HexeMaTOJIOWKHTe Kp11Tep.11yM.11 3a TOKCH4HOCT. JJ:aBaH>eTo Ha TMZ MO)Ke ,ll,a ce npo,ll,OJI)K.11
BO TeK Ha 42 ,l],eHa 0,ll, KOHKOMHTaHTHHOT nep.110,ll, (,ll,O 49 ,ll,eHa), ,ll,OKOJIKY ce 3a,ll,OBOJieH.H CHTe 0,ll, CJie,ll,H.HBe
yc110B.11:
BKyneH 6poj Ha HeyTPo<t>.111111 ~ 1,5 x 109/J,
6poj Ha TpOM60LJ,l1T.11 ~ 100 x 109/I,
OnwT Kp11Tep11yM 3a TOKCH4HOCT (Common Toxicity Criteria-CTC) HexeMarnnowKa TOKCH4HOCT ::5
CTeneH 1 (ocBeH 3a a11oneu,11ja, ra,ll,eH>e 11 noBpaK:aH>e).
3a BpeMe Ha Tepan.11jarn, e,ll,Haw He,ll,eJIHO Tpe6a ,ll,a ce npaBH KOMnJieTHa KpBHa c1111Ka. JJ:aBaH>eTo Ha TMZ
Tpe6a np11BpeMeHo ,ll,a ce npeKpaTH .111111 TpajHo ,ll,a ce npeKHHe 3a BpeMe Ha KOHKOMHTaHTaHaTa <Pa3a BO
cornacHocT co xeMaTOJIOWKHTe 11 HexeMaTOJIOWKHTe Kp11Tep11yM11 3a TOKCH4HOCT HaBe,ll,eH.11 BO Ta6e11a l.

TQ6eJIQ 1. llpeKUH UJIU npecmQHOK HQ OQBQrbe HQ TMZ 3Q epeMe HQ KOHKOMUmQHmHQ pQOUomepQnU}Q co

TMZ
ToKcuquocT IlpeKHH ua TMza IlpecrnuoK ua TMZ
BKyneH 6poj Ha HeyTpoqrn1111 ~ 0,5 l1 < 1,5 x 109/I <0,5x10 9/I
Epoj Ha TpoM6ou,.11rn ~ 10 11 < 100 x 109/I < 10 x 109/I
CTC HexeMaTonowKa TOKCH4HOCT
(ocBeH 3a a11oneu,.11ja, ra,ll,eH>e 11 noBpafaH>e) CTC CTeneH 2 CTC CTeneH 3 111111 4
a: Tepam1jarn co KOHKOMHTaHTeH TMZ MO)Ke )la npoJlOJI)KH JlOKOJIKY ce 3a)loeoneH11 c11Te Oil cne)lHHBe ycnoe11: BKyneH 6poj Ha
tteyTpoqmn11 ~ 1,5 x I 09/1, 6poj Ha TpoM6ou,11rn ~ I 00 x 109/1, CTC HexeMaTOJIOlllKa TOKCH4HOCT ~ CTeneH 1 (oceeH 3a
anoneu,11ja, ra)le!he 11 noepaka!he).
TMZ = TeM030JIOMHJl; CTC (Common Toxicity Criteria)= OnlllT Kp11Tep11yM 3a TOKCH4HOCT.

<!JaJQ HQ MOHomepQnujQ

qeT11p11 He,ll,eJIH no 3aBpwyBalheTo Ha KOHKOMHTaHTHarn <Pa3a TMZ + RT, TMZ ce ,ll,aBa KaKo MOHOTepan11ja
HajMHOry ,ll,O 6 LJ,HKJIYCH. JJ:03arn BO I-OT LJ,HKJIYC (MOHOTepan.11ja) e 150 mg/m2 e,ll,Haw ,ll,HeBHO BO poK O,ll, 5
,ll,eHa no KOH cne,ll,aT 23 ,ll,eHa 6e3 Tepan11ja. Ha no4eTOKOT O,ll, 2-oT u,11K11yc ,ll,03aTa ce 3ro11eMyBa ,ll,O 200 mg/m 2
,ll,OKOJIKY CTC HexeMaTonowKaTa TOKCH4HOCT 3a 1-oT u,11K11yc e ::5 cTeneH 2 ( ocBeH 3a a11oneu,11ja, ra,ll,eH>e 111111
noBpafaH>e), BKynHHOT 6poJ Ha HeyTpo<t>111111 e ~ 1,5 x 109/1, a 6pojoT Ha TpoM6ou,11rnTe e ~ 100 x 109/I. AKo
,ll,03aTa BO 2-0T LJ,HKJIYC He e 3roJieMeHa, TOraw He Tpe6a ,ll,a ce 3fOJieMyBa HHTY BO Hape,ll,HHTe LJ,HKJIYCH. illTOM
,ll,03aTa K:e ce 3ro11eM.11 e,ll,Haw, rnraw ma ocrnHyBa Ha 200 mg/m2 ,ll,HeBHO BO npB.11Te 5 ,ll,eHa O,ll, ceKoj Hape,ll,eH
LJ,HKJiyc, OCBeH aKO ce nojaBH TOKC.114HOCT. HaMaJiyBalhe l1 npc~.HH Ha ,ll,03aTa npH MOHOTepan11jarn Tpe6a ,ll,a ce
npHMeHH BO cornacHOCT co rn6e11.11Te 2 .11' 3.

•.
Ha 22-oT JJ.eH OJJ. Tepamtjarn Tpe6a JJ.a ce HanpaBH KOMnJieTHa KpBHa CJIHKa (21 JJ.eH no npBaTa JJ.03a co TMZ).
,Il,03aTa Tpe6a JJ.a ce HaMaJIH l1Jll1 npeKHHe BO COrJiaCHOCT co rn6eJia 3.

Ta6eJ1a 2: ,4o3HU Hueoa Ha TMZ npu MOHomepanuja

.l(03HO HHBO .l(o3a (mg/m 2/JJ.uesuo) 3a6eneuum
-1 100 HaMa.rrysalhe nopa,ll,11 npeTXOJJ.Ha TOKCl1YHOCT
0 150 ,[J,03a 3a BpeMe Ha 1-0T ll,11KJIYC
1 200 ,[l,o3a 3a speMe Ha ll,11KJIYCl1 2-6 BO OTCYCTBO Ha TOKCJ1l-IHOCT

Ta6e!la 3: HaMa!lyeal-be UflU npeKUH Ha 003ama Ha TMZ 3a epeMe Ha MOHomepanujama

ToKcuquocT HaMaJiysalbe ua TMZ 3a 1 JJ.OJHO HHBOa IlpeKHH Ha TMZ
9
BKyneH 6poj Ha HeyTpocjrnm1 < 1,0 x 10 /L BttJJ.H KOMeHrnp 6
9
Epoj Ha TpoM6011,11m < 50 x 10 /L BttJJ.H KOMeHrnp 6
CTC HexeMaTonowKa TOKCl1YHOCT
( ocseH 3a a.rroneu11ja, ra)J,elbe 11 nospaKalbe) CTC cTeneH 3 CTC cTeneH 46
a: ,[(o3HHTe Httsoa Ha TMZ ce Hase,neHH so Ta6ena 2.
6: TMZ Tpe6a ,na ce npeKHHe ,noKOJJKy:
• )J,03HOTO HHBO -I (100 mg/m2) H noHaTaMy .nasa HenpmpaTJJHBa TOKCH"IHOCT
• HCTHOT cTeneH 3 Ha HexeMaTonowKa TOKCH'IHOCT ('ocseH 3a anoneu11ja, ra.neH>e, noapai<aH>e) ce noBTOpH no HaManysaH>eTo Ha
,n03aTa.

T MZ = TeM030JJOMHJJ:; CTC (Common Toxicity Criteria) = OnwT Kp11Tep11yM 3a TOKCH'IHOCT.

B03pacHU u neoujampUCKU nauueHmu HGO 3 200UHU u nocmapu co perypeHmeH UJlU .npo2pecueeH MGJlU2HeH
2JlUOM.'
TepanHCKHOT 1.1,11Knyc ornpafa 28 JJ.eHa. Kaj nau,HeHTH KOH npeTXOJJ.HO He npHMaJie xeMOTepanHja, TMZ ce JJ.aBa
nepopaJIHO BO JJ.03a OJJ. 200 mg/m 2 eJJ.Haw JJ.HeBHO BO npB11Te 5 JJ.eHa no Koe cJieJJ.11 23 JJ.HeBeH npeK11H Ha
Tepan11jarn (sKynHo 28 JJ.eHa). Kaj nau11eHT11 KOH npeTXOJJ.HO np11MaJie xeMoTepanHja, noqeTttarn JJ.03a e 150
mg/m 2 eJJ.HaIII JJ.HeBHO, Koja BO HapeJJ.Hl10T 1.1,HKJIYC JJ.OKOJIKY HeMa xeMaTOJIOIIIKa TOKCJ1qHOCT ce 3roJieMyBa Ha
200 mg/m 2 eJJ.HaIII JJ.HeBHO BO nepHOJJ. OJJ. 5 JJ.eHa (BHJJ.eTe JJ.eJI 4.4).

Iloce6Hu nonyflayuu

IleoujampucKa nonyfla'l/u}a
Kaj 3 fOJJ.11IIIHl1 11JI11 nocTapH nau11ettT11, TMZ ce JJ.aBa caMo 3a peKypeHTeH 11 nporpecHBeH Man11reH rJIHOM .
I1cKycTBOTO Kaj 0B11e JJ.eua e MHory orpaHHqeHo (s11JJ.eTe JJ.eJI 4.4 11 5.1). Ee36eJJ.ttocrn 11 ecp11KacHocrn Ha TMZ
Kaj JJ.eua Ha B03pacT nOJJ. 3 fOJJ.11Hl1 He e BOCTaHOBeHa. HeMa noJJ.aTOUH Ha pacnoJiaraine.

Ila'lfUeHmu co xenamaflHO UflU peHaflHO Hapymyeal-be

<l>apMaKoK11HeT11Karn Ha TMZ Kaj nau11eHT11 co ttopMaJIHa xenaTaJIHa cpyHK1.1,11ja e cnopeJJ.JIHBa co oHaa Ha
nau11eHT11Te co 6Jiaro 11JI11 yMepeHo xenarnJIHO HapyrnyBafbe. HeMa JJ.OCTanH11 noJJ.aTOUH 3a JJ.aBaineTo Ha TMZ
. Kaj nau,11ettTH co TernKo xenarnJIHO HapywyBaine (Child KJiaca-C (LI)) HJIH co peHaJIHO HapyrnyBafhe. CnopeJJ.
cpapMaKoK11tteT11qK11Te oco6HHH Ha TMZ, MaJIKY e Bepojarno JJ.eKa 11Ma noTpe6a OJJ. HaMaJiysaH>e Ha JJ.03arn Kaj
nau,HeHTH co TewKo xenaTaJIHO BapyrnyBaH>e 11JIH 611JI0 KaKOB cTeneH Ha peHaJIHO HapyrnyBaH>e. CenaK, Kora
TMZ ce JJ.asa Kaj 0B11e nau11ettTH Tpe6a JJ.a ce JJ.aBa co nperna3Jil1BOCT.

Ilocmapu na'lfUeHmu
CnopeJJ. cpapMaKoK11HeTHqK11Te aHan11311 Ha nonyJiau11jarn Kaj nau11ettTH OJJ. 19-78 roJJ.11IIItta B03pacT, crnpocrn
He BJI11jae Bp3 KJI11peHCOT Ha TMZ. CenaK, nocrnp11 nau,HeHTH (ttaJJ. 70 rOJJ.11IIIHa B03pacT) no ce 113rneJJ.a ce noJJ.
3roJieMeH p11311K OJJ. nojaBa tta HeyTponeH11ja 11 TpoM601.1,11Tonel'!__11ja (B11JJ.eTe )l,eJI 4.4).

Haq11H Ha aJJ.Ml1H11cTpau11ja

TeMOJJ.aJI TBPJJ.11Te KancyJIH Tpe6a JJ.a ce JJ.aBaaT Ha rnaJJ.ttO.

3 '" •' I
I
Kancymne Tpe6a )J.a ce nporonrnaT u,em1 co qawa BO)J.a H He cMee )J.a ce ornopaaT HJIH 1.rnaKaaT.

,ZJ.oKOJIKY ce jaBH noBpakafhe no )J.aBafheTO Ha )J.03aTa, TOraw BTopaTa )J.03a He Tpe6a )J.a ce )J.a)J.e BO HCTHOT )J.eH.

XHnepceH3HTHBHOCT KOH aKTHBHaTa cyncTaHIJ,Hja HJIH Ha 6HJIO KOj O)J. eKCIJ,HnHeHCHTe HaBe)J.eHH BO )J,eJT 6.1.

XHnepceH3HTHBHOCT KOH )J.aKap6a3HH ( dacarbazine - DTIC).

TewKa MHenocynpecHja (BH)J.eTe )J.eJT 4.4).

4.4 1Ioce6utt npe.n:ynpe.n:yBalha H npeTnaJJIHBOCT nptt ynoTpe6a

OnopmyHucmur-tKU uwjJeKyuu u peaKmueayuja Ha uHpeKyuu
3a BpeMe Ha TepanHjaTa co TMZ 3a6ene)KaHH ce onopTyHHCTHqKH HHcpeKu,HH (KaKo nHeBMOHHja O)J.
Pneumocystis jirovecii) H peaKTHBau,Hja Ha HHcpeKIJ,HH (KaKo X:5B, l(MB) (BH)l.eTe )l,eJT 4.8).

Pneumocvstis jirovecii nHeeMoHuja

TIHJIOT CTY.D.Hjarn co npo.n.OJI)KeH 42-)J.HeBeH pe)KHM noKa)KaJTa )J.eKa nocToH pH3HK O)J. pa3BHBafhe Ha
nHeBMOHHja npe)J.H3BHKaHa O,ll, Pneumocystis jirovecii (PCP) Kaj nau,HeHTH KOH npHMaJTe KOHKOMHTaHTHa
TepanHja Ha TMZ + pa)J.HOTepanHja. Cnope.n. TOa, Tpe6a )J.a ce cnpoBe.n.e npocpHnaKca npoTHB PCP Kaj CHTe
nau,HeHTH KOH npHMaaT KOHKOMHTaHTHa TepanHja Ha TMZ + pa.n.HoTepanHja BO 42-)J.HeBHHOT pe)KHM (co
MaKCHMYM o.n. 49 )J,eHa) He3aBHCHO o.n. 6pojoT Ha JTHMcpOU,HTHTe. ,ZJ.oKOJIKY ce nojaBH JTHMcponeHHja, Tpe6a )J,a ce
npo.n.OJJ)KH co npocjrnnaKcarn ce )J.O)J.eKa JTHMcponeHHjarn He ce noBpaTH )J.O CTeneH :S 1.

Kora TMZ ce )J.aBa no)J.onr nepHO)l. Toraw nocTOH 3roneMeHa MO)KHOCT 3a nojaBa Ha nHeBMOHHja O)J. PCP.
CenaK, Ha nau,HeHTHTe KOH npHMaaT TMZ, a oco6eHo Ha OHHe nau,HeHTH KOH npHMaaT cTepoH)J.H Tpe6a .n.a ce
BHHMaBa o.n. nojaBa Ha PCP, 6e3 pa3JIHKa Ha pe)KHMOT. TipHjaBeHH ce cnyqaH Ha cparnnHa pecnHpaTOpHa
cna6ocT Kaj nau,HeHTH KOH npHMane TMZ, oco6eHoBo KoM6HHau,Hja co )J.eKcaMeTa30H HJJH .n.pyrn cTepOH,ll,H.

XEB
TipHjaBeH e xenaTHTHC nopa)J.H peaKTHBau,Hja Ha BHpycoT Ha xenaTHTHC E (X5B), KOj BO HeKOH cnyqaH
pe3yJTTHpan co CMpTeH HCXO,ll,. Tipe)J. )J,a ce 3anoqHe co TepanHja Kaj nau,HeHTH co n03HTHBeH xenaTHTHC E
cepoJIOWKH TeCT (BKJTyqHTeJIHO H OHHe co aKTHBHO 3a6onyBafhe) Tpe6a .n.a ce KOHCYJTTHpaaT CTpyqfhaIJ,H 3a
xenaTaJTHH 3a6onyBafha. 3a BpeMe Ha TepanHjaTa nau,HeHTHTe Tpe6a .n.a 6H.n.aT coo.n.BeTHO Ha6.Jby)J.yBaHH H
TpeTHpaHH.

XenaToToKcHqHocT
XenaTaJJHH noBpe.n.H, BKnyqHTeJTHO H cpaTanHa xenaTaJIHa cna6ocT, npHjaBeHH ce MHory peTKO Kaj nau,HeHTH
neKyBaHH co TMZ (BH)J.eTe .n.en 4.8) . Tipe)J. 3anoqHyBafhe co TepanHjaTa Tpe6a .n.a ce HanpaBaT OCHOBHHTe
xenaTaJlHH cpyHKI.J,HOHaJTHH TeCTOBH. ,ZJ.oKOJTKY He ce BO HOpMaJTHH Bpe,ll,HOCTH, JieKapoT Tpe6a )l,a ro npou,eHH
O)J.HOCOT KOpHCT/pH3HK npe)J. 3anoqHyBafbe co TeM030JlOMH)J. BKJTyqyBajKH ja H MO)KHOCTa 3a cpaTaJJHa
xenaTaJJHa cna6ocT. Kaj nau,HeHTHTe Ha TpeTMaH co 42-)J.HeBeH I.J,HKnyc, xenaTaJIHHTe cpyHKIJ,HOHaJTHH TeCTOBH
Tpe6a .n.a ce noBTOpyBaaT .Ha cpe)J.HHa Ha OBOj l.l,HKJTyc. 3a CHTe nau,HeHTH, xenaTaJIHHTe cpyHKIJ,HOHaJTHH
TeCTOBH Tpe6a )J.a ce npoBepyBaaT no ceKoj I.J,HKnyc Ha TpeTMaH. Kaj nau,HeHTH co 3HaqHTeJTHH a6HopMaJTHOCTH
Ha xenarnnHaTa cpyHKI.J,Hja, neKapoT Tpe6a )J.a ja npou,eHH KopHcrn/pH3HKOT o.n. npo)J.OJT)KyBafhe Ha TepanHjarn.
XenaTaJTHaTa TOKCHqHOCT MO)Ke )J,a ce jaBH HeKOJTKY He)J.eJIH HJTH noBeKe no nocne,ll,HHOT TpeTMaH co
TeM030JlOMH)J..

MaJIHrHHTeTH

4 , I
J.I f j
I
MHory peTKO 6m1e rrp11jaBeHH nojaBa Ha cny1rn11 Ha MHeJ10)1,HCnnacTH4eH CHH.D,pOM H ceKyH.uapHH
MaJlHfHHTeTH, BKJ1Y4YBajKH H MHeJlOH)J,Ha neyKeMttja (BH)J,eTe .uen 4.8).

AHTHeMeTH4Ha Tepan11ja
f a.uelheTO 11 noBpaKalbeTo MHory 4ecTo ce noBp3aHH co yrroTpe6a Ha TMZ.
AHTHeMeTH4HaTa Tepan11ja MO)Ke .ua ce .uaBa npe.u 111111 no p,aBal-beTO Ha TMZ.

Bo3paCHu nauueHmu co Hoeoouja2HocmuyupaH MYJzmupopMeH 2!luo6!lacmoM:

AHTHeMeT111rna npoqmnaKca ce npenopa4yBa npe.u 11H11u,11janHaTa p,03a o.u KOHKOMHTaHTHaTa cpa3a 11 cTporo ce
npenopa4yBa 3a BpeMe Ha MOHOTepanttcKaTa cpa3a.

flayueHmu co peKJ!PeHmeH U!lU npozpecueeH Ma!lu2HeH Z!lUOM:

DauHeHTl1Te KOH BO npeTXO)J,Hl1Te Tepan11CKl1 UHKJ1YCl1 HCKYCHJle TeWKH ( CTeneH 3 HJlH 4) noBpaKal-ba MO)Ke p,a
11MaaT noTpe6a o.u aHTHeMeTl14Ha TepanHja.

Jla6opamopucKu napaMempu:
Kaj nau,11eHTHTe neKyBaH11 co TMZ MO)Ke .ua ce jaBH M11enocynpecHja, BKny411TenHo npo.uon)KeHa
naHu11ToneH11ja Koja MO)Ke .ua pe3y11THpa co annacT114Ha aHeMHja, Koja BO op,pep,eHH cny4a11 pe3ynrnpana co
cparnneH 11cxop,. Bo HeK011 cny4aH, 11cT0BpeMe1;10To 113JlO)KyBafhe Ha neKOBH noBp3aHH co annacTH4Ha aHeM11ja,
BKJ1Y4YBajKl1 rH Kap6aMa3en11H, ¢eH11TOl1H H cyn¢aMeTOKCa30J1/Tp11MeTOnp11M ja KOMnJ1HU,11pa npou,eHKaTa.
Dpep, )J,03Hpal-he, CJ1e)J,Hl1Be na6opaTOp11CKH napaMeTpH Tpe6a .D,a 6HP,aT 11CnOJ1HeTH: BKyneH 6poj Ha
HeyTpo¢11nH 2: 1,5 x 109/111 6poj Ha TpOM60UHTH 2: 100 x 109/1. KoMnnema KpBHa CJlHKa Tpe6a .ua ce HanpaBH
Ha 22 p,eH (21 p,eH nocne npBaTa .U03a) HJlH BO poK op, 48 4aca op, TOj p,eH, KaKo H ep,Harn Hep,enHo ce .uop,eKa
BKYITHHOT 6poj Ha HeYTpocp11nH He ce 11CKa4H Hap, 1,5 x 10 9/I, a 6pojoT Ha TpOM60UHTH npeM11He npeKy I 00 x
109/1. AKO 3a BpeMe Ha 6HJ10 Koj UHKnyc, BKynHHOT 6poj Ha HeyTpo¢HJ111 na.D,He < 1,0 x 109/1 HJlH 6pojoT Ha
TpOM60UHTHTe e < 50 x 109/I, To raw Hape.D,Hl10T U,HKJlYC Tpe6a p,a ce HaManH 3a ep,HO )J,03HO HHBO (BH)J,eTe .uen
4.2.) . .D:o3HHTe HHBOa on¢afaaT 100 mg/m 2, 150 mg/m 2 11 200 mg/m 2. HajH11cKa npenopa4aHa p,03a e 100
mg/m 2.

ITenHjaTp11cKa nonynau,11ja
He nocTOjaT KJ1HHl14KH 11cKycTBa 3a ynoTpe6arn Ha TMZ Kaj neu,a noManH on 3 ron11HH. l1cKycTBaTa Kaj
nocrnpw .ueu,a 11 ap,onecu,eHTH ce MHory orpaHH4eHH (BH)J,eTe nen 4.2. H 5.1 ).

nocrnpw nau11eHrn (Han 70 rop,11rnHa Bo3pacT)

Kaj nocrnp11 nau,weHTH HMa 3roneMeH p11311K o.u nojaBa Ha HeyTponeHHja H TpoM6ou,HTOneH11ja BO cnope.u6a co
noMnanH nau11eHTH. 3aTOa TPe6a .ua ce npeB3eMe noce6Ho BH11MaH11e npH nasalbe Ha TMZ Kaj nocrnpw
nau11eHTH.

MawKH nau,11eHTH
MarnK11Te nau,11eHT11 KOH np11Mane TMZ ce coBeTyBaaT .ua He c03naBaaT noTOMCTBO BO npBHTe 6 MeceuH no
TepanHjarn 11 Tpe6a na no6apaaT coBeT 3a 3aMp3HyBal-be Ha cnepMa npen TepanHjarn (BH.D,eTe .uen 4.6).

JlaKT03a
0Boj Me.u11u,11HCKH npo113Bon -conp)KH naKT03a. TiauHeHT11Te KOH HMaaT penoK HacneneH npo6neM Ha
l1HTonepaHu11ja KOH ranaKT03a, Lapp naKTa3a p,e¢wu,11eHu,11ja HJlH rnyK03a-ranaKT03a Manancopnu,11ja He Tpe6a
p,a ro np11MaaT oBoj neK.

4.5 IIHTepaKQHH co .r.pym JICKOBH H .r.pym <f>opMH Ha HHTepaKQHH

Bo O)J,)J,enHa cTyp,Hja BO ¢a3a I, p,aBalheTO Ha TMZ co paHHTH)J,HH He p,asa rrpoMeHa Ha CTerreHOT Ha ancopnu,wja
Ha TeM030J10MH)J, HJlH Ha 113JlO)KeHOCTa Ha HefOBHOT aKTl1BeH MeTa60J1HT MOHOMeTl1Jl TpHa3eHOl1Ml1)J,a30Jl
Kap6oKcaMH.U (monomethyl triazenoimidazole carboxamide - MTIC).

5 -,, 1
r '

I
,ll.aBafbeTO Ha TMZ co xpaHa pe3y11THpa110 co 33% HaMaJiyBafhe Ha Cmax H HaMaJiyBafbe on 9% Ha BpeMeHcKaTa
KpHBa (area under the curve - AUC).
TeMona11 Tpe6a na ce naBa Ha rnanHo, 6HnejKH He MO)Ke na ce 3aHeMapH cpaKToT neKa npoMeHaTa so Cmax e
KJ1HHH4KH 3Ha4ajHa.

Bp3 ocHoBa Ha aHaJIH3HTe Ha cpapMaKOKHHeTHKaTa Kaj nony11auHjarn Ha6Jby.llyBaHa BO cpa3a II on CTY.llHHTe,

KOa.D,MHHHCTPauttjaTa Ha )leKCaMeTa30H, npox11opnepa3HH, cpeHHTOHH, Kap6aMa3enHH, OH)J,aHCeTpOH,
aHTafOHHCTH Ha H2 peuerlTOpH 111111 cpeH06ap611rn11 He ro H3MeHHJla KJIHpeHcoT Ha TMZ.
Koa.nMHHHCTpau11jaTa co Ba11npowrna KHce1111Ha 6H11a noBp3aHa co Ma110, HO cTaTHCTH4KH 3Ha4ajHo
HaMMyBalhe Ha KJIHpeHcoT Ha TMZ.

H e ce HanpaseHH HHKaKBH CTY.llHH 3a o.npenyBafbe Ha ecpeKTOT Ha TMZ Bp3 Mern6011H3MOT HJlH eJIHMHHauHjarn
Ha npyrnTe 11eKOBH. CenaK, 6H.neji<H TMZ He ce Mern6oJIH3Hpa npeKy xenapoT H noKa)KyBa HHCKO Bp3yBafhe
co npoTeHHH, HajBepojaTHO HeMa )la BJlHjae Bp3 cpapMaKOKHHeTHKaTa Ha npyrnTe JleKOBH (BH)J,eTe )leJl 5.2).

YnoTpe6arn Ha TMZ BO KOM6HHauHja co .npyrn MHe11ocynpecHBHH 11eKOBH MO)Ke .na ja 3roJieMH BepojaTHOCTa
3a nojaBa Ha MHe11ocynpecHja.

ITen11jaTpHcKa nony11au11ja

l1cnHTyBalhaTa 3a HHTepaKuHja ce H3Be.D,eHH caMO Kaj B03paCHH.

4.6 <l>epTHJIHTeT, 6peMeHOCT H JiaKTaQuja

EpeMeHOCT
He ce HanpaBeHH CTYJlHH Kaj 6peMeHH )KeHH. Bo npenKJIHHH4KH CTY.D.HH Bp3 cTaopuH H 3ajauH Ha KOH HM ce
.naBa110 150 mg/m 2 Ha TMZ, ce nojaBHJla TepaTOreHOCT tt/111111 cpern11Ha TOKCH4HOCT (BH)leTe ,n:e11 5.3). Cnope.n
Toa, TeMO.llM He TPe6a ,n:a ce ,n:aBa Kaj 6peMeHH )KeHH. AKo sei<e Mopa ,n:a ce yn0Tpe611 3a BpeMe Ha 6peMeHocT,
TOraw Ha nauHeHTKarn Tpe6a .na li ce o6jacHH noTeHu11ja11HHOT pH3HK Bp3 cpeTycoT.

JiaKrnu,11ja
He e no3HaTO ,[J,aJIH TMZ ce 11aq11 npeKy xyMaHOTO MJleKo; oTTyKa, ,n:oefbeTO Tpe6a ,n:a ce npeKHHe 3a BpeMe Ha
Tepanttjarn co TMZ.

)KeHH co penpop,yKTHBeH ITOTeHU,HjaJl

)KeHHTe co penponyKTHBeH noTeHu11ja11 Tpe6a .na ce coBeTyBaaT na ynoTpe6yBaaT ecpHKacHa KOHTpauenuHja 3a
.na H36ernaT 6peMeHocT 3a BpeMe Ha npHMafheTo Ha TMZ.

<I>epTHJlHTeT Kaj Ma)KH

TMZ MO)Ke p,a HMa reHOTOKCH4HH ecpeKTH. Cnope.n Toa, Ha Ma)KH 11eKyBaHH co Hero Tpe6a ,n:a HM ce coBeTyBa
.na He C03.D,aBaaT TIOTOMCTBO BO npBHTe 6 MeceuH no npHMafbeTO Ha TIOCJleP,HaTa .D,03a H p,a no6apaaT COBeT 3a
· 3aMp3HyBafbe Ha cnepMa npe.n Tepanttjarn nopanH MO)KHOCTa on HpeBep3H6HJIHa CTepHJIHOCT nopa.ntt
Tepanttjarn co TMZ.

4.7 E<l>eKTH Bp3 cnoco6uocTa 3a B03elhe u ynpasysalbe co Maumuu

TMZ HMa Mano s1111jaHHe Bp3 cnoco6Hocrn 3a B03efhe H ynoTPe6a Ha MaWHHH nopa,n:H nojaBaTa Ha 3aMop H
nocnaHocT (BH.D,eTe p,e11 4.8).

( \
-· "\
' j
6 c ·'
'/
4.8 Heca1rnnn ):(ejcTBa

HcKycTBa o.u Km1H111IK0 ttcnttTysa!-he

Kaj nau,HeHTH neKyBaHH co TMZ, 6e3 pa3JIHKa .uanH e ynoTpe6yBaH BO KoM6HHau,Hja co pa.uHoTepanHja HJIH
KaKO MOHOTepanHja no pa)J,HOTepan11ja Kaj HOBOOTKpHeHH nau,HeHTH co MYJlTH<popMeH rJIH06JlaCTOM, HJlH KaKO
MOHOTepanHja Kaj nau,HeHTH co peKypeHTeH HJlH nporpeCHBeH rJIHOM, np11jaBeHH 611Jie CJ1H4HH MHory L!eCTH
HecaKaHH .uejcTBa: ra)J,e!-he, TIOBpaKaJ-he, OTICTHnau,Hja, attopeKCHja, rnaBo6onKa H 3aMop. Kaj HOBOOTKpHeHH
nau,HeHTH co MYJITH<l>opMeH rntto6nacToM KOH npttMaaT MOHOTepanttja MHory LiecTo ce npHjaBeHH KOHBYJ13HH,
a nojaBa Ha HCHTI MHory L!eCTO 6HJ1a npHjaBeHa Kaj HOBOOTKpHeHH nau,HeHTH co MYJITH<l>opMeH rJIH06JlaCTOM
KOH npHMaaT TMZ HCTOBpeMeHO co pa.u110Tepanttja 11 HCTO 11 KaKO MOHOTepanHja, H 11ecTO H Kaj nau.11eHTH co
peKypeHTeH fJ1110M. l1 Kaj )J,BeTe HH)J,HKaU,HH KaKO lleCTH HJlH MHOry tieCTH 6HJie np11jaBeHH HajMHory
xeMaTOJlOWKHTe HeCaKaHI1 peaKU,HH (Ta6ena 4 11 5); qipeKBeHU,Hja Ha na6opaTOpHCKI1 HaO)J,H O)J, CTeneH 3 H 4 ce
npeTcTaBeHH no ceKoja rn6eJia.

Bo rn6eJIHTe HecaKaHHTe e<l>eKTH ce Knac11<l>iiu.ttpaH11 cornacHo CHcTeMcKaTa KJiactt<l>HKau,Hja Ha opraHH H

cnope.u <}lpeKBeHu,Hjarn. fpynttpal-haTa Ha <}lpeKBeHu,HjaTa ce .ue<}lttHttpaHH cnope.u cne)J,HHBe KaTeropHH:
MHory LieCTH (~1/10); qecTH (~l/100 .uo <l/10); noMaJIKY qecTH (~l/1000 .uo <l/100). Bo ceKoe rpynHpal-he
cnope.u qipeKBeHu,HjaTa, HecaKaHHTe .uejcTBa ce npHKa:>I<aHH cnope.u HaMaJiyBal-he Ha cep1103HOCTa.

Hoso.unjarnocTHQttpan MYJITtt<l>opMeH rnno6JiacToM

Bo Ta6ena 4 ce rne.ua nojaBaTa Ha HecaKaHH .uejcTBa KOH HMane noTpe6a o.u HTHa 11HTepBeHu,Hja Kaj TpeTHpaHH
nau,HeHTH co HOBO )J,HjarnoCTHU.HpaH MYJITH<}lopMeH rJIH06JiaCTOM 3a BpeMe Ha KOHKOMHTaHTHa H
MOHOTepanHcKa <}la3a o.u TepanHjaTa.

Ta6ena 4:
flojaea HQ HeCQKQHU oejcmea Ka} na4UeHmU CO H0600Uja2HOCmu4upaH My!lmUrpOpMeH 2JIU06JlaCmOM 3a epeMe Ha
KOHKOMumaHmHa u MOHOmepanucKa paw Ha mepanujama
C11CTeMcKa Knacmp11Kau,11ja Ha TMZ + KOHKOMHTaHrna pa,n,110Teparmja TMZ MOHOTeparmja
opraHH n= 288* n=224
l1mpeKLJ,HH H HH<f>eCTaLJ,HH
qecTO: l1HQ>eKu,11ja, Herpes simplex, HHQ>eKu,wja Ha 11H<f>eKu,aja, oparrna KaHn11n11ja:m
paHa, Q>apHHrHTHC, opanHa KaHJJ,HJJ,Hja3a

HelJeCTO: Herpes simplex, Herpes zoster,

fPHTI03HH CHMTITOMH
HapyrnyBalha Ha KpBeH 11
JIHM<f>eH CHCTeM
qecTO: HeyTponeH11ja, TpoM6ou,11ToneH11ja, <l>e6pttnHa HeyTponeH11ja,
JIHMcponeH11ja, neyKoneH11ja TpOM60LJ,HTOTieHHja, aHeMHja,
neyKoneH11ja

HelJeCTo: <l>e6p11nHa HeyTponeHwja aHeM11ja J111McponeH11ia, neTex1111

EH.UOKpHHH HapyrnyBaina
HelJeCTo: Kyrn11Hro11n Kyrn11Hro11n
HapyrnyBalha Ha Mern6onH3aM 11
HCXpaHa ~

MHory '-leCTo: AHopeKCJ;ija AHopeKc11ja

qeCTo: X11neprn11KeM11ja, HaManeHa Te){(HHa HaManetta Te){(HHa

' '
7 ,.
"'. \
\1
: ) \
He'-lecro: XttrrOKaJJeM11ja, rroKaYeHa aJJKaJJHa XttneprnttKeMttja, noKa'-leHa TeJK1rna
<}loc<}lanl3a, rroKaYeHa TeJK11Ha
ITc11x11j aTpHCKH HapywyBalha
l!ecro:
803HeMHpeHOCT, eMOUHOHaJJHa na6HnHOCT, BoJHeMttpeHOCT, JJ,enpecttja,
HeCOHHUa eMOUHOHaJJHa na6HnHOCT, HeCOHHIJ;a
HeqecTo:
ArnTttpaHocr, anarnja, HapyweHo XanyuttHaUHH, aMHeJttja
OJJ,HecyBalbe,JJ,errpec~ja,xaJJyUHHaUHH
HapywyBalha Ha HepBHHOT
CHCTeM
MHory Yecro: fnaB060nKa rnaBo6onKa, KOHBynJHH

l!ecro: KoHBynJHH, HaMaJJeHa cBecHocr, XeMHnape3a, acl>aJttja, HapyweHa

COMHOneHUHja, aci>aJHja, HapyweHa
paMHOTeJKa, BPTOrnaB11ua, KOHcPYJHja,
HapyweHa MeMopttja, HapyweHa
KOHUeHTpauttja, HeBponaTHja, napecreJttja,
HapyweH roBop, TpeMop
paMHOTeJKa, COMHOneHUHja, KOHcPY3Hja,
BPTOrnaBHUa, HapyweHa MeMopttja,
HapyweHa KOHUeHTpauttja, Jl,HCcPaJHja,
HeBponolllKH Hapywysalba (NOS),
HesponaTttja, nepmpepHa HeBponarnja,
napecreJttja, HapyweH roBop, TpeMop

XeMHnnernja, arnKcttja, nopeMeTeHa

Heqecro: Status epilepticus, eKcrpam1paMHJJ,aJJHO KOOpJJ,MHauttja, a6HopMaJJeH OJ],,
HapyrnyBalbe, xeMHrrape3a, aTaKCHja, xttrrepecTeJHja, ceH3opHH Hapywysalha
KOrHHTHBHO HapywyBalbe, Jl,HC<}la3ttja,
a6HopMaJJeH oJJ,, xttnepecreJttja,
x11rroecTeJttja, HeBponowKH HapyrnyBalba,
rrepmbepHa HesporraTttia
0'-IHH HapyrnyBaH>a
l!ecro: 3aMaTeH BHJJ, ,Ue<}leKT BO BHJJ,HOTO none, 3aMaTeH
BHJJ,, Jl,HIInOrrHja,

Heqecro: XeMHaHonttja, HaMaJJeHa BHJJ,Ha ocrpHHa, HaManeHa BHJJ,Ha ocTp1rna, 6onKa so

HapywyBal-be Ha BHJ],OT, JJ,e<}leKT BO BHJ],HOTO O'-IHTe, cyBH O'-IH
none, 6onKa BO O'-IHTe
HapywyBal-ba Ha cnyxoT H
naBHpHHTOT
l!ecro: HapyrneH cnyx HapyrneH cnyx, THHHTyc

HeYecTO: 0THTHC MeJJ,Hja, THHHTyc, XHIIepaKyJHja, rnyBOCT, BepTHro, 6onKa BO YBOTO

6onKa BO YBOTO
KapJJ,HjaJJHH HapywyBalba
HeYecTo: flaJJrTHTaUHH
BacKynapHH HapywyBalha
l!ecro: XeMoparnja, eJJ,eM, eJJ,eM Ha H03eTe EJJ,eM Ha H03eTe, xeMoparnja, una6oKa
BeHCKa TpOM603a

HeYecro: µ:epe6paJJHa xeMoparnja xttnepTeHJHja, ITynMoHapHa eM6onttja, eJJ,eM,

nepttcl>epeH eJJ,eM
Pecm1parnpHH, TopaKaJJHH H
MeJJ,HjaCTHHaJJHH HapyrnyBaH>a,
Yecro:
,UttcrrHeja, KalllJlalbe ,UttcrrHej a, KalllJlaH>e
He'-!ecro:
ITHeBMOHHja, ropHH pecrrttpaTOpm1 ITHeBMOHttja, CHHY3HTHC, ropHH
HH<}leKUH!1, KOHrecrttja Ha HOCOT pecrrttpaTOPHH HHdieKUHH, 6pOHXHTHC
faCTpOHHTeCTHHaJIHH
HapywyBaH>a
.-
...... .
\
8 r '' \
'
MHory '-!eCTo: OnCTwnauHja, ra)lel-be, noBpaKal-be OnCTHnauHja, ra)lel-be, noBpaKal-be

llecrn: CToMaTHTHC, LlHjapea, a6LlOMHHarrna 6oJIKa, CTOMarnrnc, LlHjapea, LlHCnencHja,

LlHCnencHja, LlHCcparnja LlHCcparnja, cyBa ycrn

He<Iecrn: A6LlOMHHaJIHa LlHCTeH3Hja, cpeKaJIHa

HHKOHTl1HeHuwja, raCTpOHHTeCTHHaJIHl1
HapywyBal-ba (NOS), raCTpoeHTep11rnc,
xeMOP011LlH
HapywyBal-ba Ha KO)l<a H
OOTKO)l(HO TKHBO
MHory '-lecrn: l1cHn, aJioneuHja l1c1m, aJioneuwja

4ecrn: ,LI:epMaTl1THC, cyBa KO)l(a, epwTeMa, npypHTYC ,LI:epMaTHTHC, npypHTYC

EKccpom1jauHja Ha KO)l(a, cpornceH3HTHBHa

He'-!eCTo: peaKu11ja, a6HopMaJIHa nwrMeHTauwja, EpHTeMa, a6HopMaJIHa nHrMeHTaUHja,
3roJJeMeHo noTelhe
MycKynocKeJierHH H
HapyrnyBal-ba Ha CBp3HO TKHBO
lleCTo:
Cna6ocT BO Myci<yJIHTe, apTpaJirnja Cna6oCT BO MYCKYJIHTe, apTpaJirnja,
MycKynocKeJJeTHa 6oJJKa, MHaJirnja
He'-!eCTo:
MHonarnja, 6oJIKa BO rp6oT, MycKyno- MHonaTwja, 6oJIKa BO rp6oT
cKeJierHa 6oJIKa, MHaJirnja
PeHaJIHH 11 ypHHapHH
Hapyrnysal-ba
4eCTo: HapyweHa cppeKBeHu11ja Ha ypHHHpatbe, YpHHapHa HHKOHTHHeHuHja
ypHHapHa HHKOHTHHeHuwja

He'-leCTo: ,LI:H3ypHja
Hapyrnysal-ba Ha penpOLlYKTl1BeH
CHCTeM H )lOjKH
He'-leCTo:
l1MnOTeHUHja BarnHaJIHa xeMoparnja, Mettoparnja,
aMeHopeja, BarHHHTHC, 6oJJKa BO
LlOjKHTe
Onwrn HapywyBal-ba 11 coCToj611
Ha MeCTOTO Ha a)lMHHHCTpauHja
MHory '-leCTo:
3aMop 3aMop
llecrn:
AneprncKa peaKUHja, TpecKa, paa11jauH0Ha AIIeprncKa peaKuwja, TpecKa,
noBpe)la, e)leM Ha JJHUe, 6oJIKa, HapywyBalhe paLlHjauwoHa noBpeLla, 6onKa,
Ha BKycoT HapywyBal-be Ha BKycoT
He'-!ecTo:
ACTeHwja, HanJJHBH, TonJIH HanJI11BH, ACTeH11ja, e)leM Ha JJHUe, 6onKa,
irnorneHa COCTOj6a, p11rop, LlHCKOJIOpauHja Ha BJIOllleHa COCToj6a, pHrop, npoMeHH Ha
ia3HK, napOCMHja, )l(e)l 3a6HTe
l1cnHTyBal-ba
lleCTo: floKa'-!eH ALT floKa'-leH ALT

He'-lecrn: floKa'-!eHH xenaTaJIH11 eH3HMH, noKa'-leHa

raMa rnyrnMHJJ TpaHccpeproa, noKrt..'-leH AST
* na1meHT 1136paH no CJlytJaeH H36op BO pa;mon~panHCKaTa rpyna, KOj npHMaJJ TMZ + pa,Il,HOTepanHja.
- .

'
'\

9 ,n J
i
I
Jla6opamopucKu pesy!lmamu
3a6e11e)l(aHa 61111a M11e11ocynpec11ja (HeyTponeH11ja 11 TpoM6ou11ToneH11ja), Koja npeTCTaByBa no3HaTa .ll.03a Ha
)l,03Bo11eHa TOKCl1l.JHOCT 3a noBeKeTO I.J.11TOTOKCl1l.JHl1 neKoB11, BK11yl.J11Te11Ho 11 TMZ. Kora 11a6opaTop11cK11Te
a6HOpMa11HOCTl1 11 HecaKaH11Te )l,ejCTBa 61111e KOM611H11paH11 Hl13 KOHKOMl1TaHTHaTa Tepan11ja 11 MOHOTepam1jaTa,
Kaj 8% O)J, nau11eHTl1Te 61111e 3a6e11e)l(aH11 3 11 4 CTeneH Ha HeyTpocp1111Ha a6HOpMa11HOCT BK11yl.JyBaj K11 11
HeyTponeH11ja. Kaj 14% O.ll. nau11eHT11Te Ko11 np11Ma11e TMZ 61111e 3a6e11e)l(aH11 TpoM6ou11TH11 a6HopMa11HocT11
0)], 3 11 4 CTeneH, BK11Y4YBajKl1 11 TpoM60I.J,l1TOneH11ja.

PeKy_pe1-1me1-1 wiu npowecuee1-1 MaJ1u21-1e1-1 2J1UOM

Bo K1111Hl1l.JKl1Te CTY.ll.1111, Hajl.JeCTl1 HecaKaH11 )l,ejcTBa noBp3aH11 co TepamijaTa 61111e raCTPOHHTecT11HanH11Te
nopeMeTyBmna, oco6eHo ra)l,eH>e (43%) 11 noBpakaH>e (36%). OB11e )l,ejcrna 611ne rpaAy11paH11 KaKo cTeneH 1
111111 2 (0-5 en1130.ll.11 Ha noBpakaH>e Ha ceK011 24 l.Jaca) 11 61111e 111111 caMopery1111paH11 111111 pe.ll.OBHO
KOHTpo1111paH11 co cTaH)l,apAHa aHTHeMeTl1l.JHa Tepan11ja. l1HUH.ll.eHuaTa Ha TernKH ra)l,eH>a 11 noBpakaH>a 61111a
4%.

Bo Ta6eJia 5 ce HaBe)l,em1 HecaKaH11Te )l,ejcrna 3a BpeMe Ha K1111HJ1lIKl1Te CTY.ll.1111 3a peKypeHTeH 111111

nporpec11BeH Ma1111rneH rn110M, a npeKy npo)l,a:>K6arn Ha TeMO)l,a11 ..

Ta6ena 5. HecaKaHu i)ejcmea Kai nat{UeHmu co peKypeHmeH unu npo2pecueeH MaJlUZHeH 2nuoM
I1mpeKuJm: II IIHcpecrnum1
PeTKo: OnopTyHIICTII'-IKII IIHcl>eKUIIII, BKnyqyaajKH II PCP.
Hapywyaatt.a Ha KpBeH II JlHMcpeH CHCTeM
MHory 1..fecro: HeyTponeHHja IIJlH JIIIMcponeHIIja (CTeneH 3-4), TpoM6ou11rnneH11ja
(CTeneH 3-4)
He'-lecrn: TiaHUIITonem1ja, atteM11ia (cTeneH 3-4), neyr<0neH11ia
Hapywyaatt.a Ha Mern6on113aM II 11cxpaHa
Mttory '-leCTo: AHopeKc11ja
lleCTo: HaManeHa Te)!(HHa
Hapywyaatt.a Ha HepBHHOT CIICTeM
MHory LJecrn: rnaao60JJKa
lleCTo: CoMHoneHuaja, aprnrnaaIIua, napeCTe3Hja
PecnIIparnpH11, rnpaKaJJHH II Me)J,11jacTIIHaJJH11
Hapywyaatt.a
lJeCTO: .D:IICITHej a
racTpOHHTeCTHHaJJHH Hapywyaatt.a
MHory 1..feCTo: ra)J,ett.e, ITOBpaKatt.e, OnCTIInau11ja
lfoCTO: .LJ:11japea, a6,ll,OMIIHanHa 6onKa, )J,Hcrrerrc11ia
Hapywyaatt.a Ha KO)!(a II nOTKO)!(HO TKHBO
llecrn: I1c11n, rrpyp11Tyc, anoneuIIja
MHory peTKO: Eo11TeMa MVJITIIcbooMe, eoIITPO,ll,eoMa,.vPTIIKao11ia, enaHTeMa
OnWTH Hapywyaatt.a II COCTOj6II Ha MeCTOTO Ha
a)J,MHHHCTpau11ja
MHory 1..feCTo: 3aMop
lleCTo: TpecKa, aCTeHHja, p11rop, Hey,ll,o6HOCT, 6onKa, Hapywyaatt.e Ha aKycoT
AneprncKH peaKii,1111, BKnyqyaaji<II aHaqmnaKca II aHrnoe)J,eM
MHory pcrKo:

Jla6opamopucKu pesyJ1mamu
TpoM6ou11ToneH11ja 11 HeyTp.oneH11ja O.ll. 3 11n11 4 CTeneH ce nojaB1111a BO 19% 11 17% coo,lJ,BeTHO, Kaj nau:11eHT11
Ko11 np11Ma11e Tepan11ja 3a Man11rneH rn110M. 0Ba BO)l,e110 KOH xocn11rn11113au:11ja 11/111111 npeK11H Ha TMZ Kaj 8%
11 4%, COO)l,BeTHO. M11e11ocynpec11jaTa MO)l(e11a )],a ce npe)l,Bl1)],11 (Hajl.JeCTO BO TeK Ha npB11Te HeK011KY UHK11yc11,
co HajH11cKa TOl.JKa Mery 21 11 28 )l,eH), a onopaByBaH>eTO 611110 6p3o 11 06111.JHO noMefy 1-2 He)l,e11a. He 61111
3a6e11e)l(aH KyMy11aT11BeH ecpeKT Ha M11e11ocynpec11ja. Tip11cycTSVTo Ha TpoM6ou:11ToneH11ja MO)l(e )],a ro 3ro11eM11
p11311KOT O)l, KpBapeH>a, a HeyTponeH11jaTa'. 111111 11eyKoneH11jaTa MO)Ke )],~ ro 3f011eMaT p113HKOT O)l, 11HcpeKI.J,1111.

10 ':} 'i,
;·1
'
Ilo!l
0,LJ, 11cKycTBOTO o.n KJ111Hl14Kl1Te 11cn11TyBafha 3a aHa11113a Ha Q:>apMaKoK11HeT11Ka Kaj nony11au11jarn 11Ma110 101
)KeHCKl1 11 169 MaWK11 cy6jeKT co HajH11CKaTa TOYKa Ha 6poj Ha HeyTpoQ:>111111 11 110 )KeHCKl1 11 174 MaWK11
cy6jeKT11 co HajHl1CKa TOYKa Ha 6poj Ha TpOM60U11Tl1. 11Mano noroneM O,LJ,HOC Ha HeYTPOneH11ja o.n 4-Tl1 CTeneH
(<0,5 x 109/1), 12% HacnpoT11 5%, 11 TpoM6ouHToneH11ja (<20 x 109/1), 9% HacnpoT11 3% Kaj )KeH11 Hacnporn
MmK11 BO npB110T u11K11yc Ha Tepan11ja. Kaj 400 cy6jeKT11 co peKypeHTeH rn110M ,LJ,a,LJ,eH11 ce no,LJ,aTOUl1Te; ce
j aBl1Jla HeyTponeH11ja o.n 4-Tl1 CTeneH Kaj 8% )KeHCKl1 Hacnporn 4% MaWK11 cy6jeKTl1 11 TpOM60Ul1TOneH11ja O,LJ,
4-Tl1 CTeneH Kaj 8% )KeHCK11 HacnopT11 3% MaWKl1 cy6jeKTl1, BO npBHOT U11KJ1YC Ha Tepan11j a. Bo 11cn11TyBafbe
co 288 cy6jeKT11 co HOBOOTKp11eH MYJ1Tl1Q:>OpMeH rn1106nacTOM, ce jaB11Jla HeyTponeH11ja O,LJ, 4-Tl1 CTeneH Kaj 3%
)KeHCKl1 Hacnporn 0% MaWKl1 cy6jeKTl1 11 TpOM60Ul1TOneH11ja OP, 4-TH CTeneH Kaj 1% )KeHCK11 HacnpOTl1 0%
MaWKl1 cy6jeKTl1 BO npB110T U11Knyc o.n Tepan11jaTa.

nep,11jaTp11cKa nony11au11ja
Opa11H110T TMZ e npoyic1yBaH Kaj nep,11jaTp11cK11 nau11eHT11 (Ha B03pacT op, 3-18 ro,LJ,11H11) co peKypeHTeH rn110M
Ha M0304HO CTe6110 111111 co peKypeHTeH acTpOU11TOM OP, Bl1COK CTeneH, BO pe)Kl1M Ha ,LJ,HeBHO ,LJ,aBafbe BO poK O)J.
5 p,eHa Bo TeK Ha 28 ,LJ,eHa. 11aKo no,LJ,aTOU11Te ce orpaH11YeH11, T011epaHu11jarn Kaj ,LJ,euarn ce oYeKyBa ,LJ,a 611p,e
11crn KaKo Kaj B03pacH11Te. Ee36e,LJ,Hocrn Ha TMZ Kaj .neua Ha B03pacT no.n 3 ro,n11H11 He e BOCTaHOBeHa.

I1CKYCTBO no CTaBafheTO BO npoMeT

C11e,LJ,H11Be ,LJ,ono11H11TenH11 cep1103Hl1 HecaKaH11 peaKu,1111 ce 11,LJ,eHT11Q:>11KyBaH11 3a BpeMe Ha ynoTpe6aTa no
CTaBafbeTO BO npoMeT:

Ta6ena 6. Ilpe2neo Ha HacmaHu npujaBeHu co meM030!IOMUO BO nocmMapKemuHutKU ycnoBut

IImj>eKUHH tt ttH<j>ecTauuu *
He IJecn1: I1mpeKU,Mja co U,MTOMera.rroBttpyc, peaKTMBau,ttja Ha MHcpeKu,Mj a KaKO
O)l UMTOMera.rroBttpyc, Bttpyc Ha xenaTMTMC E t
HapyrnyBalba Ha KpBHHOT H JJHM<j>HHOT cttcTeM
Muory peTKH: Tipo,LJ,omKetta nauu,ttToneuttja, annaCTwrna aueM11jat
HeonJJaJMH, 6eHHrHH, MaJJHrHH H Hecneuu<j>uuupauu
Mttory pcrKH: Mttenom1cnnacT11IJeH CMH,LJ,pOM (MJJ:C), ceKyHJJ:aptt11 Ma.JIIffHMTeTtt,
BKJJYlJMTeJJHO M MMeJJ011,LJ,Ha neyKeM11ja
EHJlOKpHHH Hapyruynalba *
He IJeCT11: JJ:11ja6crec 11HCl1Dl1.llYC

PecnuparnpHH, TopaKaJJHH tt MeJlHjaCTHHaJJHH HapyrnyBalba

Muory peTK11 :
.
I1HTepCT11U,Mja.JieH ntteyMOHl1Tl1C/ntteyMOHl1Tl1C, nynMOHaptta
qm6po3a, pecrmpaTOpua cna6oCT
Xenarn6uJJttjapHH Hapyrnynalba
llecTO: TioKaqyBafbe tta xenaTa.JIHMTe ett311MM
HeIJeCTo: X11nep6MJ111py6tttteM11ja, xoneCTaJa, xenaT11Tc, xenaTa.rruo
owTeTyBafhe, xenaTa.rrtta cna6oCTt
HapyrnyBalba Ha KO/Ka H nOTKOIKHO TKHBO
Muory peTKH : ToKCHIJHa en11)lepMa.rrtta ueKpontt3a, CTttBeuc-I,IoucouoB c11u)lpOM
t BKllY'lHTeJJHO H CllY'!aH co cjJarnrreH HCXO.U
' <t>peKBeHUHH npeCMeTaHH Bp3 6a3a Ha perreBaHTHH Kll HHH'!KH HCTIHTyBalha

ITp11jaByBafhe Ha cycneKTHl1 HecaKaH11 peaKu1111

ITp11jaByBafheTo Ha cycneKTHttTe HecakaH11 peaKu,1111 no crnBafheTo Ha neKOT BO npoMeT e Bm1rno. Toa
OB03MO)KyBa npo.D,OJl)KeHO MOHl1TOpttpafhe Ha COO)J.HOCOT Kop11c/p H1Hk~Ha JieKOT. 3,LJ,paBCTBeHHTe CTPYYfhaLJ,11 ce
,? I '

~i. I ,-'
11 , ., \
,:! \ '· 1
~
MOJiaT .n.a fH np11jaByBaaT cycneKTHHTe HecaKaHH peaKUJUI npeKy Hau,HOHaJlHHOT CHCTeM 3a np11jaByBa!-he Ha
HecaKaHH peaKU,HH.

4.9 Ilpei:.OJupalhe

Bo KJlHHW-IKH ycJIOBH Kaj nau,11eHTHTe 611Jle 11cn11TyBaH11 .n.0311 o.n. 500, 750, 1.000 11 1.250 mg/m2 (BKynHa .n.03a
Ha IJ,HKJlYC 3a BpeMe o.n. 5 .n.eHa). .IJ:o3BOJleHaTa ,ll.03a Ha TOKCHYHOCT ce o.n.pe.n.yBaJia xeMaTOJIOlIIKH H ce
np11jaByBaJla npH ceKoja .n.03a, HO ce oYeKyBaJlo .n.a 611.n.e noTelIJKa npH noBHCOKH .ll.03H. HecaKaHHTe .n.ejcTBa
KOH ce nojaBHJle Kaj e.n.eH nau,11eHT Koj 3eMaJl npeKyMepHa .n.o3a o.n. 10.000 mg (BKynHa .n.03a BO e.n.11HeYeH
IJ,HKJlYC 3a BpeMe 0,ll. 5 ,ll.eHa) 6HJle naHU,HTOneHHja, nHpeKCHja, OTKa)!{yBalbe Ha noBeKe opraHH H CMpT.
nocTojaT H3BelIITaH 3a nau,11eHTH KOH ja npHMaJle npenopaYaHaTa .n.03a no.n.oJlro o.n. 5 .n.eHa (.n.o 64 .n.eHa), a Kaj
KOH ce nojaBHJle HeCaKaHH .n.ejcTBa KaKO cynpecHja Ha KOCKeHaTa cpu,eBHHa, co HJlH 6e3 HH¢eKU,HH, KOH BO
HeKOH CJlyYaH 6HJle TelIJKH H npO,ll.OJl)!{eHH H pe3yJlTHpaJle co CMpT. Bo CJlyYaj Ha rrpe,ll.03Hpalhe IIOTpe6HO e
xeMaTOJlOlIIKO 11cn11TyBa!-he. Cnope.n. noTpe6aTa, Tpe6a .n.a ce npeB3eMaT coo.n.BeTHH IIOMOlIIHH MepKH.

5. <l>APMAKOJIOUJKH OCOliEHOCTH

5.1 <l>apMaKOAHHaMCKH oco6eHOCTH

<I>apMaKOTepaneBTCKa rpyna: AHTHHeonJlaCTH';IHH areHcH - .n.pyrH aJlKHJlHpaYKH areHcH,

ATC 03HaKa: LO 1AX03

MexaHH3aM Ha .n.ejcTBO
TeM030JlOMH.ll,OT e TpHa3eH, Koj npH tPH3HOJ10lIIKa pH nO,ll.Jle)!{H Ha panH.ll,Ha xeMHCKa KOHBep3Hja BO aKTHBHa
cocTOjKa: MOHOMeTHJl TpHa3eHOHMH.ll.a30Jl Kap6oKcaMH.ll. - MTIC. Ce cMeTa .n.eKa U,HTOTdKCHYHOCTa Ha MTIC ce
.ll.0Jl)!{H rrpHMapHO Ha aJlKHJlaU,Hjarn Ha 0 6 n03HU,Hjarn Ha rnaHHH co ,ll.OIIOJlHHTeJlHa aJlKHJlaU,Hja Koja ce jaByBa
Ha N 7 no3HUHjaTa. Ce cMeTa .n.eKa U,HTOTOKCHYHHTe Jle3HH KOH cne.n.cTBeHo ce pa3BHBaaT BKJlyYyBaaT 11
a6epaHTHO onopaByBalhe Ha MeTHJl a.n.yKTOT.

KmrnHYKa ed?HKaCHOCT H 6e36e,LJ,HOCT

HoeooujaZHocmuyupaH My;1mu<jJopMeH 2Jluo6JlacmoM

BKynHo 573 nau,HeHTH 6HJle cJiyqajHo H36paHH .n.a npHMaaT HJlH TMZ + pa.n.HoTepanHja (RT) (n=287) HJlH
caMo pa.n.110Tepan11ja (n=286). ITau,HeHTHTe o.n. rpynaTa Ha TMZ + RT np11MaJle KOHKOMttTaHTeH TMZ (75
mg/m 2 ) e.n.Halll ,ll.HeBHO noYHyBajKH o.n. npBHOT .n.eH na ce .n.o nocJle.ll.HHOT .n.eH o.n. RT, 3a BpeMe Ha 42 .n.eHa (co
MaKCHMYM o.n. 49 .n.eHa). Ha oBa ce Ha,ll.oBp3aJla MOHOTepanttja co TMZ ( 150-200 mg/m 2 ) BO 1-5 .n.eH o.n. ceKoj
28-.n.HeBeH U,HKJlYC BO Tpaelbe 0.ll. 6 IJ,HKJlyca, IIOYHyBajKH 4 He.ll,eJ111 no 3aBpllleTOKOT co pa,ll.HOTepanHjarn.
nau,11eHTHTe BO KOHTpOJlHarn rpyna npHMaJie caMo pa.n.110Tepan11ja. 3a BpeMe Ha pa.n.110TepanHjarn 11
KOM6HH11paHaTa Tepan11ja co TMZ 6HJla crrpoBe.n.eHa npo¢HJlaKca npoTttB nHeBMOH11ja o.n. Pneumocystis
jirovecii (PCP).

TMZ 6HJ1 .n.aBaH KaKo cnacoHOCHa TeparrHja BO npO.ll.OJl)!{ttTeJlHaTa (follow-up) ¢a3a Kaj 161 o.n. 282 nau,HeHTH
· (57%) BO pa.n.HoTeparr11cKarn rpyna H Kaj 62 o.n. 277 nau,HeHTH (22%) BO rpyrrarn Ha TMZ + pa.n.110TepanHja.

PeJlaTHBHHOT pH3HK (hazard ratio-HR) 3a u,eJioKynHOTO npe)!{ttByBafhe H3HecyBaJl 1,59 (95% CI 3a HR= l ,33 -
1,91) co log-rank p<0,0001 BO KopHcT Ha rpyrrarn co TMZ. Mo)!{HOCTa 3a npe)!{HByBafhe o.n. 2 H rroBeke ro.n.HHH
(26% BO cnope.n.6a co 10%) 611Jia rroB11coKa 3a rpynarn co RT+ TMZ. CrnTHCTHYKH rne.n.aHo, .n.o.n.aBafheTo Ha
KOHKOMHTaHTeH TMZ KOH RT, no Koj cJle.n.yBaJia MOHOTepan11ja co TMZ BO Teparr11jarn Ha nau,HeHTH co HOBO
.n.11jarnocT11u,HpaH MYJITH¢opMeH rn1106JlaCTOM noKa)!{aJl 3HaYHTeJlHO no.n.o6pyBalhe Ha u,eJlOCHOTO
npe)!{ttByBafhe BO crrope.n.6a co nau,11eHTHTe KOH 611Jle caMo Ha pa.n.110TeparrHja (cJlHKa 1) .

.\
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;. I
12 •I
,/
I
 ITT Pbp..1a11cn.: ovw-.. 11 SU.vi"" r
1.0

0.9 HR (95% C.I.) • 1.H (1.U - 1.11)

la 11-rnk p-v•ln c .0001
0.8

0.7

0.6
i 11.6
~ 0.4

o.s 26%
~~ RT+TMZ
0.2
-~----·
10'1.
0.1
RTOlllV
0.0 1Z.t 14.5
0 8 12 16 Z) 24 :<B
Time ...,.,, ...,...,..,._,Ion ~<>nU-18>

C!IUKa 1 Kaplan-Meier Kpueu 1a 4eJ10CHo npe:J1Cueyea1tJe (ITT nonyJ1a4uja)

Pe3y11rnn1Te OA CTYA11jaTa He 61111e KOH311CTeH-rn 3a IIOArpynaTa Ha nau.11eHT11 co 110W CTaTYC Ha ycnex (WHO
PS=2, n= 70), AOAeKa naK u.e110KynHoTO npe:>K1rnyBafhe 11 BpeMeTO AO noAo6pyBafhe 6mie 11cT11 3a ABeTe rpyn11.
CenaK, Kaj oBaa rpyna Ha nau.11eHTl1 He 6ea np11cyTHH Henp11<Parn11B11 p11311u.11.

PeKype1-1me1-1 UJ/U npo2pecuee1-1 MaJ1u21-1e1-1 2!1UOM

IToAaTOLI.HTe 3a KJll1HJ1l.!KaTa e<P11KaCHOCT Kaj nau.11eHTH co Mym11<PopMeH rn110611aCTOM ( CTaTYC Ha ycnex no
Karnofsky [KPS] ~ 70), nporpec11BeH 111111 peKypeHTeH noc11e onepau.11ja 111111 paA110Tepan11ja, ce TeMe11aT Bp3
ABe K11HHH1IKl1 CTYA1111 co opa11eH TMZ. EAHaTa e HeKOMnapaTl1BHa CTYAHja co 138 nau.11eHrn (29% npeAXOAHO
np11Ma11e xeM0Tepan11ja), a Apyrarn e paHAOMl1311paHa KOHTponHa cTy.n11ja Ha TMZ 11 npoKap6a3HH Kaj BKYIIHO
225 nau.11eHrn (67% npeTxo.n:Ho np11Ma11e xeM0Tepan11ja Bp3 6a3a Ha HHTP03ypea). KpajHaTa u.e11 Ha ABeTe
CTYA1111 61111a npe:>K11ByBafhe 6e3 nporpec11ja Ha 6011ecrn (progression-free survival - PFS) OApeAeHo npeKy MRI
cKeHOBl1 111111 npeKy HeBpo11owK11Te B11owyBafha. Bo HeKoMnapaTHBHaTa cTyA11ja, PFS BO wecT110T Meceu. 611110
19%, npoceKOT Ha npe:>K11ByBafheTo 6e3 nporpec11ja Ha 6011ecrn 61111 2, 1 Meceu,, a npoceKOT Ha u.e110KynH0To
npe)!rnByBafhe 5,4 Meceu.11. 06jeKTl1BHl10T cTeneH Ha o.nroBop OApeAeH Bp3 6a3a Ha MRI cKeHOB11 61111 8%.

Bo paHAOMH3ttpaHaTa cTy.n11ja, PFS BO wecT110T Meceu. 61111 3Ha1111Te11Ho no.no6ap co TMZ 0TK011Ky co
npoKap6a3HH (21 % cnope.neHo co 8%, - chi-square p=0.008) co cpeAHa BpeAHOCT Ha PFS o.n 2,89 11 1,88
Meceu.11 noeA11He11Ho (log rank p=0,0063). ITpoce11HoTo npe:>KttByBafhe 611no 7,34 11 5,66 Meceu.11 co TMZ 11
np0Kap6a311H, noe.n11HeYHO (log rank p=033). Bo 6-110T Meceu. <PpaKu.11jarn Ha npe:>KHBeaHH nau.11eHTH BO
rpynarn co TMZ 61111a 3Ha1111Te11Ho noBHCOKa (60%) BO cnopeA6a co rpynarn co npoKap6a3HH (44%) (chi-
square p=O,O 19). Kaj nau.11eHTHTe KOH npeTXOAHO npttMane xeMOTepan11ja, no.no6pyBafhe ce n0Ka)Ka110 Kaj
0H11e co KPS OA 80 111111 noBeke.

ITo.naTOLJ.HTe 3a BpeMeTO .no B110IIIyBafhe Ha HeBpo11owKHOT crnTyc 61111e BO Kop11cT Ha TMZ BO cnopeA6a co
npoKap6a3HHOT, HCTO KaKO 11 nq.naTOLJ.HTe 3a BpeMeTO Ha B110IIIyBaH:.e Ha CTaTycoT Ha ycnex (HaManyBafhe Ha
KPS OA < 70 111111 HaMa11yBaH:.e 3a HajMa11Ky 30 noeH11). ITpoce11HOTo BpeMe Ha nporpec11ja 3a 0B11e KpajH11
Bpe.n:Hocrn ce ABH:>Keno OA 0,7 AO 2,1 Meceu.11 IIOA011ro 3a TMZ OTK011KY 3a npoKap6a3HHOT (log rank p=0,01 .no
0,03).

Bo MY11THLJ.eHTpH4Ha, rno6a11Ha, npocneKTHBHa <Pa3a II cTyA11ja BO Koja ce eBa11y11pa11a 6e36eAHOCTa 11

eqrnKacHocrn Ha nepopa11H110T TMZ BO Tepan11jarn Ha nau.11eHTH co aHan11acT1111eH acTpOLI.HTOM BO npBHOT
pe11anc, 6 Mece11H0To npe:>K11ByBaH:.e 6e3 nporpec11ja Ha 6orrecrn 6-Hno 46%. ITpoceKoT Ha npe:>K11ByBaH:.e 6e3

lJ \.\I l •'
,<
' _, ......:-. "''
nporpecHja Ha 6onecrn H3HecyBaJI 5,4 Meceu,H. TipoceKOT Ha u,enoKynHOTO npe:>IrnByBafhe 6HJI 14,6 Meceu,11.
CTeneHOT Ha oD,roBop, 6a3HpaH Bp3 npou,eHKarn Ha u,eHTpaJIHHOT npHKa:>KyBalJ, 6HJI 35% (13 CR 11 43 PR) 3a
u,eJIHaTa nonynau,11ja. Kaj 43 nau,HeHTH 6HJia npHjaBeHa cTa6HJIHa 6onecT. WecT MeceYHOTO npe:>KHByBafhe 6e3
nojaBa Ha 6onecrn (event-free survival ) 3a ITT nonynau,Hjarn 6HJIO 44% co npoceK Ha npe:>K11ByBafhe 6e3
nojaBa Ha 6onecT OD, 4,6 Meceu,H, lIITO 611no CJIHYHO co pe3ynTaTOT OD, npe:>K11ByBafhe 6e3 nporpec11ja Ha
6onecrn. CJIH4HH 611Jie H pe3yJITaTHTe 3a e<t>HKaCHOCTa 3a TIOD,06HaTa XHCTOJIOlIIKa nonynau,Hja.
TiocTHrHyBafheTO Ha o6jeKTHBeH paD,HOJIOlIIKH OD,fOBOp HJIH OD,p:>KyBalheTO Ha CTaTYCOT 6e3 nporpec11ja 6HJI BO
roJieMa Mepa noBp3aH co OD,p:>KaHHOT HJIH noD,o6peHHOT KBaJIHTeT Ha :>KHBOT.

IleoujampucKa nonyflayuja

TiepopaJIHO D,a,lJ,eHHOT TMZ 6HJI 11cn11TyBaH Kaj neD,HjaTpHCKH nau,HeHTH (Ha B03pacT OD, 3-18 roD,HHH) co
peKypeHTeH rJIHOM Ha M0304HOTO CTe6Jio HJIH peKypeHTeH acTpOL!,HTOM OD, BHCOK CTeneH, BO TepanHCKH pe:>KHM
D,aD,eH D,HeBHO BO TeK Ha 5 D,eHa Ha ceKoj 28 D,eHa. TonepaHu,Hjarn KOH TMZ e CJIHlJHa Ha OHaa Kaj B03pacHHTe.

5.2 <l>apMaKOKHHeTCKH oco6euocTH

TipH cpH3HOJIOlIIKa pH, TMZ cnoHTaHO ce xHD,poJIH3Hpa D,o aKTHBHHTe cocTOJKH, 3-MeTHJI-(TpHa3eH-l-
yl)HMHD,a30JI-4-Kap6oKcaMHD, (MTIC). MTLC cnoHTaHo ce XHD,pOJIH3Hpa D,O 5-aMHHO-HMHD,a30JI-4-
Kap6oKcaMHD, (AIC), TI03HaT nocpeD,HHK BO 6HOCHHTe3aTa Ha nypHH H HYKJieHHCKH KHCeJIHHH, H D,O
MeTHJIXHD,pa3HH, Koj ce BepyBa D,eKa e aKTHBHaTa aJIKHJIHpaYKa cocTojKa. Ce BepyBa D,eKa LI,HTOTOKCHYHOCTa Ha
MTIC npHMapHo ce D,OJI:>KH Ha aJIKHJiau,Hjarn Ha .D:HK rnaBHO Ha 0 6 11 N 7 no3HL!,HHTe Ha rnaHHHOT. Bo OD,Hoc
Ha BpeMeHcKaTa KpHBa (AUC) Ha TMZ, H3JIO)l<eHOCTa Ha MTIC H AIC e ~ 2.4% H 23%, noeD,HHelJHO. In vivo,
t112 Ha MTIC e CJIHYeH co oHoj Ha TMZ, OD,HOCHO 1,8 qaca. ·

Ancopnu11ja
Tiocne nepopanHa aD,MHHHCTpau11ja Kaj B03pacHH nau,HeHTH, TMZ ce ancop611pa 6p3o H ro nocTHrttyBa cBojoT
nHK Ha KOHUeHTpau11ja 20 MHHYTH no D,aBalhe Ha D,03aTa (npocel.JHO BpeMe noMery 0,5 H 1,5 Yac). Tiocne
nepopanHa aD,MHHHCTpau,11ja Ha 14 C-o3HaYeH TMZ, 7 D,eHa nocne D,03HpalheTO npoceKOT Ha cpeKaJIHaTa
eKcKpeu11ja Ha 14 C H3HecyBallle 0,8% lIITO yKa:>KyBa Ha KOMnJieTHa ancopnu,Hja.

Il11cTpH6yu11ja
TMZ CJia6o ce Bp3yBa co npoTeHHHTe (10% D,O 20%) H nopaD,H TOa He ce Ol.JeKyBa D,a pearnpa co BHCOKO
Bp3yBa4KHTe npoTeHHCKH areHCH.
PET (no3HTpoH eMHCHOHa TOMorpacl>11ja) CTYD,HHTe Kaj nyte 11 npeD,KJIHHHYKHTe noD,aTou,11 cyrepHpaaT D,eKa
TMZ MHory 6p30 ja TIOMHHyBa KpBHO-M0304HaTa 6ap11epa H D,eKa e np11cyTeH BO u,epe6pocnHHaJIHaTa Te4HOCT.
HaBneryBalbeTo BO u,epe6pocnHHaJIHaTa Tel.JHOCT 611no noTBpD,eHo Kaj eD,eH nau,HeHT; H3JIO:>KeHocTa Ha
u,epe6pOCTIHHaJIHaTa Te4HOCT Bp3 OCHOBa Ha BpeMeHCKaTa KpHBa (AUC) Ha TMZ 6HJia npH6JIH:>KHO 30% OD,
OHaa BO nna3MaTa, lIITO ce TIOKJionyBaJIO co TIOD,aTOU,HTe D,06HeHH Kaj :>KHBOTHH.

En11M11ttau11ja
' nony)l<HBOTOT BO TIJia3MaTa e npH6JIH:>KHO 1,8 l.Jaca. fJiaBHHOT naT Ha eJIHMHHau,11ja Ha 14 C e npeKy 6y6pe3HTe.
TioCJie nepopaJIHa aD,MHHHCTpau,~ja, npH6JIH:>KHO 5% D,O 10% OD, D,03aTa OCTaHyBa HenpoMeHeTa BO ypHHaTa BO
TeK Ha 24 Yaca, a OCTaTOKOT ce H3Jial.JyBa KaKO TeM030JIOMHD,Ha KHCeJIHHa, 5-aMHHOHMHD,a30JI-4-Kap60KCaMHD,
(AIC) HJIH KaKO HeHD,eHTH<l>HKyBaHH nonapHH MeTa60JIHTH.
Kottu,eHTpau,HHTe BO nJia3MaTa ce 3roJieMyBaaT BO 3aBHCHOCT OD, D,03aTa. TIJia3Ma KJIHpeHcoT, KOJIHYHHaTa Ha
.D,HCTpH6yu,11ja H TIOJIY:>KHBOTOT He 3aBHCaT OD, D,03aTa.

Tioce6HH nonynau,HH

AttaJIH3HTe Ha <t>apMaKOKHHeTHKaTa Ha TMZ Bp3 ocHoBa Ha nonynau,.Hjarn OTKpHne D,eKa TIJia3Ma KJIHpettcoT Ha
TMZ e He3aBHCeH OD, B03pacTa, 6y6pe:>KHaTa <l>YHKU.Hja H nyuielbeTO. sc) ·~~BOeHa <t>apMaKOKHHeTHlJKa CTYD,Hja,

14 " .
cjJapMaKoK1rneT114Kl1Te npocpmm Ha nna3Marn Kaj nau,11eHTH co 611ara .n.o yMepeHa xenarn11Ha .n.11ccpyHKu11ja
61111e CJ1114Hl1 co om1e Ha6Jby.Il.yBaHl1 Kaj nau,HeHTl1 co HOpMaJlHa xenaTaJlHa cpyHKLI,11ja.

Ile.n.11jaTpl1CKl1Te nau,11eHTl1 HMaJle TIOBHCOKa BpeMeHCKa Kp11Ba (AUC) o.n. B03paCHHTe nau,HeHTH ; cenaK,
MaKc11Ma11HaTa .lJ.03BOJ1eHa .n.03a (maximum tolerated dose - MTD) no u,11K11yc H3HecyBana 1.000 mg/m 2 11 Kaj
.n.eu,a 11 Kaj B03pacH11.

5.3 Ilpe)l,KJIHHH'IKH OO)l,aTOU,H 3a 6e36e)l,HOCT

CTy.n.1111 3a TOKC114HOCT npH e.n.11Hel.feH-LI,HKJ1yc (5-.n.HeBHO )J.03HpaH>e, 23 .n.eHa 6e3 TpeTMaH), Tp11-LI,HKJ1yca 11
wecT-u,11K11yca forne cnpoBe.n.eHH Kaj crnopu,11 11 KY4HH>a. Bo npB pe.n. ce jaBm1a TOKCHl.fHOCT Ha KOCKeHarn
cpu,eBHHa, Jll1McpopeT11Ky11apH110T Cl1CTeM, TeCTHCl1Te, racTp011HTeCTHHaJ1Hl10T TpaKT, a npH noroneMH )J.0311
KOH 6m1e CMpTOHOCHl1 3a 60% .n.o 100% o.n. 11cn11TyBaH11Te crnopu,11 11 KYl.fHH>a ce nojamrna .n.ereHepau,11ja Ha
peTHHaTa. Bo noBeKeTO c11yqa11 ce TIOKa:>KaJlO .n.eKa TOKC11l.fHOCTa e peBep311611nHa, OCBeH 3a MaWKl10T
penpo.n.yKTHBeH cttcTeM 11 .n.ereHepau,11jarn Ha peT11HaTa. MefyTOa, 611.n.ejKH .lJ.03HTe noBp3aHH co peT11Ha11HaTa
.n.ereHepau,11ja 61111e BO onceroT Ha 11ern11H11 .n.0311, a BO KJ1HHH4Kl1Te cTy.n.1111 He 61111 3a6e11e:>KaH .n.pyr
KOMnapaTHBeH ecjJeKT, OBHe Hao.n.11 He ce 3eMaaT 3a KJ1HH11l.JK11 pe11eBaHTHl1.

TMZ e eM6pttoTOKCH4eH, TepaToreH 11 reHOTOKCHl.feH a11K111111pa4Kl1 areHc. TMZ e noTOKCH4eH 3a CTaopu,11 11

KYl.fl1H>a OTKOJlKY 3a nyfe, a KJ111Hl14KaTa .n.o3a 3a nyfe e np1161111:>KHa Ha MHHHMaJlHaTa 11ern11Ha )J.03a Kaj
crnopu,11 11 KY4Hlha. HaManyBalhaTa Ha 11eyKou,11T11Te 11 TpoM6ou,11T11Te noBp3aH11 co .n.o3aTa ce oceTJlHBH
HH)J.11KaTOp11 3a TOKCl1l.fHOCTa. Bo wecT-LI,HKJlYCHaTa CTy.n.11ja Bp3 crnopu,11 3a6e11e:>KaHa 61111a pa3HOBpCHOCT O)J.
HeOTIJ1a3Ml1, BKJ1yl.fyBajK11 KapLI,11HOMl1 Ha .n.ojKa, KepaTOKaHTOMa Ha KO:>Ka 11 a.n.eHOM Ha 6a3aJ1Hl1 KJ1eTK11, .n.o.n.eKa
BO cTy.n.1111Te Bp3 KYl.fHlha He ce nojaB1111e TyMop11 111111 npe-HeorrnacTH4H11 npoMeH11. ITojaByBa!-heTO Ha npB11Te
TyMop11 BO poK o.n. Tp11 Meceu,11 o.n. npBoTo .n.0311palhe n0Ka:>Ka110 .n.eKa cTaopu,11Te ce oco6eHo 4YBCTB11Te11H11 KOH
OHKOJ10lllK110T ecpeKT Ha TMZ. 0Boj naTeHTeH nep110.n. e MHory KpaTOK .n.yp11 11 3a a11K111111pa4K11 areHc.

Pe3y11rnT11Te o.n. TeCTOBHTe 3a xpoM030MCKarn a6epau,11ja no Ames/salmonella H 1111Mcpou,11T11 BO 40Be4Ka

nep11cjJepHa u,11pKy11au,11ja (HPBL-Human Peripheral Blood Lymphocyte) n0Ka:>Ka11e no311rnBeH MyrnreH
o.n.roBop.

6. <l>APMAIJ;EBTCKH OCOI>EHOCTH

6.1 JIHCTa ua eKCIJ,HUHeHCH

Co.up:>K11Ha Ha Kancyna:
6e3BO,nHa JlaKT03a, 6e3BO)J,eH KOno11,neH CHJ1HLI,11YM )J,HOKCH)J,, HaTpHyM CKpo6eH rJ111KOJiaT THTI A, BHHCKa KHCeJTHHa,
CTeap11HCKa KHCeJTHHa.

Ha o6BHBKHTe Ha KancynHTe:
Kancy11u 00 5mg: :>KeJTaTHH, THTaH )J,HOKCl1)J, (E171), HaTpHyM nayp11n cympaT, :>KOnT :>KeJTe3eH OKCH)J, (E 172) H 6oja
HH)J,lffO KapMHH (E 132);
. Kancy11u 00 20mg: :>KenaTHH, THTaH )J,HOKCHA (El 71), HaTpHyM nayp11n cympaT, :>KOnT :>KeJTe3eH OKCHA (E 172);
Kancy11u oo 1OOmg: :>KenaTHH, THTaH JJ.HOKCHA (E 171 ), HaTpHyM nayp11n cympaT, u,pseH :>Kene3eH OKCHA (E 172);
Kancy11u 00 250mg: :>KenaTHH, THTaH .IJ:HOKCH)J, (El 71), HaTpHyM nayp11n cympaT

Ha MaCTl1JTOTO 3a ne4aTe!-he:
wenaK, nponHJTeH rJIHKOJT, np04HCTeHa BO)J.a, aMOHHYM x11.n.poKCH)J., KaJTHYM XH.lJ.pOKCH,n H u,pH :>KeJTe3eH OKCHA (E
172).

6.2 HnKoMnaTu6uJiuocT
He e Hase,neHa.
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c \')
/,.
•
~ ·' I

[' .J
15 l
.... , . /
6.3 PoK Ha ynoTpe6a
3 roP,HHH

6.4 Iloce6Hn npe.n,ynpeAyBalha Ja qyealhe

ITaKyBal-be Bo w11ruettue
,[(ace YyBa Ha TeMnepaTypa nop, 30°C.
,[(ace LfyBa Bo op11rnHaJTHOTO w11wettue 3a .n,a ce 3arnTHTH op, BJTara.
,[(ace LfyBa Illl1IlleTO QBpCTO 3aTBopeHO.

I1aKyBal-be BO i<ecHYKa
,[(ace 'lyBa Ha TeMnepaTypa no.n, 30°C.

6.5 Ilpupo.n,a u co.n,pmnHa Ha aM6aJiaJKaTa

ITaKyBal-be BO w11weHua
TeMo.n,an rnp.n,11Te Kancyn11 3a nepopanHa ynoTpe6a ce cMecTeH11 BO w11ru111-ba o.n, o6oeHo CTaKJTO T11n 1 co
non11npon11:neHcK11 3arnopaLf 3a 3aruT11Ta o.n, .n,eu;a, KOH co.n,p)l(aT 5 Kancyn11 . E.n,Ha KyT11ja co.n,p)l(11 e.n,Ho w11we.

DaKyBal-be Bo KeCHLfKH
Kec11YKHTe ce cocrnBeHH op, n11HeapeH non11eTlrneH co Hl1CKa rycT11Ha (HajBHaTpewH110T cnoj), anyM11H11yM 11
non11enmett TepecjnanaT. CeKoja i<ecHYKa cop,p)l(11 1 TBpp,a Kancyna 11 e naKyBaHa BO KapTOHCKa KyT11ja.
KyT11jarn cop,p)l(H 5 Kancyn1111HAHBHp,yantto cnaKyBaHH BO i<ec11YK11.

6.6 Iloce6Hn MepKn Ha npeTnaJJIHBOCT npu OTCTpaHyealhe u .n,pyru paKYBalha co JICKOT

Kancyn11Te He Tpe6a .n,a ce ornapaaT. AKo KancynaTa ce owTeTH, H36erttyBajTe KOHTaKT Ha npawoKoT co KO)l(aTa H
MYK03HHTe MeM6paH11. AKo TeMo.n,an p,ojp,e BO KOHTaKT co KO)l(aTa 11n11 CJTY30KO)l(aTa, Tpe6a Be.n,Haw .n,a ce 113Ml1e
3acjlaTeHaTa n0Bpw11Ha TeMeJTHO co canyH 11 Bo.n,a.

I1au;11eHT11Te .n,a ce coBeTyBaaT .n,a m 'lyBaaT Kancyn11Te Ha Mecrn BOH .n,ocjlaT 11 norne.n, Ha .n,eu;a, Haj.n,o6po BO
wKacjiqe no.n, KJTYLf. Cnyqajttarn 11HrecT11ja MO)l(e .n,a 611.n,e nernnHa 3a .n,eua.
CeKoj tte11cKop11cTeH npoH3BOA 11n11 oTna.n, Tpe6a .n,a ce oTcTpaHaT cornacHo noKaJTH11Te nponttc11.

7. IlPOH3BO,[J;HTEJI
Schering-Plough Labo N.V., lndustriepark 30, B-2220 Xe11cT-on-.n,ett-Eepr, Eenrnja

8. HOCHTEJI HA O,[J;OEPEHHETO 3A CTABAlbE BO IlPOMET

ITpeTCTaBHHWTBO lllEPHHf-ITJIAY IJ,EHTPAJI HCT Af-CKonje,
yn. ,[(aMe fpyeB 6p. 28, 5-rn KaT, 1000 CKonje, P.MaKe.n,oH11:ja, Ten. : 3217 268

9. EPOJ II ,[J;ATYM HA O,[J;OEPEHHETO 3A CT ABAlhE BO IlPOMET

.TeMO.D,aJI 5 mg, TBPA11 Kancyn11, naKyBal-be BO CTaKJTeH KOHTejHep- 15-1358/12 OA 29.03.2012
TeMo.n,aJI 5 mg, TBp.n,11 Kancyn11, naKyBal-be BO e.n,HOA03Ha i<ec11YKa - 15-1358/2-12 o.n, 29.03.2012
TeMO.D,aJI 20 mg, TBPAl1 Kancyn11, oaKyBal-be BO CTaKJTeH KOHTejHep - 15-1359/12 OA 29.03 .2012
TeMo.n,aJI 20 mg, TBp.n,11 Kancyn11, naKyBal-be BO e.n,HOA03Ha i<ecHLfKa- 15-1359/2-12 o.n, 29.03 .2012
TeMO.D,aJI 100 mg, TBPA11 Kancyn11, naKyBal-be BO CTaKJTeH KOHTejHep-15-1360/12 OA 29.03 .2012
TeMo.n,aJI 100 mg, TBp.n,11 Kancyn11, naeyBal-be BO e.n,HOA03tta i<ec11qKa - 15-1360/2-12 op, 29.03 .2012
TeMo.n,aJI 250 mg, TBPA11 Kancyn11, naKyBal-be BO CTaKJTeH KOHTejHep- 15-1361/12 OA 29.03.2012
TeMo.n,aJI 250 mg, TBp.n,11 Kancyn11, naeyBal-be BO e.n,HOA03Ha i<ec1111Ka - 15-1361/2-12 o.n, 29.03.2012

10. ,[J;ATYM HA IlOCJIE,[J;HA PEBH3H:JA HA TEKCTOT

CemeMBpH 2015

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