7 KPATKA XAPAKTEPHCTHKA HA IIPOAYKTA 1, HME HA JIEKAPCTBEHHS TIPOAYKT MSMbAHMTEAHA APEHUMA TIO EKAPCTBATA AGaruxcerrr $ mg pummmpann TaGIETKH Abatixent 5 mg film-coated tablets 2. KAYECTBEH H KOJIMYECTBEH ChCTAB Besxa waMupana TaGnerKa craspoka 5 mg anuxcaban (apixaban). Tk H Bel wespecTa He Beaxa ismmpana TaGzerKa oT S mg cemEpKa 96 mg naKtosa (KATO MoHOXHApAT) (Bs, TOHKA 4.4), 3a MBANHA cHHCEK Ha noMoUNHTe BemecTBa BYOKTE TOHKA 6.1. 3. JEKAPCTBEHA ®OPMA ‘Dasmnpana taGxerka (raGeTKa) Posona, obaiva, nBoHNONSTEKHAAA, SHNMHpaHA TaBETKA, ¢ HOMEKHAAO penei>HO OGosTIAVeHHe “AX” of eanata crpaua mS” or apyrara crpava, ¢ mmpHtia oT 5,0 5,7 mm # AbTKHHA OT 9,6 ~ 10,3 mm. 4. KIMHWUHH AHHH 4.1 Tepanestaunm noxasanan Tlpopaaaxruka Ha MNcysIT H CHCTeMeH CMGONHSbM NpH BLIPACTHA NALHEHTH C HeKNANHO Mpeacspano MExneHe (non-valvular atrial fibrillation, NVAF) c eaHH HIH TOBeye PHCKOBH ‘axropH, kaTo npemuectsaMk wiicymT HIM TpansuTopya HexemMuHa araKa (THA), Bespact > 75 oan, XHNepToWK, zaxapeH susaGer, caMTTOMATHAHA CEPIENNA HeAOCTATbAKOCT (Kae No NYHA> ID. Tlewenne Ha s416oKa netiosta TpoMGo3a (JIBT) GenompoGen eGonuses (BE) H npogiiakruka Ha peunmshpauu JIBT 4 BE np seapacrun (x. TouKa 4.4 oTHOCHO XeMonMHaMHHO HECTaGHAHH nauwenTi c BE). 42 Josupooxa » nasna wa npuacwenneTowposka Pr a unica u cuct 3M npu nayuenmu c Hexnanso npede»pono aeowdene (NVAF) Tipenopesurenuata nosa amaxcaGan ¢ 5 me, MpHeMauia nepopanko RBA ETH ANEBHO. Hawanseaue na dosama Tipenopourrennara josa anmxca6ant ¢ 2,5 mg, npHeMalia nepopanto Ba ITBTH ANeBHO NpH nauvenra ¢ NVAF X none ase oT caemmeTe XapaxTepHCTHKH: BbapacT > 80 roHHIH, TeseCHO Tero £60 kg, tine cepymen xpeaTmnme > 1,5 mg/dL. (133 mrmpomona/L). Tlesenneto rpx6ea na xsarocposo. Tevenue a BT, nevenue xa BE u npoduraxmuxa na peyudueupawu JIBT u BE (VTEt) TIpenopeunrennara osa ammakcaSan 3a nevexme Ha octpa JIBT n nesenne 1a BE © 10 mg, npuewaun epopanto Asa IrsTH AHeBHO Mpes NEpBHTe 7 JNM, HOcAeZBAHH OT S mg, pweMaNN nepopaHO MBA TIBTH JMEBHO. CEIACHO HAMHUHHTE MEMUUMHCKK MPOpEKM, KPATKATA MPOMBLAMTEAHOCT Ha Jevenero (Hali-manko 3 Mecetta) TpaGBa A ce OcHORARA Ha TPANSMTOPHA puckosH dbaxropm (wanp. CKOpoMTHa OnfepaliMa, TpasMa, HMOGHITHZALHR). Tipenopewrennara zosa amukeaGan sa npogwnaxruxa Ha peuusupaut JIBT u BE ¢ 2,5 mg, ‘Apwemanu nepopanto apa srs aKesHo. Koraro e noxasaa uposuairuxa Ha penynumupany JIB wou BE, avesnara no3a or 2,5 mg A8a ImsTH AHeRHO TpsGsa 2a ce sarlo¥Ne cred 3aBDpUIBAHE Ha G-mecewen Kype Ha teueune ¢ amMKcaGaH S mg Alba NTbTH AHEBHO WAM APYT AKTHKOAy:AHT, KaKTO € oxasano wa TaGsmmua 1 no-nony (mx. Chuo TONKA 5.1). ‘Ta6amna 1: Hpenopsxa 3a nosara (VTEt) Cxena wa mpwrarane Maxermamna Hera E osa Tlesenne a ABT nam BE 10 mg apa mova nmesno pes 20 mg mrspaure 7 ja nocneanann or Smg asa mera — | 10mg. 7 dl anesHo eH TIpocpanaxraxa Ha 2,5 mg aga TsTH JHEBHO Smg pewaaBapane BT win BE cuiea 3a8punBane Ha 6-mece4en ype wa nevenne 32 JIBT 11a BE Tipoxematrentocrra Ha wyulocmioro slevenHe TpxGea na Gare onpenertena MAAABAAYATHO cre BHHMATENHA OllenKa Ha naitsara OT NeMeHMETO CIIpRMO PHCKa OT KEpBEHE (wx. TOHKA 4,4), ‘Mponycnama dosaAxo Gore mponycuara emia 7o3a, namenTst Tps6ea HesaGaBHo Jia mpueme AGarakceH 4 cure, TOBA {7a MPORBIOKH MpHEMA J18a TIBTH HeBHO, KAKTO MpedT Tpemmocane Tipemniasanie Ha nevenuero o7 napeHrepantia aHTuKoarynanrn Koa AGaTuKceHT (1 o6paTHo) Moxe 2a ce HBEUIH pH cHesBauara rHIaNtHpana rosa (BK. TOUKA 4,5), Te3H NekapeTBeHH MpORYKTH He ‘TpaGpa na ce npHnarar eHospementio. TIpestunasane om revenue c anmaconucm a eumanun K (VKA) xan AGamuxcenm Korato npexsspasre nauivenrH oT nevenne ¢ axrraronncT na sistant K (VKA) xo AGaruxeet, ‘apapun WH apyroro sesenne c VKA TpaGea 2a ce cnpe a AGarHKCeHT cxemBa na ce 3a/ouHe, xoraTo MexciyHapomHOTO Hopmamisupano oTHouIcHMe (INR) © <2. Tpesunasane om AGamuxcenm kam seuenue ¢ VKA Korato npexespasre nauwexti or AGaTHKceHT KEM sieweHHe ¢ VKA, mpaioxenueTo na AGaTHKceHT TpaGna sa MpOAKIKH owe 2 HM cen sanONBAKE Ha TepanuaTa ¢ VKA. Ces 2 AHH cbBMECTHO npanoxeune Ha AGaruxcexr c VKA repanns, INR xpsGna na ce Haqepx mpen cneapauara Iwranmpana nosa AGaruxcenr. CramecTHoTo npaioxenne Ha AGatuxcent ¢ VKA Tepanusra TpaGsa {ta npotanx, oxaro INR ¢ > 2. Cmapwecka sexpacm VTEt — He ce nanara Kopexuna Ha nosara (Bx. TouKH 4.4 1 5.2). NVAF —He ce nanara Kopexiws ua osata, OcBeH ako c& HOKPHTH KpHTepMire 3a HaManaBaHe Ha nosara (na. Hamanseane na dosama B HaxaiOTO Ha TOAKA 4.2). Bebpewno yapecoane Tip nanerra c exo WIA yMeperio GLOpesHo yepexnane ca NpHAOKAMH CcIeAHHTE MPCHOpEKH: * sa nesenne Ha JIBT, nevenne Ha BE 4 npodwacrnxa na peummesupaut BT 1 BE (VTEQ ne ‘ce Hanara KopeKums Ha jo3aTa (Bx. TONKA 5.2) ¢ sa npodwraxrixa wa uncysr H cHcTeMeH eNGommsM pH nauweHTu c NVAF u cepymen kpearunas 2 1,5 mg/dL (133 muxpomona/L) wa sxapacr 2 80 romwMHM waw c TenIecHO Terno < (60 kg, e HeoGxomtmo HaMameBaHe Ha 2038Ta, KAKTO € oMHCAKO Mlo-rope. He ce Hanara KOpexIUMa Ha 0387, akO JIMNICBAT APYTH KpHTepHH 3a HanaeHMeTO H (sBspact, TesIecHO ‘Tero) (Bx. TouKa 5.2). Tipu mauwetrra c Texcxo 6s6pesno yapexnane (kpeaTanHioe KapEuc 15-29'mL/min) ca mpuaoxcaren ‘careaHHTe MpertopEKH (Bx, TOUKH 4.4 15.2): + samesenne Ha JIBT, newesne Ha BE 4 npodwiaxruka na pemmumusspauus JIBT win BE (VTEt)¢ HeoGxOHMO TOBHIIEHO BHMMAHHe MH ynoTpeGara Ha alMMKcaGan;© sa nposunakruka na micynt cHcTeMeH eGonmsEM npH nanwenta ¢ NVAF nauwenrare ‘TpxGea nia noaywapat no-HucKara joa amKeaGax 2,5 mg Asa METH AHEBHO. Tluncea knususes onur mpi nanienTit ¢ KpeaTHHHHoR KnappHe < 15 mL/min am npH nauMeNTH Ha ANaTusa Uno TASH NpHUHHA TIpHeMET Ha ATMKcaGaH He ce Npenopbypa (Bx, TOHKH 4.4 H 5.2). Hepuodpobuo yapeacdane Ynorpeata na AGaTHKCOHT © npoTHBOTOKasAHa IIpH TalCHTH ¢ YepHORPOGHO saGonABAHIC, ‘CBEp3AHO c KOATYsIONATHA H KAHICIHO 3HATHM PHCK OT KBPBEME (8K. TONKA 4.3), He ce npenopsana yrtorpeSara my np nawetrrH ¢ TexkKo HeprONpOGHO YRpERTANE (BX. TOUKH 4.4 11 52). ‘TpsGna Aa ce wanox3ea BHEMATEHO IPH TaNHEHTH € sIeKO WAH YMePeHO HEpHOAPOGHO yepEKANE (Child Pugh A win B), He ce wanara Kopexuns Ha osaTa TIpH naLMeHTH C steko Hl yMepeHHO NepHoapoGio yspexknane (ex. TowK 4.4 ¥ 5.2). Tipu xameurenvtre npoyseamas ca GT HOKMOYEHH OT YHACTHE NALMEHTH ¢ TOBHLLICHH cToHHOCTH a YepHonpoGKHTe eHOHMH aTAHHH aMMHoTpancdepasa (ALT)acniaptat annmnorpancipepasa (AST) >2 mem Hag roprara rparnma Ha Hopmara (ULN) 1H 061 6wimpyOun > 1,5 msra Hay roprara rpannua va Hopmara, To TasH npmna AGaTHKceHT TpaGsa Jia Ce HBNOI3RA BHAMATENHO pH Tas nonyaaua (Bx. TOURH 4.4 1 5.2). Mpenn sanouBane Ha AGaTHKCeHT € HeOSXORHMO sMA ce TIpOREAE wscneqsane Ha YepHompoGHaTe YHKUMOHATHH MOKAsaTeIH. Tenecno mezio VTEt- He ce nanara xopexmmn a nosara (Box, TouKH 4.4 H 5.2). NVAF - He ce Haitara xopextpia Ha 1030Ta, OcBeHt Axo Ca NOKPHTH KPHTepuuTe 3a HaMananane Ha osara (Bx. Hamaneane xa dosama B waNasioTo Ha TONKA 4.2), Tox He ce Hanara kopextua Ha 203aTa (Bx. TO4KA 5.2). Hlauenmu, nodnoscenu xa xamemmpua aGxayus (NVAF) Tlaunermirre Morar na npomwnkar npveMa 1a annxcaGaH, AOKaTO Ca NOATOKEHM Ha KaTeTHpHa aGnanuea (Bx. TONKH 4.3, 4.4 114.5). “eu ua Kapouoaepsuo AnuxcaGan More Aa Gane SanouHaT HAH MpomBIDKeH MPH nayHeHTH c NVAF, pH KOHTO Moe 1a © HeoBxoaHMo KkapaMoBepsKo. Tipw nauwenrure, Kono npenM Toba He ca JlekyBaHA ¢ aHTHKOATYs1AHTH, TpAGBA a ce OOMHCTH -MBIOTIONBAHE Ha TPOMG B ABO MPERCEPAKE c MPHIOKEHHETO Ha NOgXOR ¢ OGpasvo wiciemBaHe (HANIp. ‘Tpanceso*pareamma exorapanorpadus (TEE) wim xommorspiia romorpadia (CT) npexn KapAaHOBepaHO B CboTBeTETBHLC ¢ YCTaHOBEHITe MOHLMHCKH PEKOBOACTE, Cis nue ‘enw ns 4Tipu nauerrure, konro 3anowar xeyenue c ammxcaSan, 5 mg 7paGea na ce npwsarar Ba TH ‘avteaHo 3a niowe 2,5 su (5 esMHMNNM AoA) Nem KAPAHOBEDAKO, 38 Aa Ce OCHTYpH aeKBATHA aurruxoaryaaiyas (8, Touka 5.1), Joampoaxara Tpa6sa na Gee Hamanena a0 2,5 mg anuxcabax, Nphiaral 1Ba ISTH JMeBHO 3a MOHe 2,5 AH (5 ENMHHYHH 403K), AKO TANMeHTBT OTTOBAPA Ha kpirepuiure 3a HaManaBaxie Ha 2osaTa (BX. ToUKUTe 110-rope Hamaimeane na doxama u Bobpewo yopencoane). Axo e HeoGxoaMMo KapaHoBep3Ho, NpeZH Na Morar AA GbilaT NpHioakeHH 5 nos anuKcaGaH, TpAOBA a ce piioxct naTosapsama N03a oT 10 mg, MocaenBAHO oF $ mg ABA METH AHeBHO. CxeMaTa Ha ‘Mpaarane TpaGpa Aa One HaMasena 10 HaTOBapeallTa 03a or S mg, MoCcneaBAHo oT 2,5 mg Ba TsTH aMeBHO, aKo MAuseHTUT OTTORApA Ha KPHTepHHTe 3a HAMANABAHE Ha 103aTa (BX. TOMKHTE O~ rope Hamanasane na dosama u Bebpemo yepencdane). Tipanonennero wa warowapsaulara 1038 ‘TpaGpa na Gee HaBEpiteHo TioNe 2 aca MpenH KapaMOBepsHO (BK. TOHKA 5.1). Tipu scwaxn nauvenrs, noaToxKcHH Ha KapaMOBepsHo, TpaGEa a Ce NOTBLPAH, He MPCs apqMonepaHo naugieHTST ¢ npHen aniKcaGay, KaKTo € npeancano, Tipx mBeMaHIe Ha PeuICHe ‘oTuocHo SaTlosnaHeTO H MpONBIDKMTENHOCTTA Ha eeHHETO, TpAGRA MA ce BIeMAT NpeBH YeTAHOBEHHTe NpeTlOpEKH 3a airTHKoarysattTHO sleweHHe NH NALMeHTH, MOATOKEHH Ha Kapnuosepsuo. Tayuenmu c NVAF u ocmep xoponapen cundpor (ACS) wuru nepxymanna xoponapxa unmepeenig @Pch ima orpannves on no OTHOUIEHHE Ha .eNeHMeTO ¢ anMKcaGaH pH npenopouuTennara Osa pH naywentw ¢ NVAF, Koraro ce usnouisna 8 KOMGunalyis ¢ aetruTpoMBorHuHM cpesicTEa TIPH MAWHEHTH C ACS n/n rakuna, KonTo ca nonoxxenM ta PCI cen nocruranie Ha xemoctaza (wx. ToHKH 4.4, 5.1). Tledwampusna nonynauua [BesonacHocrra eduxacvocrra Ha AGaTHKCeMT MM seta M JOHOMIM Ha BEIpACT Hox 18 roNMHA He ca yeranoses, JInmesar anim. wa 1 Tlepopannio npaioxerne AGaraxceHt Tpa6ea 2a ce norimsa ¢ Bona, cbc mum Ges xpata, 3a navioHTure, KOHTO He MoraT Aa NpernbmlaT Hem TaGnETEH, TAGuETKHTE AGaTHKCeHT Morat 1a co ATpoUlaT H pasTROPAT BRE BOA WMH 5% ROReH pasTBop Ha rmoKosa (GSW), HAH AGBAKOB COK, HAH, a ce cMeomT c AGwIKOBO mope H BeqNara Za ce MpHioxat Nepopa.tHo (Bx. TOHKa 5.2). pyr Hawn © ‘raGneranTe AGaruxcerr 7a ce Harpouiar H pastaopsr 8 60 mL noua win GSW w pemnara aa ce Mpwoxar pea nasoractpasa core (Bx. ToHKa 5.2). Harpomeniere TaGnerkn AGaTAKCCHT ca craGuntn men Bona, GSW, 2GamK08 Cox H sGEsIKORO MHOpe 10-4 ¥aca.43 Tiporasonoxasanaa © Coppxyyscrsirrestoct KBM aKTHBHOTO BeMLECTBO WI KBM HAKOE OT loMOLUTHTE BeUIeCTBA, s6poer 8 rouxa 6.1 Knunuuno stasino aktunio xoprene. “Yepronpo6uo saGonsnane, cBEpaaiio ¢ KOaryAONATHS H KAHHHEHO 3HAYHM PHCK OT KbPBEHE (wx. T04Ka 5.2), © Tlesna waim cectossne, KoMTO Ce oneHABAT KATO SHAYHM PHCK 3A MECHBHO KBpBCHE. TOBA MO:Ke 2xa BRAONBa HaCTORIMA WIM CKOpouma FACTPOMHTECTHHAMHA ABA, HaAMIME Ha SHOKAYECTBCH HOBOOGpASyRANHA ¢ BHCOK PHCK OT KBPBEHE, CKOPOITHA MOSBYHA MH CPBOHATMA TPABMa, Hackopo WSBEpUIEHA MozBHHa, rpEGHANHA HH O*pradwoorHna onepaNHA, CKOPOLIEH [BBIPeHeponen KPBAOKLING, MBBECTHH HAM NOMOSHPAHA eso(parcaHM BapHILH, apTEepHO- BeHOSHE MANIPOPMALINH, CHIOBH aHEBPHSMH HIM TOOKKA JHTPACTINNATHH HAH mmrpanepe6paHH CEnOBH aHOMATHM. ‘© Compretmanto nevene ¢ peako apyro npoTHBocEcHpBallo ¢peZICTEO, HAN. HerppaKuMoHMpatt xenapuit (UFH), nckomonexyaHn xenapHi (eHokcanapnH, AATTeNApHH H 7.1L), XenApHHOBH AepuBarH (borjanapunyxc Hi T.H,), nepopasHH aHTHKOArynaHTH (BapipapHH, pHBApOKcASan, AAOHTATpai 4 7.H.), OcBeH B KONKPETHH CYHAH Ha NpeMMAHABANe OT EHO artTHKOAryAaHTHO severe ta apyro (Bx. To¥Ka 4.2), Koraro UFH ce mpuzara B 03H, HeoBxOAHNa 3a TOAAEPKARe Ha MpOXOAMMOCTTa Ha LEHTpaNleH BEHOSeH HAH apTepHATEH KATETSP, WH KOTATO UFH ce npunara no apeme a kaTeropria aGaliua 3a mpenc>pawo MEKHEHe (Bx, TONKH 4.4 H 45). 44° Cuennasnu npeayupexienua u upenuasau Mepku npa ynorpeba Puck or xppponoue Kaxro 4 npx apyrirre atrukoaryaawmu, naueHrire exyeaKn © anmKcaGax, tpaGna ja Gosar BHEMaTeNHO HaGMORABaHH 3a IPHHANA Ha KEpReHe. TTperlopBYBa Ce BHHMATENHOTO MY IPHIOKEHHE npn aaGOxARAKHA ¢ HoRMIeH pHcK oT KpHRONUIN. YnorpeGara Ha amMKcaGaH TpxGea na Gone MpeycTaHOReHa, ako HACTRIM Texka xeMoparHs (mx. TOUKH 4.8 1 4.9). Bompetat ue revermero c anuxcaGat ie Hatiekea pyrHHHO npocnensBaHle Ha eKcrIOsuIDLETa, xasiiOpypant MeTon 2a KomuecTReHO onpeensHe Ha auicpaxrop Xa Moxe ma Gxye MoseseH pi ‘HSBBHPEAHM CHTYALINM, KEeTO HEGOPMALIEATA 3a eKCTOSMUNK Ha anNKcaGaH Moxe sla NOMOTHE 38 ‘B3EMAHETO Ha HHOPMHPAHH KIHHHGHK PellleHHs, HAN. NpeHOsHpAHe M CreMIHA ONepaLins (Bx. ‘rouka 5.1). Hamveaio ¢ epexerso 3a neyrparmsupane na anrruipatcrop Xa axrusuoerra wa amiccaban. BoanmonelicraHe c apyru sexa Mat MocTanara EamospemernioTo MpAOxeHHE ¢ BCCKH pyT aHTHKOEFyAaHT € MpOTHBOTOKasaHO NOpa;tH _YBeMIMEHHA Duck OT KEpBEHe (Bx. TONKA 4.3).Exnospemextoro npwioxenne Ha ariukcaGan c aiTHTpOMGOTHYAM cpencTRa YBeaMvaBa PHCKA OT Kepaente (te. rouKa 4.5), Heo6xonnMo € BHHMAHHe, ako NallHeHTHTe Ce slekKYBaT eHOBPEMEHHO CkC CeseKTHENH HiXH6HTOPA ‘ma oBpatoro saxsamiane Ha cepotonmita (SSRI) HH HHXHOMTOPH Ha O6paTHOTO 3axBamtaHe HA cepotounl # Hopaapenamay (SNRI), 114 HecTepowIiM nporBossananyremin cpenctsa (HCTIBC), ‘BRIUOUHTENTHO aLleTILICATHMATORA KHCERHHA, pyr moxnGuropy na TponGounTHara arperanix ne ce Mpenopb sar exHoBpeMento c anuKeaSaHt ‘enea onepauis (Bx, TOHKa 4.5). TipH nanwettn ¢ mpencepato MiskIcHE H CBCTOAHHA, KOHTO HalaraT MOHO HTH [BOM anTHTpomOounTHa Teparis, TpxGBa Na co HANpABH BHEMaTeNHa ONeHKa Ha NOTeHUHATHATe NOH Cpamo noTeHUMaMHHTe PHCKORE, MpeIH Na ce KOMGuHMpa Topa eseHHe ¢ AGATHKCCHT. B smmoeano npoysiane mpi nauneHTH ¢ MpemcspaHo MExvIEHE, eIHOBPeMcHHaTa ynoTpeGa Ha amerwcatHiniiosa kcestata (ASA) e nosminiuta picKa oT MaCHBHO KbpBCHE MPH aTHKcaGaH OT 1,8% na romana 10 3,4% wa roaHHa H € yeennano pncKa or KUpSEHE NpH Bapdapant OF 2,7% Ha Toma 10 4,6% na roma. B ona KiHHK4HO npoyuBane e HMarO orpanHuesla ynorpeba (2,1%) Ha eanoupemenna sofia anrrurpomGoumna Tepars (Bx. TouKa 5.1). B kamiwano npoyunane ca BKMOWeHH nauMeHTH ¢ TpesICBpAHO MIKEHE ¢ ACS W/HnK No;LIOXxeHH ‘a PCI n rmaaninpan nepuon a nesene c P2Y12 uHxuGwTop, cbc HIM Ges aueTHTcaTHLULTOBA xuicenuwa, H mepopaien adrrukoarytair (antuxcaGan wan VKA) 3a 6 meceua. Cemmsrersauiara ynlorpeGa Ha anerHicanHitToRA KHceTHHa NOBHUNABA PHCKa OT MacHBHO no ISTH (MexayHapoHo Apyxkect#o no TpoMGosa K xeMocrasa, International Society on Thrombosis and Haemostasi CRNM (Krinisio stasHMo He-MacBHo, Clinically Relevant Non-Major) xepeene px rauinentH, JlexyBaw ¢ anuxcaGan, or 16,4% na roniMia 0 33,1% na ronmia (Box. TouKa 5.1). B olumwaxo mpoyunaHe MpH BHCOKOPHEKOBH MaNLAeHTH ce OCTHP KOPOHApeH CHIAPOM Ges DeACEPAO MEAITEHE, XapAkTePHSHpAMl Ce ¢ MHOTOGPONHH CHPAEIHH H HECPIEHHH CHITBTCTRALIUN ‘sa6onapans, KOWTO ca TOMTY¥aBRIM aNeTHIICANMUWTOBA KHCETHHA WIM KOMGMHALULA OT AUCTHNICATHIPLIONA KHCeNAHa H KAOMHAOTPEA, € CLOGIMEHO 34 SHAUHTTETHO YBETHTICH PHICK OT MacusHo Kxpsenie no ISTH npu anuxcaGax (5,13% sa romuma), cpasneno ¢ riaue6o (2,04% wa rouMHa). Ynonpess TEN ‘ta nevenne Ha ocTEp noxeMHNeH wNeysrT ‘Viqa ncsoro orpannuen on c yriorpeSara iia TpomGommrrHMnin cpesICTBa 3a sleHeHHe Ha OcTEp ‘HeXeMITHeH HHLCYSTr NH NAMGHCNTTH, Ha KOHTTO ¢ HpAMaraH artuKcaOaHt (BK. TOAKE 4.5). TH ce. xan 7 ‘Besonacnocrra edpmxactiocrra wa anxca6an We ca Mpoy'ieHH NPH MIAUIHEHTTH exe CEPIENHO WATHO nporesmpane, cic Win Ges npencepaNo MiokneHe. Topaa TasH mpavama ynorpeSara Ha amnkcaGast He ce nperiop4pa nw TaKwaa yestonHs.‘Tauweuts c anrubocbonmmmyen cumpom Aupextno gelicrsamu nepopamn axrakoarynatr (DOAC), BkmouHTeAHO arAKcaGant, He ce [penlopeyBat MH MaUHEHTH ¢ aHaMHe3a 3a TpOMGOSA, KOHTO Ca JHATHOCTHUMpAHH C anmudocdommusen cuxapoM. Tlo-creumao npH tpoliHonoswTusHu nauwesT (2a nynyceH ATHKOArynaHT, HTHKapAHOANEHOBH attTHTeTa Ht aNTHTeNA cpewty Geta-2-ranKonpotentt I), aevenuero ¢ DOAC Moxxe 1a Grae cBupsalio ¢ NoBHineHa YecToTa Ha NOBTApALM Ce TPOMGOTHSHH cx6umaa 8 cpantienue ¢ Tepamaaa c ararowncr Ha nieraman K. ‘Qnepauna H HHBa3HBHH MpouenyDA Armxca6ait tpx6sa na Gone cnpax none 48 aca mpenH exeKTHBH XMpYpri HIM MEBASHBHH POUeAYPH C YMepeH HH BHCOK pHCK OT KEpBerte. TOBA BKMIONBA HHTEPREHIDH, 38 KOHTO BLIMOAMIOCTTA OF KAHIMTHNO SHAYHMO KBPBCHE He MOK fla GLE HIKMONeHA IIH 38 KOHTO PHCKET OT wopsene Gut Grin HenpnencTAB. ‘AnmxcaGan tpaGea na Gore cnpan none 24 Naca npenw eNeKTHEHa XHPYPCHA WI HHBESHBHH pOUeAYPH C HCBK PHCK OT KBpREHE. ToKA BKIMONRA MHTEPRCHINM, 3 KOHTO BCAKO KPBCHE, KOETO ‘C€ ORBRBA Ce O¥AKBA a € MHHMATHO, HEIJTHREHO KATO OKALUIR HLTH TECHO KOHTPOAIHPYEMO. ‘Axo onepauusra JU1M MiBaSMBETe MPOUIEAYDH He MOTT 1a Guslat OTIOKEHM, TpAGBA 1a Ce HOKOH (C HYHOTO BHHMAHKe, KATO Ce B3EMe MPEMBHT MOBHILEHHS PUCK OT KbpBeHe. PHCKET OT KBPBEHE ‘TpaGpa a Gre mpeuenest cnpsMo cneuIHOcTra Ha MirrepReHImAsTa. Crea nnessupnara mpoueaypa HIM XHPyprusma HITepBEHUAE, ReveHHeTO ¢ anNkcabant tpAGxa sia Ce ‘BLa06HOBH RemHArA HIOM € BEAMOxKHO TPH YemIOBMe, se KIMHHMHATa CHTYSLIMR NOsBONABA He MOCTHTHaTa aekBaTHA XeMocTata (3a KApLMOBEp3HO BAK, TOAKa 4.2). Tipy naunenrure, nomvioxkeun Ha kaTeTEpHa a6 ALMA 3a NIPEACEPALHO MBATIEHE, EYEHHETO ¢ amuxeaSan We e neoGxoAHMO 2a ce Npextcna (wx. TOK 4.2, 4.3 44.5). Bpementio empane Crupaneto 1a axTaxoaryaaitrH, pkmosuTenHo anikcaGar, NOpasiH AKTHBHO KEPREIe, eeKTHBHA XMPYPTHs HI HHBASIBHH POLE YH, NOCTARS NIANWEHTHTE B MIOBHILEH PHCK OT TPOMGO3A. ‘Oriaonenns p Teparmista rpaGea ja ce 1Garear 4, exo aHTHKoarynanmarra © AGaTuKceHT 1px6Ba Bpemeno na Gbile cHpAHAa No KaKBaTO M Ja € MIpHuHa, neYeHHETO TpaGsa Aa OLxe BL206HHOBEHO BeqHara MOM € BESMOXHO. ‘eMOMMaMETIHO HecTaGHAHH nauMeHTH ¢ BE Wa Ht KOTO € Hi 2 TPOMGomUa HH Genompobia ewGonexToMus AmakcaGant ne ce mpenopsssa karo arrrepHariea Ha HedpaxuMonMpaxa XenlapHH MpH nanyteHTH c GenonpoSex eMGamlsEM, KOHTO ca XeMOMHAMHCYHO HECTAOWINH WIE € BEIMOAKHO 1a GrsAT omnoxeHH Ha TpomBomusa 11M Genoapo6wa eMGoNeKTOMH, THil KATO GesOHacHOCTTa H eqhuxactocrra na anmxcaGan ne ca ycraHOBeHM MpH TeIM KIMHHYHH CHTYAIAH.a6onseat Tlauneirru c acrusio pakono 2a6onabase Morar sia GAar © NOBKINEH PACK KAKTO 32 REHONCH ‘TpoMGenGommseu, Taxa u 3a Kepaene. Koraro ce OOMHC:X YrloTpeGaTa Ha anuKcaGaH 2a sleweHHe Ha TIBT wim wa BE npy nawsesrs c pax, € HeoGXOmHMO BHMMATESHO fa ce OUEHIT THONSHTe CrIpAMO ackonere (sink culo TOuKA 4.3). ‘Tlauenty c Gs6peqto yapexstaue COrpanavern cami ani cover, He iienMeKtsre KOHILetTpALIMH Ha anuKeaGaH ca NOBMULEHHL pH nayheHTH c TeKKO GL6peo yepeRyane (KpeaTHITAHOB koINpEAC 15-29 mL/min), KoeTO MoxKe {2a joBelle 0 TlosHMseH puck oT KEpaeHe. 3a neveHMe Ha JIBT, nevenne Ha BE a nporpaiaxrnca Ha peunausupaumt JIBT win BE (VTE), e HeoGxonHMO HoBHUIeHO BAEMAHKe npH yrioTpeGaTa Ha amnkcaGat mpH nauerTH ¢ Texko Os6peHHo yeperaane (KpeaTHAHHOB KuAPEHC 15-29 mL/min) (ox. Toss 4.2 45.2). 3a mpodpwnaxruka a MnCy:TT m cxlcTeMeH eMbomHsEM pH nauuerTH ¢ NVAF, nalfenH ¢ TeKKO Gs6peHm0 yepexuiane (kpeaTmution Kaupenc 15-29 mL/min) naueNTH uc cepyMen KpeaTaAH > 1,5 mg/dL (133 Muxpowona/L) na spspact > 80 roaHHH WH c TeNecHO Terao < 60 kg TpaGea na ce Tipwara No-HHckaTa 203a ankca6an or 2,5 mg aBa TsTH AHeBHO (fx. ToHKa 4.2); Tip nauserrra ¢ xpearimmios xampuue <15 mL/min 1 naumeHTn, nomioxeHN Ha AMA, JTATIcBa KAKHHGEH OMT, opann KOeTO NpHeMBT Ha aNAKcaGaH He ce MpenopBuBa (Bx, TOUKH 4.2 52). ‘Taumetrr p crapyecea propact ‘Henpeasarara ssapacr Moxe fla Nosexe 0 nosumaRane Ha pucka OT KpBBOMSIMBH (mx. TOUKA 5.2), Couto Taxa, extHospemennoTo npHiaraie Ha anuxcaGan ¢ aueT#sicanHuviona KUCesTMHA MPH THanWeNTTH 8 erapuecka BLapacr TpaGRa /la Ce HARBPUTRA C NOBMUNEHO RHMMAHME TOpAH NOTEHLUAIHO ‘O-BHCOK pHeK OT KEpBCHE. ‘Tenecno rerao ‘Futckoro Tenecto rer. (< 60 kg) Monke 1a € CBLpsaHO ¢ MOBMMeH PHCK OT KbpREHE (BX. TOUKA 5.2). Tlannerrty c sepHoapo6no yepexuate ‘Anmmxca6ax € mpoTHsonoKasaH npH ttanueHTH ¢ YepHoapobHo saGanapalic, eBbpsaHo ¢ KOAryAONATH 1 KAMHWIHO 3HAMHM PUCK OT KEpBEHE (BOK. TONKA 4.3). Tipunaraniero my ne ce npeniopuna npy maNlHeHTH c TEKKO YepHONPOGHO yapemLiatle (BX. TOHKA 52). HeoGxoaHMo € pHaraHeTo My ¢ NOBHINEHO BHHMAHKE NpH NaUIHEHTH CBE EKO HII YMepeHo ‘epHoapoGxo yapeanane (Child Pugh A wi B) (8x. TowKH 4.2 15.2). Tamera ¢ nosurern crofinocTa na vepHoapoSnnre exsuMn ALT/AST >2 nota Ha ropHara panuya Ha Mopmara (ULN) wii o6ui Gumapy6uu 21,5 meTH Hag ropnaTa rpaxiaus ¥ca GHAW BKMONeHH B KTHHITE mpoysBasas. TlopamH TasH NpHHHHa, anvKcaGax tpsGna fa ce Msnow3ea BHMMaTeHO NpH TasH HlonyaaulAs (wk. TOUKA 5.2). FIpeqM sanowBane Ha antHKcaGaH € eo6xouHMO fa ce upobexe HestemBaNe Ha YephoApOGHMTe PYHKUMONANHH NOKAsATENTL He HEXHO ut PASO 3A4 (CYP3A4) wa P. rauwonporeut (P-gp) He ce npenoppsna ynorpeGara Ha amuxcaGan mpH naujeNTH Ha ¢xHORpeMeHHO CHCTEMHO s1eHeHHe ‘moun winxeGropa na CYP3A4 H P-gp, KaTo a3008H arTTHMMKOTHIEH (Han. KeTOKOHA307, HTpakONASON, BOPHKOHAION 1 TlosaKoHAon) M HIV nporeasHe HExHOHTOpH (Hap. pHTOHABHp). TesK sekapcTaenH MpOAYKTH MOTAT Ja NOBKILAT eKcTIOSMMATA Ha amaKcaBant 2 muri (mx. TOUKA 4.5) HTH oseve pu Manne Ha AOMTAHTeRIH axTOpH, KOHTO yBeHUaRAT eKcHlOsHMATA Ha arHKcaGaHt (uanp. texxxo 6s6peuno yapenxnaxe). ‘Boaumoyelicrane ¢ wayxropn Ha CYP3A4 # P-gp Egnospemennata ynorpe6a Ha arxcaban ¢ MOuIHH HEJyKTopH Ha CYP3A4 # P-gp (naripumep Puan, demrrow, kapSamaseniat, hero6apGirTaN HK AIT KaETapHOH) MOK Aa OBEN 10 oxono 50% nommnxente B excnosnunara Ha anukcabad, B KAMKHIKO HOMHTBaHe MPH MALMeHTH C MpencEpIO MmAKTEHE ca HAS TOARAHM HaMANeHa e)HKACHOCT H {10-BHCOK PHCK OT KBPBCHE PH ‘eTHOBPeMCHHO NpHioxeHHe Ha anMKcaban cbc CHIHK HHJKTOpH Kaxto Ha CYP3A4, Taka H Ha P-gp, cpantieno exc caMocroarema ynorpe6a wa anaxca6aH, TIpx nauseHTH, Ha KoWTO ce npiuiara CHIrbTCTBAMIO CHCTEMHO ACMEHHE ¢ MOULHH MILIYKTOPH KAKTO a CYP3A4, taxa # na P-gp, ca mpiutoxxun entensuTe npenopeKn (Bx. ToHKa 4.5): © sampodunarrixa Ha uncyorr H cHeTeMeH eNGosTEEM npH mauesTa c NVAF 13a npodwntakruxa Ha peunuBnpanqa JIBT 4 BE € se06xoa4Mo NoBHuieHo BMKMAHHe Tp ynorpeSara Ha anuxea6ax, © sanevenne Ha ZBT 1 sesenwe wa BE we TpaGsa 2a ce wanionsna amaxcaGan, Toi KATO ecpukacHocTra My Moxxe la Gbue KOMMpOMeTHpaHia. aGoparopn noxaseren Koarynauyonrurre nokasatenu [Hampamep mporpowGunoo Bpeme (PT), INR x axTHBHpaHio aptwaHo TpoMGoruiacTHHoBO BpeMe (aPTT)] ce NORIAABAT cnopen OYAKBAHHATA OT MexAHHSMa Ha efictowe a anaxcaGan. [pa ovaksanara Tepanesriria 03a NpoMeHHTe, HaGmMOAABAHH B Te3H KoaryaanvoHHH NOKA3ETE:H, ca MATKH H BBE BHCOKA creneH BapwaGwre (sx. TOUKA 5.1). ‘Hnhopmanus sa nomouurre nemecrsa AGaTuxcent cbatppoka waxTosa, TlauetTH ¢ pemk HaCTeCTECHH SAGOnABAENA KaTO rasiaKTOsHA HeTlOMOcHMOCT, ToTaseH naxrasen Ae(pHIUAT HIM FIHOKO30-ranaKTosHa ManaGcop6uMs He TpAGBA Aa IIpHemar To3H slekapeTBeH mpomyK. AGataxcen cesepxa no-wasiko or 1 mmol Harpai (23 mg) Ha dunwumpata raGnerka, T.c. Ha Tpaxtaxa ne chaepxa naTpHil.‘Vapcu6uropa a CYP3A4 w P-gp Enfloppenesioro npwioxenne 1a amixcaSan w xeToKouason (400 mg seAHLax mHeBHO) — MoIeH AXHOHTOP KaxTO Ha CYP3A4 , Taka H Ha P-gp, BoAH 0 AByKpaTHo yBenuueHHe Ha cpentiaTa AUC ‘aa anmxca6an x 1,6 TTsTH 110-BHCOKa CpemHa Cog, HA ANHKCABAN, ‘He ce npenoppusa npanaratieto Ha anmkcaGaH IIpH NaujeHTH, KOHTO NOTYYaBaT CAHOBPEMCHHO ‘cHCTEMHO sleYeHHe ¢ Mou HIXxHOWTOpH Ha CYP3A4 m Ha P gp, KATO as0mIOBH axTTAMHKOTHID (ianp. KeToKOH|30N, HTpAKOHason, BOpMKONAsON H NosaKoHAsOn) M HTV nporeasHn HEXHGHTOpH (samp. prrotiannp) (mx. rosKa 4.4). ‘Ouaxsa ce aKTHBHHTE BeillecTBA, KOMTO He ce CNHTAT 3a cHLTAM HiEXHGHTOpK Ha CYP3A4 H Ha P-gp ((ranp. ammonapon, KnapHTpOMHUMH, IMLTTHAGEM, Q\IYKOHASOR, HANPOKCOH, XMAKAAH, BepanaMrt), Jaa yscamuanar B o-Mavika CTenen muiasMenara KoMLIeH paws Ha arKcaGan. He ce wanara Kopexto# Ma 03aTa Ha aTHKcabaK, KOTaTO Ce NpHUIara EAHOBPeMEHHO CEC CpeETBA, KOHTO He ca Mout HixHGnTOpH Ha CYP3A4 x P-gp. HanpHmep aNrTasem (360 mg vezHbxK suteBHO), cMATAH 3a yMepen HiExHOHTOp Ha CYP3A4 H cxa6 mixnGuTop Ha P-gp, nome 0 1,4 eta MO-BHCOKS ‘epeatia AUC u 1,3 MBTH NO-BHCOKA Cogs Ha amtakcaGan. Hlanpoxcet (500 mg embioxparia 03a) — nurxnGurop 1a P-gp, Ho He Ha CYP3A4, sont caorBeTHO Ho 1,5 msrH o-BucoKa epeaKa AUC 1,6 mini T0-BHCOKA Cage Ha armnkcaGan. Kraperposaum (500 mg, mea ETH HHEBHO), MiEXHENTOP a P-gp 4 MouieH HEXHOTOp Ha CYP3A4, BoaH Jo cboTBeTHO 1,6 METH H 1,3 mbTH NO-BUCOKH ‘epee AUC H Cay HA aTtaxcaSan, ‘Hnayesrops na CYP3A4 n P-gp Enuonpemessoro npwioxenne Ha anvikcaSan u Mousa rimyxrop Ha CYP3A4 u P-gp, Pucpaxrunnt, BonH 20 okono 54% nlotiexanaKe Ha cpemuara AUC H 42% non¥oxasave Ha cpesiNaTa Cac Ha ammaxcaGan. Eadonpemennara ynorpe6a Ha amukcaGan c APYTH MOLLNH HHAYKTOPH 18 CYP3A4 u P-gp (Hamp. dhenmromn, xapGamasermmn, henoSapOwran wim KAT KAHTApHOH) CDLlO MOE 3a nOBene NO HaMaeHA haasMeHH KONMEMTpauuAH Ha anMKcaGaH. He € HeoGxomMMO sa ce NpaBH KOpeKiveN Ha 1O3ATA Ha AMHKcaGAH TpHt EAHOBPEMeHHO eHeHHE C TAXHBA NeKAPCTBEHH NPOAYKTH, HO Boe Tak MH NaIWeHTH, Ha KOWTO Ce TIpHara CMTATCTRAMIO CHCTEMHO sTeMeHME € MOLLE HIYKTOpH xaxro Ha CYP3A4, raka H Ha P-gp, e HeoGxonHMo oBHieHO BHHMaHHE MpHt ynoTpeGara Ha anuxcaGax 38 npodwnakrika Wa MHCyIT H cHCTeMex eMGomHa6M MpH nattHenT# ¢NVAF #38 mpodwnaxtaxa na peunaMenpan JIBT 1 BE. Anuxca6an He ce mpentoppasa 3a nevertne aa ABT 1 BE npw nauyeTa, Ha KoHTO ce Mmponexna CRIIGTCTBAINIO CHCTEMHO TEYEHHE c MOULIN HEUAYKTOPH xaxro Ha CYP3A4, Taxa Ha P-gp, Toil karo exhnKacHocTTa Moxe 1a 6bn¢ KoMMpoMeTHpaHia (BX. ‘roxna 4.4), aT, Ht Ha TpoMOouerH 8 (CBE Tlopa.in oaminenHs puck oT KEpEeHe, eMHOBPEMEHHOTO TeMEHME C BOCK JApyr AHTHKOBTYAAHT © MpOTHBOMOKA3aHO, OcBeH B KOHKDETHH CATYWAH Ha MPEMMHARAHE OT EHO AHTHKOArYAAHTHO /1e4eHHE 1a Apyro, xoraro UFH ce npwnara 8 03, HeOOXOAHMH 3a NoATEpxKaHe Ha MPOXOMMOCTTA Ha ‘etTparien BeHoneH wa aprepuasien KaTersp, HH Koraro UFH ce mpwmara no upeme Ha KarerepHa aGnauua 3a npexcopaHO MExCIeHE (Bx. ToMKe 4.3).TIp#t KonGuumpano npwutonxeune Ha enoxcanap (40 mg enNoKparua osa) M amuxeaGan (5 mg, ‘eqHOKpaTHa 03a) € 3a6ens3aH ALUTHBEH eceKT BEPXY aHTHaKTop Xa aKTHBHOCTTA. He ca aaGmonasarn gapwaxoximerHurd ur apmaKonHHaMITIAN ssaMMOneliCTBHA npH ‘@qHOBpeMEHHO NpWiarake Ha aNuKcaGan M akeTWICANMiKAOBA KucesTHHA 325 mg REDE AHEBHO. Tipa eanospemenno npwiarane wa antixcabax ¢ knonaaporen (75 mg pemttaK aHeBHO) HULK xomGunauiirra ot xonmapores 75 mg w aueTHNICaTHITORA KHCENMHA 162 mg BeAHSAK ANeBHO, WAH ‘empasyrpex (60 mg, nocnensarm or 10 mg Beni AHeBHto) MPH wIETTRANH BEB asa I, ue © aGmonasano SHAYHMO YaEmDKABAHe Ha BPeMETO Ha KEpBeHE WIH ROMEAHHTENHO KHIXHOMpANe Ht ‘TpomGouHTHaTa arperaulMa, B CpasHeHve ¢ NpwlaraHeTO Ha axTHTpoMOoUHTHH CpescTBA Ges: amuxcaban. Yecamuennara 8 Koarysiatmonnre TecTose (PT, [NR # aPTT) ca xoucncrenttun ¢ ‘erhexate mp camocTorTemHo npHlomeHHe Ha armixcaGan, Tipmtoxesero Ha nanpoxcent (500 mg) — suxnGurop ta P-gp, nome 20 1,5 moni ¥ 1,6 msTH o- BHCOKH CpeaHH CTOMHOCTH, cKOTRETHO Ha AUC 1 Cig, Ha amaxca6an. [pH anixcaGart ce HaGmonasa ‘cboTBeTHO NosMeHMe Ha cTOHMocTHTe NpH KoaryaauMoHHsTe TecToRe, He ca HaGmoxaBaKH NPOMeHH no OTHOWeHHE Ha edbekta Ha HaMpOKCeH BLPXY HEMTYMNpAHATa OT apaxWAOKOKaTa KACENMHA ‘TPOMGouNTHa arperalis 1 He € HaGmOgaBAHO KAMHMNHO 3HAYHMO YiTKDKABAHe Ha BPEMETO HA XKEpBee pH e”lHOBpeMeHHO MpHNOKeHe Ha aTAKcaGaH H HANpOKCeH. BUmpeki Te3H HaXOAKH, € BLIMOAHO IPH HEKOH MIAHBHAH 1a Ce Ha6MojABA NO-ACHO HBpaseH ‘PapMaxoanuanarieH oTroBop, KoraTo arrruTpoNGoUETH cpeneTBA ce MpHNAraT eHOBPEMEHHO © annkcaGait. Heo6xomumo ¢ TOBHINeHO BHNMAnHe NpH eNHOBpeMeHHOTO Mpiuiowetine Ha attaKcaGalt exe SSRIVSNRIs, HCTIBC, auerwicanuipuiona kuceauna warn P2Y12 HHXHOWTOPH, Thi KATO Te JeKapeTBeHH MpOAyKTH OSHKHOReHO NopHiMtaBAT pAcKa OT KEPBENE (sx. TOHKA 4.4) ‘Hina orpanitien omer mpi exHoppemeNHioTo MpHACACHHe ¢ APYTH HEXNGHTOPH ita TPOMGOLUTHATS arperauna (ka7o GPlIb/Illa penentopiin atrraronmern, AMnHpHaMon, AeKeTpaH WH eyaduarmpasor) nam tpomGonmiail cpexersa. Tei karo TesH cpericTsa NOBHUIaRET PHCKA OT KGPBGHE, EAHOBPEMEHHOTO NPHTOKeHMe Ha TeSH NlekapeTBEHH NpOnYKTH ¢ anuKcaBan He ce peniopeusa (Bx. ToHKa 4.4). Zpyru comsrersama repanni ‘He ca wa6monanaint xTmAIHO sHasHME cbapMaxOKHReTHTaHH WM dapMaKO HAMA BaAHMOASHICTBMA MpH EHOBPeMeHHOTO MpHAOKCHHE Ha amKcaan H aTcHOON HH aMoTHAHH, Enwospemenmoro nparoxeHue Ha anmkcaSas 10 mg ¢ arexonost 100 mg He HoKassa KoIMAHSIIO Has ecbexT BEPXY DapMaKoKHHeTHKaTa Ha anHkcaGan Tipu exvonpemertHoro npmIORHHe Ha [BATA eKApCTBCHH MpORYKTa, cpeasare crofirioeTH Ha AUC 1H Cone 1a artHKCaGaH ca 15% H 18% O- HHCKH, OTKOTKOTO NH CAMOCTORTESIIOTO HM MIpHIOKEHHE. Tipwnaraneto na amaxcaGaxt 10 mg ¢ amoruaHt 40 mg He HoKaspa exhext Bepxy AUC 11M Coax Ha ammxca6an,Hi a a Tipoyseanas ¢ aTTHKcaGan We ToKaspar HiEKHOMpaun edpext BBpXy akruBHoctra Ha CYPLA2, (CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 wm CYP3A4 (1C50 >45 uM) u noxasear cna6 waxnGupam edext Bypxy axruBHocrTa Ha CYP2CI9 (IC50 >20 uM) mpH KoRMeHTpauiaH, KOHTO ca SHA4HIMO TIO-TOmeMH OT NHKOBHTe TULASMEHH KOHMEHTpAUENH, HAS MOAABAHH NPH TANHeHTH. Anmxca6an ne uazyuupa CYP1A2, CYP2B6, CYP3A4/5 npu xonmentpamva 10 20 uM. To Tam [pau He ce owaKsa aNHKcaGaH a MpoMeHH MeTAGOTHTHAA KIMPBHC Ha enHORPEMEHHO TMpAaraHHTe AeKapCTBeNH NPOAYKTH, KONTO ce MeTaGOmMSHpaT upes TesH exsHMH. ANHKcaGaH He © ‘smasHM HHXHOUTOP Ha P-gp. Tipu warmrrpanna coe sapanx no6poso.tiar, KaKTO € omisieano Mo-OTY, anKcaGan He ORAHABR SHAUNTENHO apMaKOKHHeTHKATA Ha AMTOKCHH, HANPOKCEN HAM ATeHOMOM. Aucoxcun Ennospemessoto npwionenne 1a amikcaGan (20 mg Bema sIHeBHO) H mAroKeHH (0,25 mg BERIT -aseBHo) — cyGerpar na P-gp, He nosm#sna AUC wt Cog Ha AMTOKCHH. Ero ammo amiKca6an He wsounGupa P-gp Messmpasis Tpaxicnopr a cyGerpara. Hanpoxcen EqHoBpeMeHHOTO TpHIOKeHHe Ha CAHOKpaTHH 103 anHKca6aH (10 mg) 4 HanpoKceH (500 mg) — ‘weeTo Hnonpano HCTIBC, we noxasea nuxaxen edvext appxy AUC HK Cag, Ha HANPOKCEH, Amenonox Ennospementoro mpisionenme a eaHoxpaTia nosa amaxcaGan (10 mg) 4 arexonon (100 mg) — ‘ecto wanonsnaH Gera-Gnoxep, He NORMtRA SeapMaKOKMHETHKATA Ha ATEHOTOA. Axrapen server Tipmnoxxenuero Ha aKrMpeH BErIeH HaManasa excrlosMumara Ha amaKcaGan (px. TOK 4.9), 4.6 @epraaurer, 6pemennoct a KEpmene Bpemennocr Jluncear nanmn 3a ynorpeSara Ha annxcaSant npn SpemenHH xeHM. [poyyBanusera c RUBOTHH HE OKASB2T ANPOKTHH WAH HEMMPERTHH BHENHH e*eKTH ¢ Ores Ha PeMpoAyKTMBHA TOKCHHOCT (Bx. ‘Touka 5.3), Karo mpennasia mapxa ¢ 3a nipeamouHTanre 1a ce HIGATBA YnOTpeGaTa Ha ankKcaBAH NO Bpeme fia Gpementtoct. Kepmene He e wszectvo naan amaxcaGan wk HeroaHt MeTaGOsIMTH ce EKCKPCTMpAT B KBPMaTa TPH HOREK. Haawsmire aHkM MpHkUBOTHM Tlokaanar EKCKPEMIAR Ha aTMKcabaH B MIAKOTO (BH. TOHKA 5.3). He Morke J Ce HSKINOHM PACK 3a KRPMANETA H MeL.HeoGxommMo € aa ce Bseme pelienie AATH Na Ce NpeKparH KBPMeHETO IK Jia Ce NpeKpaTH/sa He ce ‘sanousa severe c amuKcaGaH, KATO Ce BIEMUT MpEABHN NOSHTE OF KEPMEHETO 3a NETETO M HossHeTe or mesenweto ta malixara. Depranurer Vomirsanusra mpa axxBoTH ¢ npitionenie Ha ansiKcaBan, He MoKaaBaT edlexT BRPAY eprastrTera (ex. To: 5:3). 4.7 Egexta sepxy cnocoGnocrra sa modapane paGora ¢ Manan AGaTHKCENT He NOBTHIBA KK NOBAMEBA NpeHeGpExUMO crlocoGHoCTTa 3a inoxpupane H paGora c Manu, 48 Heenan sexapernenn peaxamH He Sesonact Besonacnocrra #a amxcaGan e wacressana B yonopiaTa Ha 4 cma npoysBanns dasa I, 8 KoHTO ca nkmnoweHH Hayy 15 000 raumeerH: Hat 11 000 nangenTH 8 mpoyananusta 3a NVAF 4 Ha 4.000 naunetTH 8 npoysBannxra 1a neerne na BTE (VTEt), ce cpea o6ma exenosiiuia ‘eporwetio 1,7 rome H 221 zum (Bx. ToaKa 5.1.) Vectu Hexenaim peaxumn ca KpbEOMRIMB, KONTYSHA, EMHCTAKcHE M xeMaToM (Bx. TaGsmMua 2 OTHOCHO NPOtpna H UeCTOTHTe Ha HeKenaHMTe peaklWH No OK&3aHHe). B mpoyasanusra sa NVAF oGmara Yectora Ha HexeaHHTe PeaKUNH, CBEPSAHM ¢ KBPREHE TH -MpweM wa amuxcaSan, e 24,3% n npoyspanero Ha armnkeaGan cmpsao apspapus x 9,6% B MpoysRavero Ha anukcaOan cnpamo aueTwscalMuWioea kKcetMHa. 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TaGpwuen cnnebk Ha HexkenaHMTe peakusn ToGanua 2 noKasna HeweraHMTe peakinNH, OPeNeHH Mo cHCTEMO-opralleH KRG H HO HeCTOTA, KATO ce Hsnon3Ba cheaHaTa KOHBeUHA: MHOTO ¥ooTH (21/10); 4ectH (21/100 0 <1/10); HewectH (21/1 000 x0 <1/100); pemtku €1/10 000 10 <1/1 000); moro peaks (<1/10 000); ¢ HersnectHa uecroTa (or nammure aannn He Moxke aa Gone HanpaneHa oneHKa) cRoTReTHO NVAF w VTEL. ‘TaGanma 2: TaG.nmven enucnx Ha nexezanNTe peancueremen eGoasaeM mp Jevenue ua JBT, xevenne na BE w upodusaxraxa na muspacran nanwenta cNVAF,¢ | peuuqusupamn JBT x BE ‘eH WAH NoBeTe pACKOBH (TED) sbaxrops (NVAF) Hapywenue na xposma u swuowama cucemema ‘Anemns ecru Yeon ‘Tpombousronesus Hevecta Heer Hapyuenua na wynnama cucmena Capexuyscrentemtocr, Heuectm Hewecra auepriies nem anadustaKcHa Tpypirye Heveert [| __Heseem* Hapywenus na nepsnama cucmena Mospyest xpapowatus? Hevecrt Penk ‘Anrnoezen C newaneeria wectora Crenssecria ecrora | Hapyuenus na ovume | Kppnowsne B oKoTo : ecm " Hexeors (exmowrrento KoHoxrusa1eH xpseowua) Cedoeu napyuenus Kpsnoruinp, xewarom Yeo Meera ‘XanovoHua (wonouHTeNKO ecm Hevecrn "npoueaypia xinorouia) i Visrpaa6zommuanen Heveots C nemsnectuia vectora KpsBoHH Pecmupamopnu, 2pednu u meduacmaaniu napyuenis Ennctagenc Yecta Yeom Xemomrusa Hesectt Hexeot Kpsnomsime 8 uxaTemaHTe Pears Peaxit BsTama Cmomawno-upesnu napywenua Tagene HeerTacrpousrecramaicn eo ecm | xpssowanne Xemopornaner xpBBOHSINE Hevecra Heyects Kpspousnus yerara Heveorm Meer Xemaroxeana Heveora Heyecnt Pexranex xpBsona1HB, Weer Yeerm Funrapamuo KopBEHe Petponepuroueaten Penwn CC ewapectua wectora Kppsowewtus XenamoGuruapnu napyuenas Ornnonesia ® Hesecra Hever Seprionpobunte ébynkumouanin noxasaTen, nopmiueHa acnaprar aMHHoTpancdepara, Nosuurena ankanua hocparasa, 8 KpBBTa, rloBHeH Gnampy6ue 5 Kppera Tlosmmena rama rryramnst eer Yeora Tpanchepasa Tlosmmesa anarts Hesecrn Yecrm AMHHOTpaHcepasa, Hapywenua na xoxeama u nodxosenama moxan Koxen of pas Hevectu Heer Anoneuna Hesecta Hesect Epitema mysrrabopwe Muoro peat C memspectua uecrora Hapywenua na Mycxyno-cxenemnama cucmena u ceedunumennama moan Myckyniia xemoparna Penku Heuect# Hapywenus na Ge6peyume u nuxounume memuuya Xematypus Yecra Yeerm Hapywenus na evsnpouseodumennama cucmema u zvpoama ‘AGHopMen parnnasien Hevecrs f Yecth kpsonanun, yporenuraen kpsaowanns OGuyu napyuenua u eiperme na uacmomo na mpurowenteKepsetic a mactoto Ha Hesecma Hesect mpwnoxenne Hacnedeanun Tlonoxsreen pesyarrar 3a Hesecta Hesecra oxyamia kpea. -Hapanasanun, ompasanua u yeroxcnenua, evsnuxnant 6 pesyamam ha uamepaeniyier Korrysus Weer Yecm Tlocmmpoueaypum Heveera Hevecrs KpbBouAMBH (BkoUONHTEAHO ocTTIpotleaypeH xeMa70M, KPDBOHSIMB OT pata, xeMaTOM Ha MACTOTO Ha MyHKTHpAHE Ha KpBBOHOCEH chit H KpBBOMLIMG Ha MsCTOTO Ha xaTeTbpa), panes ceKper, KpDBOHSMHB Ha MACTOTO Ha MHA (BKIIONHTEAIHO XeMATOM Ha MsCTOTO Ha HRLUSHA), xpBBOMTHB NPA conepansx ‘TpasMarauen KpbBon31HE Hesecta Heseern + He ca naSmonanann ciy4an Ha reHepanasapan ipypityc B pamKue Ha CV185057 (iesrocpowna npodanaxraxa Ha BTE) + Tepwntrsr , mosses kpuaowaHe” oGxnaa RCHEKM KETpakpAHHAHH uM METPACHMHATHH XPBBOWSIMBM (F.e. XeMOPArHueH HHCY:TT WsIK KPLAOKAIMB B NYTAMEHA, LepeGpateH, nittpanesrpuxysapen man cy6ypanen KpseoHui. ‘Ynorpetara na anuxcaGan morxe na Ghile CELpsaiia © NOBKIIEH PUCK OT OYITHO HH HBHO KEPBEHC ‘OT TBKAE WH OpraH, KOeTO Mome Ja HOBENe NO MOcTXeMoparuna axenus. [IpHsvaLye, ‘CHMITTOMHTE H TEXCCTTA BapHpAT 8 34BUCHMOCT OT MACTOTO H CTeNeHTa KIA MPONWRHTENHOCTTA Ha eppewe (wx. TORK 4.4 1 5.1). CeoSutanave 1a noqosHpany HexxenayH peaxtumt ‘CroSmasaniero Ha noosupanH HexeNaNH peaKtIMH cilen paspemasane Ha ynoTpesa na sleKapeTBeHAs npoayKT € BaxHO. Tosa noanOnaBa 1a NpOABIDKH HAGORCHHETO Ha CLOTHOUICHHETO nonsa/pHck 3a nexapcraeHna npogy«r. OT MezMUMHCKHTe CHeUMAHCTH ce HSHCKBA Ja cboSmaBaT BoaKa lovOapaHia HEXeaHa peaKus pes NAIWOHATHA CHCTeNA 3a ChOOMIABAHE KEM ‘Vismastesnara arenas io nekapersara, ys. ,Jlawsn Ppyes”, Ne 8, 1303 Cospus, nga: 4359 2 890 34 17, yeGcaitr: www. bda.bg.49 Upexosupane Tipextoaupasiero Ha anuxca6a Moxke /la RoBene 10 NoBHUIeH puck OT KEpoeHe. B cayaali Ha XeMOparvMliH YonOATHeMA, eveHHETO TpACBA Ha ble MpeKXpaTeNo H HSTOMRNKGT Ha KOPBEHe sta Ce ‘yeranosn. Tpa6xa 1a ce oGMMCmK BLSMOALOCTTa 3a NpHArANE Ha HONXOARUIO MeNeHHe, HATpHMEP Zupyprivana xemoctasa, rpaHcibysis Ha MpACHO saMpaseHa 1ulaaMa WK NpHAAraHeTO Ha NeyTpamusispaiuo cpecrBo crpsMo HixHEHTOpH Ha haxrop Xa. Tips korrrpompann xan spoysnanix nepopanio npwioxeHust amiKcaSan pH 3Apanit AOGponoMLU 8 N03H 0 50 mg AHEBHO H NPORRIDKeHME Ha 3 10 7 mM (25 mg ABA STH AHEBHO B Npombnxenve Ha 7 nun wii 50 mg BemTEK AHERHO & NpORMDKeHHe Ha 3 AMM) He BOIIM JO KAMHYHO SASH HEXKEMLAHM peak Tipu sapasn WNAMBHIIH MpHOKeHHeTO Ha aKTHBeH BEIVIeH 2 H 6 Haca crea MOraEMAHE Ha Osa OT 20 mg anukcaGan nawasiasa cpemtata AUC Ha anuxcaGan chorpeTHo ¢ 50% 4 27% u Hawa eqhext BOPXY Cyuy- Koravo anvixcaGaH € MpATOXeH CAMOCTOSTENIHO, CPENHHAT NONYKHBOT Ha arluKcaGaH Hamanapa or 13,4 vaca cboTBeTHO Ha 5,3 daca U 4,9 Yaca npH MpAnoxeHMe Ha aKTHBeH Buren 2H 6 ‘uaca c7e7 anuxcaGat. ETo 3aill0 NpHIOXeHHETO Ha AKTHBEH BEECH MOE fae OT HO:T3a 38 onnazapane ha npenosHpane WK cHysalino normbulane Wa ariMKeabaH. B cayuaure, Korato ¢ neoSxoaMMo NeyTpanusupane na aHTHKoary.nalHiaTa NOpaTHt 2kuROTOSACTPAMIABAINO HH NEOBIANAHO KBPECHE, © HATHIHO HEYTPALHSHPAIO CPeACTBO CTPAMO mutxuGirtopi na cbaxtop Xa (Bx. TosKa 4.4), Mowe na ce obceaH culo npHnarave Ha KoMeHTpATHL Ma npotpomuos kommutexc (PCC) aan pexomOunairen axtop Vila. OGparumoctra na dapmakomannuetHre eeKTH Ha anuKcaGaH, NoKasaHa pes MpoMertH B Tecra 3a OGpasyparte Ha ‘TPOMGHH, © BHARA B KpaA Ha HIdyaHATA H OCTHTA WsXoMHH cTOHINOCTH Ao 4 aca cneA HaXATOTO Ha 30-mmmyria anysua ¢ 4paxropel PCC npa sapasi MHMBHNE, Jlricba O6aNe KAHEHYEH OTT © ynorpe6ara wa mponyxru ¢ 4-arropent PCC 3a cnupane Ha KepBeneTo MpH HRAMBHAM, NpHe TH annxca6an Tlonactosmem anica ont ot ynorpeSara Ha pexomGunairren ¢asrop Vila np AUB, veKyeanH c anKcaGaHl. PoKoMOnHatTeH dbaxtop VIla Moxe Za Ce MPHOXKH NOBTOPHO 1 Aosara 1a ce THTpHpA B ABHCHMOCT OT HaMBAIABANTETO Ha KEPBCHCTO. B caryian na MaciHo KDpRCHE, B SABHCHMOCT OT KONKPETHITE BESMOMHOCTH, TPAGRA fa Ce HMA TMPenBH KOHCY.RTAUINX Che CHLWMANNCT NO KOAFYAAIMOHEH RapyINeHHs. ‘Xenonmanmara Hamansea AUC na annxcaGant c 14% npu nua ¢ Tepaanantia GEOpestia nenocrarsanocr (end-stage renal disease, ESRD) np nepoparuio npwioxenMe Ha exHEMNHA 1038 anuxcaGan 5 mg. [lo ra2H npisusia e Mako BeposTHo XeMomMATHBATA na Gane expeKTUBHO CpesteTBO 3a ORNAMABAHE Ha MpesloaMpave c annKcaGaH. 5. @APMAKOJIO‘HUHH CBOHCTBA5.1 @apsaxonmmanutan cootiersa ‘Dapwaxorepanesritina rpyna: ArmHTpOMGoTINTHH cpenCTBA, AMpeKTHH EXHOHTOpH Ha (baxrop Xa, ATC xox: BOLAFO2 Mexannspm Ha peficrsne AnuxcaGan © MouleH, repopasten, o6parHM, MEKTeH H BHCOKO ceneKTHBCH MEXHOMTOP Ha AKTHBHOTO MacTO Ha GakTop Xa. Toll He ce Hysae OF aXTTHTPONGHE IIT sa axrerpoMGOTHAIA axrueHocr. Anukcabat HaxHOupa caoGoqHMs H TpoMO-cebpsaH daxtop Xa m npoTponGunasHaTa axTHsxoct. AmakcaGan Hama xHpeKten edlekT BEPXY TPOMGOMMTHATA arperaLues, HO MAHpeKTHO exnGnpa TpomGoummara arperauns, mutyuMpana oT TpoMOun. Karo wExH6upa haxtop Xa, auxcaGax npeorsparana opMupanieTo Ha TpomGut H OGpasysaveTo Ha TPomOx. [TpeakAMTHHH mpoyynana Ha anlaxcaGan pH AMBOTMACKH MONCII OKASBAT aHTHTpOMGOTIEMA edbHKACHOCT pH Mpodunaktukata Ha aprepHaniia H BeHosHa TPOMGO3a IPH 03H, KOHTO sallasbaT XeMocTazaTa, Dapwaxosnnammurth epeKTH ‘Dapmaxoannamnsnnte edbextu Ha ankcaGan ca OTpaxeHNe Ha MexaNHEaNa Ha jelicTaHE (urnxnGupanie wa cbaxtop Xa). B pesysrrar Ha wnxnGnpantero na haxtop Xa, anuxcaSan yarwnKapa KoaryaannonsTe TecToRe KATO MpOTPOMGHHOBO BpeMe (PT), INR (MexayHaponHo HOPMaNIHHpAHO ‘hoTHOUIeHHe) M axTHBMpaHoTo Nappa TpoMGonaacrHHoRO BpeNe (aPTT). Tipomenre, aGmonasain Tipw Te3H KoarynatgOHAH TecTORe NIpK ONAKBAHATA Tepartestwina 1024, Ca MAVIKH HO romma cteneH papnpar. He ce npenopeusa HsTl0aBaHETO HM 3a oleHKa Ha dapMaKonHHaMmaHHeTe eihexra wa anaxcaGan. B Tecra 32 oGpasysane Ha TpoMONis, ammakcaGam KaManana eHOreH MHS ‘TpoMGHHO® oTeHUBIaN — MapKa 3a OOpasyBaHeTO Ha TPOMOMH 8 YoBeUIKa r1asMa. AmuxcaGan noxasea cbujo H anmudaxrop Xa akTHBHOCT, KaKTO Ce BIDKIA OT MOHWKEHHETO 1a axtop Xa erswMHera aKTABHOET ¢ MHOFO OT roTOBHTe aNTHaxrop Xa KyTOBE Ha Nasapa, KATO oGaue pesynratire ce pasmeapar npH oTmenwHTe xiTope. J[AHHM OT KAMHUEHH npoyyBANA ca HAHAHA CANO 34 xpoMoreHHHs Tecr Rotachrom® Xenapun. AnTHdpaxrop Xa akTHBHOCTTa noxasBa ‘TACHA JMPeKTHA JTHHeliHa BpEIKA C MAIMeRHTe KOHMENTpANN Ha annKcaGax, KATO zocTHTa MaKcHMamin cTOHMOCTH NO BpeMe Ha MIMKORHTe nuasMeHm KOHUCHTpAUHH wa anHKca6an BaBvCHMOCTTA MEATY NAASMENHTe KONUEITpALTM Ha anMxcaGan w aHTibaxrop Xa axtupnocrra © pHOnuswTenHo AuHelia NpH ALMPOK 0308 MaNasoH Ha amTHKcaGan, B TaGimmua 3 mo-zony © nokasasa mpenswenara excnosnuma w axtudaxtop Xa akristioct. Tp NAuHeHTH ¢ HeKZIaTIHO MpenCEPANO MBATENE, TpHeMaKH armaKcaGaH sa Mpodunaxraka Ha HCYAT eHCTEMeH eMGonesEM, pesysTraTHTe NOKASBAT (AYKTYSINA MEY THKOBHTE H HAli-HHCKHTe HABA T1O- manka ot 17 more. Tp naunerr#, npwemama anmxcaGan 3a nesenne wa HBT u BE wn mpopinacrixa na peunaBnpamm JIBT « BE, pesysratire nokassat ro-anka of 2,2-Kparua Pmykryaums Menqy Hall- BACOKHTe H Nali-HHCKHTe HHBA. Ta6.anma 3: Upexsnzena excnosnyus u ante Xa akTmsnocT wa anukcaGan 8 cranHonapHoAumxe. Maxe. anra-Xa | Mus. aura-Xa Coie (ng/mL) | axrapnoct aa | axrmpuocr ua amuxe. anne. i U/mL) (U/mL) Mennana [5-%, 95-# nepcetr#i] Tpoxburanmura na uncyim ucucmenen exGomurea: NVAF 2,5 mgapa mera | 123 (69, 221] 79 [34, 162] 1,8 [1,0;3,3] 1,2 (0,51; 2,4) aHesHo* Smg asa mere 171 (91, 321) 103 [41, 230) 2,6 11,4; 4,8] 1,5 (0,61; 3,4) aHeBHO : evenue na BT, nerenue na BE u nporburaxmuca na peyudusupaugu BT u BE (VTE) } 2,5mgneamsra | 67 (30, 153] 32 [11,90] 1,0 [0,46;2,5] | 0,49 (0,17; 1.4] AnesHo z HEH 5 mg asa morn 132 (59, 302] 63 (22, 17] 21 (0,91; 5,2] 1,0 [0,33; 2,9] seo 10mg.asa mera | 251 [111,572] | 120(41,335) | 4,2 (1,8; 10,8] 1,9 (0,64; 5,8] ge HO = * Tlonynaupix e Kopurapana 02a Bis OcHoBa Ha 2 oT 3 KpHTEpHa 3a MaMAnADANe Ha NO3ATA B npoypaniero ARISTOTLE. ‘Maxap ve pu stewese c anvixeaGati HMA HeOOXO;MMOCT OF pyTHHHO cTEEHE Ha eKCNOSMYORTA, xastHOpupali MeTOR 3a KONMMUeCTBeHO OnpenensHe Ha axTHdaxrop Xa Moxe Aa Geste MoneseH MPH {YSUBHPesIHH CHTYALUAM, KOr2TO HHKHOpMALUARTA CTHOCHO EKCHOSMIWOATA Ha aMKcAGAH MOKE 12 TONOTHe 24 eaHMaHeTO Ha HHKOpMUpaAHH KIMHKUNH peMleHs, KaNp. rpH ipeaosHpane M crema Xupyprauna HiTepReHN, ‘Kanna edukacnoct H Gesonachoct Ih Mk cuch one Ho, aawoicdene (NVAF) O6u1o 23 799 nautexra ca paxtomMonpaHH B KAMAMHaTa Mporpama (ARISTOTLE: anmxcaGon cnpsmo sapépapim, AVERROES: anuxcaGan crpawo aueracanmiuiona KuceuMHa), BKIIOBALIO 11 927 pariomusupan a amakcaGan. JbnsaiiitT Ha nporpawara LEM a ce AeMOHCTpHpA edbuxachoctra u GesonacHoctra Ha anakcaGas 3a npodwNaKTHKa Ha MHCY;T H CHCTeMH eMGORISEA pH nanHeATH ¢ HeKaNHO NpencEpAKO MIUKRENE (NVAF) M enKH HAM Ose HOMMTHNTC TH acosn axtopa, Kav0: *mpemxonen nrcyarr a rparairopua nexenneua araxa (THA)Baspacr > 75 roman xamepToHHa saxapen mna6er ‘cumrromaTia cepaewHa Heyocrarbunoct (Knac no NYHA > II) TPOVUBAHE ARISTOTLE B npoyssanero ARISTOTLE o6mo 18 201 naumesru ca pariqommsupanis Ha qRofiHo-cnana Tepanax c armmcaban 5 mg ypa mera aHeBHo (suIK 2,5 mg Ra METH AHeBHO MpH wGpann Hauwera [4,7%], x, TowKa 4.2) wa4 Bapdapun (dees INR o6xear 2,0-3,0), W naliMenTiTe ca excnoHnpani Ha SIIMTBAHOTO AKTUBHO BeULecTBO 2a epuon OF cpeAKiO 20 Meceua. CpeaNaTa BESpact € 69,1 rom, ‘epennust CHADS, ckop € 2,1, 18,9% or nauwertire mMar mpeaxonen wneysrr un THA, B mpoyspanero ammxcaGax nocrura crarHcTH¥eckH 31a4IHMO NpeBLsXONeTBO NO oTHOUeHTHe Ha mppaetnara kpaiita TouKa 3a Mpenciums Ha HHcyiTr (KeMoparH¥el WAH HexeMuNteH) H CHeTEMeH. emGomom (Bx. TaGnaua 4), cpassteno c naphapin. TaGanua 4: Pesyxrarn no ornomenne na ecpuxacnoctra mpu manweuTH ¢ mpenewpano uaaene 6 mpoysnaxero ARISTOTLE. Annxca6an | Bappapaa | Koepuawenr ua N=9120 | N-9081 | puck (95% HM) | p-croiiuocr ___| a @%iron) | 0 (o/ron), Muneyr wom cncremet 2121.27) | 265(1,60) | 0,79 (0,66; 0,95) | 0,0114 eMGarHs5M a Wineyar | Hexenmen nat 162(0,97) | 175(1,05) | 0,92 (0,74; 1,13) eonpenenca ‘Xemoparnuent 40(0.24) | 78(0.47)__ | 0,51 (0,35; 0,75) (Cucremex emGomsM 150,09) _[17(0,10) _|0,87(0,44;1,75) | | 3a naumeuTHTe, pavviontesHpan Ha BapapHi, MesHaHaTa HA NpOUeHTa OT Bpewe B TepariesTHTeH auanason (TTR) (INR 2-3) ¢ 66%. AmmxcaSant rloxasea HaMasiazane Ha WiIcy.ITa H CHCTEMHIAK eMOOTHSBM, CpaBteHO c Baphaplin, pH pasmmanrre mapa na TTR 8 OTAenHNTE HScTeROBATEACKH NeTPORC; B Hali-BHcoKHA Kaaprisa Ha TTR (Oped HSCTENOBATENCKHA LeHTEP, KOEdHIEHTET Ha pHCK Ha amAKcaGan onpAMO BapdapHtt € 0,73 (95% 1A, 0,38; 1,40). Kiowonire sropwsiik Kpalinl TOukH 28 MACHBHO KBpBENE H CMBPT No BoaKaKBa MpHsMHa ca ‘TecTBAHH B NpestBapHTeTHO OnpesleneMa crpareris 3a iiepapxH'HO TecTBaHE, 3a 2a Ce KOHTPOAMpA o6inara Tun | rpeuika 8 npoyusasieTo. CraTuCTAHECKK SHaHHMO MPeRESXOACTBO CBuLO € NOCTATHATO § KIHOYOBHTE BTOPHYHM KpaliH TONKH, KAKTO 38 MACHBHO KEPBEHC, Taka H 3 CMBPT MO BoAKAKRA"pwuntia (ax. TaGsumua 5). C nono6panane wa npocrenssavero #a INR HaManasar na6monananire mosa# OT aTHKcaGaH, cpaBHen c BapibapHii, M0 OTHOMIEHHE Ha CMBPT No BeaKaKka MpHUnHA. ‘TaGnaua 5: Bropusun xpaiiun TOKE UpH HamMenTa € mpeAcEpANO MLAeHE B MpoyTBAHeTO ARISTOTLE Bappapan | Koeunnesr na | p-croiiuocr N=90S2 puck (95% JI) n(%ironaua) | 0 (%/ronmun) Pesyaramw rio oTHOUIeHHe Ha KEpBeHE Macunnio* 327,13) 462.3,09) | 0,69 (0,60; 0,80) | <0,0001 Daranio 10 (0,06) 370,24) Burpewepento 52.(0,33) 122.(0,80) Macupiio+ CRNM"| 613 (4,07) 877 (6,01) _| 0,68 (0,61; 0,75) [_<0,0001 Beacacso __|__2356(18,1) | _3060(25,8)__| 0,71 (0,68; 0,75) | <0,0001_ Apyra xpaiian row O6ua cmepruoct | 603 (3,52) 669 (3,94) | 0,89 (0,80; 1,00) | 0.0465 Muoxapaen alee 90 (0,53) 102,(0,61) | 0,88 (0,66; 1,17) * Machbno xepsenie, onpeaeneno ceraacio Kpmrepuare na MexkayHapoanoTo ApyxKeCTBO 110 TpomGosa H xemocTava (ISTH). + Clinically Relevant Non-Major — Kawunsno-anawino He-MacBHO KEpBeHE O6mara vecTora 1a npexpatapanie nopann HexenaNH PeaKLmH ¢ 1,8% 3a amukcaBati H 2.6% 3a BapdapaH B mpoyyarero ARISTOTLE. Pesynranire no omHomenne ua eduxacHocrra 3a npempapHTesHo onpesienewitte toArpyntt, ‘sxttospamm CHADS; ckop, siapact, TeslecHO Tero, lo, cratyc Ha GBGpennara byMKuH7, npenxozen uneyar vam THA v aMaGeT, choTBeTCTBAT Ha IspauuticTe pesysTrarH 3a eihMKACHOcT Ha ‘Stara nonynauHs, npoysena B HIMHTBAHETO. ‘ecrorara wa macnauo racrpousrectuHaio Kepzeve no ISTH (skmowsresHo kepBeHe OF TOpHH acrpomiect¥salteH TpaKr, AONHNS FACTPONHTeCTHHALTeH TpaKT H pexrasIHo KEpBene) € 0,76% na romna c anuxcaGaH i 0,86% ta rogama ¢ napibapHt. Pesysrrature 10 OTHoIeHHe MacHBHO KBpBeHe Sa NPenBaphrenHo oMpeneseMetTe NOAMPYIIK, swtousatrm CHADS; ckop, BEspacr, TeNIecHO Ters10, Nout, cTaTye Ha GLbpermtaTa YHKUUA, npeaxozen uuicyart youn THA 4 aHaGer, cboTseTcrsar Ha peaynTaTH 2a O6maTa NonyslaNHA, Mpoy'ens B usnuTBaHeTo.