Xoov 3s peli ta- CISsy 17 -01- 2003 KPATKA XAPAKTEPHCTHKA HA IIPOAYKTA. 1. HME HA JIEKAPCTBEHHA DPOAYKT Cuntpom 4 mg raGaerku Sintrom 4 mg tablets 2. KAYECTBEH HM KOJIMYECTBEH ChCTAB ‘Aue#oxymapoa (acenocoumarol) 4 mg, ta6nerKa. Tlomouuo() Bewectso(a) c HaBecTHO AelicTBHe: naKTosa (304,4 mg). 3a Iba CHHCEK Ha TOMOWIHHTe BeulecTBa, BHATE TOUKA 6.1. 3. JEKAPCTBEHA ®OPMA TaGaer¥0 3a nepopannio npaoxenne Bean, Kpbran cbc ckoceHH pEGose, Or canara crpatia ¢ oTneyaraHo “CG”, a oT Apyrara ¢ nocrasena AeAMTeNHA YepTa MOA MOpMaTa Ha KPCT H BBB BCEKH CeKTOP € NocTaBeHo A, [IpexEcBayET NpaBH No- JECHO NpHeMaHeTo Ha TaGAeTKATA, HO He & pages Ha PaBHH LO3H. 4. KIMHW4HH AHHH 4.1, Tepanesraanu noxasanus Jlevenne 1 npodinaxuxa na TpoMGoeGoawsnn saGonaBan. 42. Jommponxa 1 nan na npnzoxenne osuposxa O6mu npenopoxu ‘UyscTaHTenHoctra kbM aiTHKoaryaanTH ce pasiHaba MPH OTACAHMTE MaLMEHTH H MOxke Ja BApHpa B ‘XOMla Ha AeyeHMeTO. 3aTOBA € BaxkHO Aa Ce NPOBEAKAT PeAOBHN TECTOBE 3a NpOTPOMGHHOBO Bpeme (PT)/ international normalized ratio (INR) # 2a ce cboOpasapa 03aTa Ha alIMeHTHTE, AKO TOBA € HEBEIMOKHO, ve tpaGxa aa ce wsnonsea Sintrom. ‘Zsesuara aosa TpaGea suvaru 2a ce npHeMa enHoKpaTHo. 3a npomana Ha AO3HPOBKATA MPH PASIMUHH KIKKUYHH CECTORHHS BIKKTE TONKH 4.4 CneuManHH npexynpexienns H npeanasin MepKH npx ynorpeda n 4.5 BsamwonelicTane c ApyrH AeKapcraeHH Mpoaykra W apyrH copa Ha ssauMoneHicrane. Haxaina dosuposxa Tlosupanero na Crtpom TpaGsa 2a Gee ueAMBHAyATHO. Ako PT/INR ci aeseHHeTO eB HOPMAN rpaniun, OHvaiHaTa Hadama 03a CHHTpO!npeasapirenia Harosapsauta 1032, JleenHeTo Moxe sla Ce Mposesle H.C Hava HaToBAPBALLIA 2032, KORTO 3a MHpBHIA eH OGHKHOBEHO € 6 mg, NocaeABAHa OF 4 Mg Ha BTOPHA NH. ‘Axo 8 navanovo PT/INR crolinocrra e naabi rpaHHulre Ha HopMara, neveHHeTO TpsGBa na ce sannowne TnpH MoBHUeKO BHMMAHHe. Tipu naunent# 8 HanpeaHana seapact (= 65 roaHHH), nauveHTH ¢ YepHoApoOHH NPOGREMH, ¢ TexKKa ‘copiestia HexOCTaTBNHOCT M HepHOPOGEH 3acTOH WIN CrpALAULM OT HEAOXPAHBAHE MOXe a ca HeOGXOMNMH NO-HHCKH 03M MIpH 3anowBAKE H NOIUTHpAKAHE Ha sleweHMeTO (Bx. 4.4 CremnasHH peaynpexienns w npeanasiM MepkH pH ynoTpeGa). Hsqepsaneto na PT/INR tpa6sa 2a ce wsBppuiBa exeAHeBHO KaTO Ce 3anowBa OT BTOpATa HAH TpeTaTa ‘2034 Ha CHHTPOM M NPOTRIDKABA 20 BPEMETO, KOTATO KOArYAAILNOMHILAT Crary Ce CTAGMIMIMpA B PAMKHTE a e7eBHa OOxsar. B sasHcHMocT oT craGwaHocrTa Ha PTVINR pesy.1Tatire c Te¥eHHe Ha BpEMeTO HITTepBAMBT MewAY TecTOBeTE MOE 1a Ce yBesNH. TIpenOPEHHTEATHO € KPBBKHTE MPOOH 3a 3eaeqBAHUATA 2a Ce BIEMAT MO EAHO H CBiLLO BpEMe Ha EHR. Tloddwp2cama mepanua u Koazyzayuonnu mecmose Tloaxspxawara 03a sapupa npit ornemmiTe naueHTH H TpAGBA AA ce OMpeNEAR MHLAMBHAYAAHO Ha Gasata Ha PT/INR cTolinoctire # TpaGpa a ce H9BEpUBA Mpes PABH HHTEPBATH OT BpeMe, Hall-MamkO ETHER MECEHHO. Tlonmypxamara nHesHa 03a OGHKHOBeHO BapHpa B rpanmunTe oF | mg no 8 mg H SaBHEH OT Sa60A8BAHETO, KAHKNUHHTE NOKASAHHA H KeAAHATA MHTEHSHBHOCT Ha ANTHKOATYNANTHA AKTHBHOCT, B sascuwocr of KaMMHUHiTe HoKasaHH ONTHMAIHATA HITeHSHBHOCT Ha aNTHKOAry.ZaIHATa, Tepaniestasnata o6.1act o6uKHOBeHO ce Hanna Mexaty 2,0 4 3,5 m0 INR (sik TaGanua 1). B orzeann ceaysan aosu waa 4,5 INR Moxe 1a ce npHeMar 3a HOpMasi ‘TaGanua I TIpenoppuntenio INR* np nepopaiio aNTHKOary.1aHTHO e4eHHE Tloxasanna Tipenoppamreaxo INR TIpodanaxtuxa n reveHHe Ha BeHosHa TpoMOoeMGo.Hs, 2,0- 3,0 (xsiosrTemHo nyaMoHa.THa eMGo.HKs) TIpeneepano nrwxaene 2,0- 3,0 Tloctmuoxapaen mipapkr (c Hapacraaut pick ot TpowGoemGoamsnH 2,0- 3,0 yeroxweHns) (Copewna kana OHomporesa 2,0- 3,0 Bropusa npodusaicruxa np nauwenrH c axtudbocsorunuaen cHiapom 2,0-3,0 Tlaunentu ¢ anrudocdoannizen cnuapoM # peHoseH TPOMGOEMGOmHSEM 2,0-3,5 JeKYBaHH C AHTATOHNCT Ha BHTAMHH K ‘Mexanusnn eppaesiit kann 2,0-3,5 * PT, Koero orpasapa tiawanasanero wa puTawiit K sapneuwnTe axTopi wa xpueoceeupaaero VII, X w Il, asic OT ¥yBcTBHTenHOCTTa Ha TpOMGonLTacTHHA, HBTONIBAH MPH HBCTEABAHE Sensitivity Index (ISI) orpasasa 4ysctauTesHocrTa Ha CbOTRETHHS MeCTEH T] Mex2yHapOgHHTe petbepeHTHH NpenapaTH Ha CeeTosHara 3apasHa Opran:“International Normalised Ratio* (INR) € tepwni, sesenen c wen crangaprnsauns wa PT. INR € ‘cnoTHOUIeHMe Ka attTHKOarysIaHTHOTO MLiasMeHo PT ia nantMeHTa KbM HOPMaTHOrO NiasMeHO PT, KaTO ce vonlonspa CbulHA TPOMBonON.TACTHH B CEUlATA CHCTeMa 3a HSCHeTBaNe, DedbHHHpaNA ype Intemational Sensitivity Index. Tpexpamssane na newenuemo ObnKuoperio Tepannsrta cee CautTpom Moxxe sa Gbe npexparcHa Ges na ¢ HeOBXORNMO NlocTeNeHHO Hamanapaxe Ha Zosata. Yeraxoneno € OGave, e MH HSKMONHTETHO PeNKH CAYAH H MPH HRKOM BHCOKO PHCKOBH rlaueHTH (Han. cnex MMOKapseH HAapKT) Moxe fla ce HaGmonaKa "rebound xwnepkoary.taua", T]pH Taxwsa fiaumentTH CrMpalleTO Ha aHTHKoarysanTHara TepanHa TpRGBA ja CTaRA nocrenenHo. Hponycnama dosa Anrtukoarysmpanutar edext Ha CHHTPOM ce mposaana 8 pamknTe Ha 24 Yaca, AKo nauneHTsT nponycHe ‘2a npheme ipeanicatara My 1034 HaBpeMe TpsGBa 18 KaNpABH TOBA SEIMORHO Haii-Gup30 CbULKA EH. Tayuenror we Tpa6ea Aa yabonea aMeBiiaTa CH sl03a pH MponycKaNe ta MpHeM, @ TPAGBA na ce ‘KONCYATTHpA ¢ neKAps cH. Tipemuuasane wa Cnurpom or xenapatiopata Tepanus Tips komt eaysaH, KouTO usucKBaT 6op9a axTHKoaryaauH, Ce HpeATOWNTa Sano¥BAHe Ha TepannaTa (© Xeniapi, Toil KaTO astTHKoary.tauiTHnaT ecbext Ha CrTpOM € saGapex. [pemmnazanero sa CHitrpoM Moxe a 3ano¥He NIpH enHoBpeMeHeH MpHEM Ha XeNApHE HIM Ja Ce OTOH B-3ABHCHNOCT OT KAMHMYHHS conyvall, 3a na ce rapantTupa nacroTBaneTo Ma aNTHKOAry.TaUMA e NPENOpeYHTENKO fa Ce MpOAB AH npeanuesaneTo Ha mbmwaTa TepanesTHta 03a XenapuH 3a MepHON OT Nowe 4 nM Cre” 3aNONBAHE Ha npvewa Ha CHITTpoM 1 Tepantisra c XenlapH a npomBADKH ZoKATO INR ¢ B KeAeBiIA OOXBAT 3a HAll-MaKO saga nocaeaopareiH 21H. Tlo BpeMe Ha MpeXOAHHA TlepHOn € HEOGXORHMO CTPOTO MoHHTOPHpAHE HA anTaKoarysiaunra. Jlenenue no speme Ha cromaToaoruni 4 XHpyprHsInH HiTepoeHTM Tipu naumextute wa CuuTpoM, #a KONTO MpesCTOsT OnepaTHaHH HAM HHBAHBHH MpoNeAypH & HeoGxommMo CrpHKTHOTO HaGmIOAeHHe Ha KOArynaLWOHHNA CTaTyC. ITpH OnpegesIeHH YCORAS, HAN. Koraro onepauonHoTo MACTO ¢ OrpanitdeHo H OCTBTNO, H 1lo38On%Ba YnoTpeGaTa Ha noKaZHA Tpouenypit 3a XeMOcTa3a, CTOMATOOTHHH H MARKH XHDYPTHYHH MPOUEAYPH MOXE 14 Ce NPOBEKART MPH hnpostokuTesna anrTuKoaryaauus Ges PACK OT XeMoparHa, PewlenHeTO Ha ce cnpe mpHeMa Ha CuHTPOM, ZOpH 3a KpaTBK NepuOn OT BpENe, Tp5Gua BHUMATENHO Aa OTMATA HHAMBHAYAIHMTE PUCKOBE M NOM. BanowBaneTo Ha KOMGHANDAHO AHTHKOATYAHTHO seYeHHe € XEslapHH HANPHMEp, TpAGBA na ce OcHORABA ‘Ha BHUMaTesMa OUeHKA Ha O¥AKBAHHA piCK OT TPOMGOEMGOAHA 4 KEpDEHE. (Cnequanen rpynm naqwenra Bo6pexno yepencoane Cunpow te ce npenoptasa mpi aueHTH c TexKo Gu6pesto yepexane, NopaNH MOBHILIEH PHCK OT pbaou3KB. HeoSxoqMMo € NOBHINeNO BHHMAHHE MpH MaLLHEHTH C TeKO AO yMEpeHO OBOpeXHO Yapexane (sx. Chuo 7. 4.3 TIporssonoxasanis, T. 4.4 Ceuuanii npeaynpexsienHs H mpemasiM MepKiL nnpw ynorpeGa Hr. 5.2 DapmaxoxnuerisnH cBoticrBa). Yepnodpobno yepencoane ‘Sintrom He ce npenopbuna npH TallHeHTH ¢ TexKO NepHOAPOSHO yBpexMAHE, TOpagH NOBUILEH PUCK OT KpbBon3/M5. Heo6XOAMMO € NOBKILEHO BHAMAHME MH TaL|MeHTH C AeKO s10 YMSpIERG HEROR yepexknake (Bx. cbul0 T. 4.3 TporHeonokasaina, 7. 4.4 Cneunanun npeayny (a MepKH ‘pH ynorpe6a i t, 5.2 PapMaroxunerirutt csoiterea).Heduampuana nonynayua Onurar c nepopain axrruoaryAakTH, BKIHONHTEIHO alleHOKyMaPON, MPH Jewa OcTaBA OTpAKHCH. TIpenopspa ce smMaTemHo npHtoxeHHe H MO-¥eCTO MOHHTOpHpaHe Ha poTpoMOMHOBOTO BpeMe H INR (wx. cso T. 4.4 Cewnansn npeaynpexaens H npenna3Hn MepkH mpH yrorpeGa). ‘TauneuTa » nanpeanaa sespact © 65 ronan) Tipu nauuewrute 8 nanpezHana seapact nonaKora ce Hamlara MpHaraHeTo Ha NO-HHcka HaNuaAHa H nomureprxauna 20aa. TIpenopbusa ce TloBHWeHo BHHMAHHE H TO-HecTO NpocreAABAHe Ha NPOTPOMGHHOR speme W INR (ex, 4.4 Creiurannn nperynpexnexia W mpennasia MepkH npa ynorpeta H 5.2 ‘apmaxoxnneTasatn cBolicrsa), ‘Hacwa na upazoxenne Tpessiara nosuposka Tps6sa fa ce npeMa BHHATH No EHO H CbullO BpeMe Ha Reus. TaOneTKaTa TpsGpa 7a ce Tormsuna Wasa ¢ sama Bona, 4.3, Mporimonoxasanna + Hisnectna copexsyscreirenHocT KbM aileHOKYMapO.T M.APYTH KYMaPHHOSH NPOHSBOREM, MAM KDA aoe or rowomutTe BeutecTBa, H3BpOCHH B TO¥KA 6.1. + Bpemeunocr + Tlauwex7n, kowro we ca s chcToRHMe a MposeXAAT LeveHHETO CaMH H HE Ca Tox HaBmONeHNe (HAN, HeKOHTPOAUpAHH CeHHAHH TaNHEHTH, ANKOKORHUM H TCHXHYHO Gomi) ‘Citpom © mporuBomokaseH CbILO H MH CECTORHE, 8 KOHTO PHCKBT OF KPEBOHSIHBH € NO-ronaM, ‘OTKOAKOTO BRSMOKHHTE KAMHMYHM NOMSH, Hamp: + Xemoparrinia anaresa HM Xemopanwsia KpHBHA ANCKpAIHS + Henocperersexo npeau iam een onepauna Ha leHTpasara HepBHa CHCTEMA, KAKTO H ONHH nepali H TERKH TPABMMpau XHPYDrHvE HTepBeMUH + Tlenraaia sea wii KpyBOHsmHB B racTpOHHTECTHHAMHNA TpaXT, YPOTEHRTATHHR TPaKT HTH AMKaTesHaTa CACTEMA, KAKTO H MPH MOSB4HOCK/OBH KPBAOHAINBH, OCT NepHKAPANT, NepHKapaeH NOAH H HECbeKUHOSeH enROKApHET Texxxa xineprostix ‘Texcxo yepnoapodno yapexaane (wx. T. 4.2 Jlosuponka H HauHH Ha MpanoxeHHe) Texxko Gs6peano yapexiane(sx. r. 4.2 Jlosuponxa u naan na npanoxenne) Tlosnurena dapunomirusmna axruanoct eneA onepauiis Ha SeHA ApO6, MpocTarara, MaTKaTa H T:t, 44. Cnenuaam mpexynpexsenus mpexnasun mepKu npH ynoTpeda Yepnodpobuo yepeacdane HeoGxoauMo € noBuweHo BHAManHe MpH NaIHEHTH ¢ AeKO oO YMepeHo YepHOAPOGHO yapexnaHe, Toit karo Moxe sia Gene Hapyluen H CHHTeSbT Ha GbakTOPHTE Ha KOATY.AALHATA HIM AA BESHHKHE TPOMGOUNTEA anceyuRuia (Bx. T. 4.2 Jlosxponka H Na4HH Ha NpHAOKeHHE HT. 5.2 DapMaxoKHNeTH4HH CBOfICTEA). Bebpewo yepexcdane Tlopagi s:3MoxknocrTa 3a Rarpynbaiie na MeTa6onKTH NpH Hapyurena GhOpesa dyHKUNA € HEOSXOTEMO TOBHILeHO BHUMAXHE TPH NaLWeHTH c AeKO NO yMepeHo OLOpesHO YapEKAAHE (BX. CbIIO T. 4.2 Tlosmposxa w Hasuet Ha npHsioxenne 4.7. 5.2 apaxoxnneTHHnH CBoticrEa). Cepdeuna nedoemamreunocm B ciyuam wa Texka copaeuta HenocTarauHocT AosupoBkaTa TpaGsa BHMaTeAHO, saLOTO AKTHBH(pAXETO HAM FaNa-KapGOKCHLAAPAHETO Haj‘ce Hamann Tp NepHoApOGeH sactol (sicxcre 4.2 Josuponka H HANH Ha NpHAIOKeHHE). [px BuCTaHOBABAHe cen YepHOTpOGeH SacTOMI OFaYe, MORE AA Ce HAO NOBHUASANe Ha LOSHPOBKATA. Xewamoroers HeoGxoqMMo € NoBHiveHo BHUMAHHe MPH TALHeHTH c YCTAHOREH TeduiluT HI Np ChMMEHMS 3a Ae>HUHT (amp. npomsrxuTesko KepseHe Culex HapansBane) Ha npoTenn C wan nporene S (wx. 4.8 Hewezain TeKapcrbeHM peaKuin), Creyuannn epynu nayuenmu TIpw nexnarpasin nauentn m nauwenTa 5 Kanpenwana seapact (> 65 ronHHH) ce mpenlops4sa NoBHueHO ‘BHEMAHHC H TIO-HeCTO NPOcaeARBaNe Ha npoTpONGHHOBO BpeMe H INR (6K. TOK 4.2 JosHpoBKa H Hawt Ha Mpunoxenne H 5.2 @apmakoxterwmn cpolicraa). 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Pickosi diaxTopi 3a kupsetie aimioupaT HitTeHsMBHa axTHKoarysauna (INR> 4.0), sespact > 65 Tost, Moro NpoMeHAHBa HcTOpHR Ha INR, aHaMHesa 3a CTOMALIO-Npenen KPBEOHSAMB, XHTIEPTOHAS, nepe6posackyzapHo saGonanane, TERKO CBpNeYHO 3AOONABAHE, AHEMMA, STOKANECTBERO SACOANBAHE , ‘TpanMa, GLOpeuia HenoCTaTEHOCT, cBMETCTBAILM AeKapcTea (BK, TONKA 4.5 BoauMonelCTBHA c Apyru JlekaperseHt mpoalyxTH # pyri dopant Wa BsanMORelicTaKe). TpaGBa na Ce HSBbpILIB2 PexOBHO Monutopupante wa INR mpl Bcw4KH sieKyBaimM nauweHTH, Apyeu HeoGxoanMo € cTporo MEAHIHHCKO HAGMONEHNE B CHYNA Ha CECTORHHS HIN 3A008BAHHER, KOHTO MOAT Ja nawaixt npoTenKHoTo caEpseane Ha CHHTPOM, HANPHMEP THPEOTOKCHKOIA, TYMODH, GBOPEYHH SAGONABAHHA, Madexuni H BESTATCHHE, Hapywewus b cromanmio-ypesiara a6copSuita Morar fla NpoMeHsT aNTHEKOAry 1aHTTHHA exEKT Ha Cirrpom. Tlo speme Ha seveHHeTo c AHTHKOATY:AHTH TpsO8a a Ce HIGArBAT MYCKY.IMM HEDKEKKMM, IAILOTO MOKE a InpHNHHAT xewatomn. OT Apyra CTpaHa, NOAKOKHHTE M HEHOSHHTE HEKEKIUAN He MPETHSBHKDAT TAKHBA yeroxnenta ‘TpaOba xa ce Baumasa, ocoSeHo KoraTo ce nanara ckecabane Ha PT/INR 38 aHarHoCTHNHN HAH ‘TepaneBTH4HN nETepseHUM (HAN. aKTHOrpadhus, syMOania NYHKUMA, Mada XUpYPrHUHa MTEpBeHUHA, excrpaxuna Ha 386 H 2p.) Tlayuexru c peak HacreacTsenl npoSaemm Ha ranaKTosHa HenowocMoct, OW naKTaset AepHMMT HH m10Ko30~ ranaxrosHa masa6copOuMa He TpAGBa Ja ipHeMaT TosH JeKapeTBeH Ty 45. Baumoneiicreas ¢ apyr JlekaperseHH MpoayKTH K ApyTH (bop!Mexxay KyMapHHoBitTe pOHSBORHH H APYTHTe HeKapCT#a ca BRAMOKHH MHOTO BsanMOeCTENA. TexHHTE MexanusMH BKGHONBAT NapyLICHHA Ha esopOUHsTa, MHXHOMPAHE HAN HENYKUMA Ha MeTaGOHSHpAWLHTe ‘ensinamn cHtcTeNit (FAaBHO MpH CYP2C9, sxx, coino H 5.2 CapmaxoxsneTianH cpoficTBa) H HamaneHia anHyHOcT Ha BHTaMHH K, HeOGXOAMM 3a raMa-KapOoKcHAMpave Ha axTopHTe Ha npoTPOMOMHOBHA KommiieKe. Baxkio e sa ce ua NpeABHAL, Ye HAKOM JleKapcTBa MOxKe Jia BsaKMojtelicTBAT NO NOBENe OT ‘eAHH MexannceM. TIpH BCeKH BHA TepanH CbLLECTBYRA PACK OT BIAHMONEHCTBME, BBIPEKH ME HE BCHIKH BSQHMOACHICTBINA Ca C MeAHUMICKO sHa‘cHKe, 3ATORA € HANNO Ha Ce NPOBEKa BHAMATEAHO HABMoneHHe HW 4eCTH (Hanp. 3a METH CeNMHNHO) Koary AAUMOHHH TecTOBE MPH MAMUMHpaHe Ha Tepans WAM Inpexparasave Ha npHeMa Ha KaKBOTO H sta € lekapeTso B KOMGNHatIHR cbc CHHTPOM. Bhanmonelicrans, pcaeacrane Ha Konto enmospemennaa ynorpeda ne ce npenope ina Expercra wa apyrH stekapesa BEpxy auleHoKyMapost (Caegumre sexapersa noTeHmupat auTHKoary.1aHTHaTa AKTHBHOCT Ha aleHOKYMApON W/TH HMeHRT XeMOCTASATA Taka TOBAWAT PHCKA OT XeMoparMa: XerlapHH (OCBEH B CAY'AATE, B KOHTO € NeoGxonmMa Gupsa aNTiiKoaryaauieR; Bx. T. 4.2 JoaNpoaKa H HATHH Ha NpHAOKeHHe), TPOMEOUMTHH anTuarperaiTy KaTo canHiuLioBa KHCeTHHa H HeMHTe NPOHSBOANH (Kamp. aNeTHICATMUNsIOBA KUCETHHA, apa-amHocanMuvuioga KuCeNHHa, ANdnyMHsan), KNONMAOTpen, THKAOTARAH, peMHUAGyTAsON HAM yA upasonoHosn npousBoaHH (cy:HRTMpaso#) H APYTH HecTepONAKH MPOTHBOBSITAAMTEANH JeKapCTBA, BKMOHTeaHO HHIXHGHTOPH Ha LUMKTO-oKeMreHASA-2 (COX-2 HExHGHTOpH) (Hamp. LleneKOKCHO). Cregosarenio, ynorpeSara na Citpow 2aeqwo ¢ TeaH neutecTaa He ce npenopeisa. Koraro ce Hashasit CCiiitpom B KoMEHHaUNa ¢ TeaH nexapcToa, € HEOBXOAAMO Ja Ce MARAT NO-¥ECTO KOArY.TaNMOHHH rrecrose. Bsaumogelieraus, xowro TpaGna ja ce msemar no BHNMANHE CaeguuTe ackaperea Mowe Aa MOTeHUMpAT ANTHKOaryTaNTHA CeKT Ha aleHOKYMApO: ‘sionypunon, anaCoaHn cTepowAH, aHApOreHH, AHTHApHTMHIHH eKapCTaeKH MpOnYKTH (HAND. AMMORAPOH, XHHMAKH), ANTHGMOTHUM (HANIP. AMOKCHUMIMH, ed>alOCHOpHAH BTOpa M TpeTa reHepanHs, XOpaMeHHKON, ePHTPOMHUNH, AYOPXHHOTONH, HeOMMUHI, TETPAUMKSLAH), WAMETHMM, MACYAHpAM, eraxpunoaa xucesma, uSpar, (Hanp. xxoHOpHHONA KHcenHNA), rmoKaroH, MPOHIBONHE Ha HMNIas0n (Hanp. Metpoxnizason # MuxoHaG0T np OKANO NPHLTOxeAIHe), NapalleTaMOn, CeeXTUBEI HAXEGHTOPH a ceporononis pesnreix SSRI (Hamp. uuTasIOnpaM, noxceTHy, ceprpanul), craruu (san. aysacrarun, aTopsacratim, canpacTarvH), cynoHaMiNaM, BKIHOMITERHO KOTpHMOKCAIOA (Ceynbametoxeason+rpumeTonpim), cyadanny pelinit 2eKapcrBeHl mpodyKTH (KATO TONGYTAMMA XAOPNpONaMHN), THPEOHH XOPMOHH (BKM. eKCTPOTHPOKCHH), TAMOKCHAEH, TPAMALON, KHXGUTOPH Ha MpoTonnara roma (Hamp. OMenpa30d), 1la3MHHOTeH aKTHBATOPH (HAM. YPOKHHA3A, CTPenTOKHHasa H axrennaaa), TpoMGmionn MNxAOWTOpH (HanpHMep aprarpoGaH), npoKKHeTHHAH MeMKAMENTH (waNp. {UyBANPH), aRTHALAH (HATPHME MarHesHeS XHAPOKCHLA) H BHLIOKCABHI, BHTAMH E, KOPTHKOCTEPOHAM (Hamp. MeruanpeaHHaOOH, NpemHNIOH) H MHXHGMTOpH Ha CYP2CO (Caeamure sexaperoa Morar Aa HaMansT auTHKoarysawTHoTO jelicTaNe Ha alleHoKyMapom: AmimorayTeran, airTaneonmacTH4iit 1ekapcTea (asaTHomputs, 6-mepkantonypHH), Sapoutypara (Han. ‘enoGapSuTal), KapOanasemun, Xostecrupawmet (Bx. 4.9 TIperoanpane), HIV npoteasuu HAXHOUTOPH (eanp. putonasup, HenpunaBup), rpHseopy BAH, MepopanNl KOHTpallenTHBH, pl aHtrapvor (rosa BsaMMonelicrave € onlcaHo Nps Bapibapal # (beHNpOKYMOH 38 attenoxyMapon). 6Vinayseropure wa CYP2C9, CYP2C19 wan CYP3A4 moxe la HaMaasT aNTHKOArysaHTHOTO eicTaHe Ha aneHioxymapoa. Toil kaTO He € BEIMOAHO sta Ce MpencKAxAT HMTO TEKCCTTA, MHTO PAHMHTE MPHHAUH Ha BuaHMOZeliCTENA, NaLMeRTHTe, npHeMauIN CHHTPOM, OcocHO TesH ¢ HapyIMeHA HepHOApobHA SYHKUNE, ‘rpaGea 4a orpanitaar ynorpeOata na anKoxon. Eiexru na autenoxymapont sspry apyru aewapcrna Tipu eawospeMeso nexexie ¢ XiaNTosHoBM npoHSBORIH cepyMHara KOHLCHPpALWA Ha xHAALTOM woxe aa ce noRutt, Sintrom moxce aa yeuns xunornHKeMnuHorO jelicraHe Ha cya\paHKAypeliniTe MPOHSBOAHH. Xpanureaum Komnonewt 6oraTu Ha puTamun K Xpanit, Gorara wa euTamuat K Morar Aa waMasat e”pexruTe Ha auenoxyapon. 4.6 Deprmanrer, Gpemennocr n kupmeHe Bpemennocr ‘Cunrpomm, kato # apyritte KyMapHHoaH MpoHBOAKH, Moxke Aa ase COBpIAH ¢ BPORENM MarKpOPMaltHit xa nizona. Caezonaremio Tolle nporuonoxasaH no BpeMe Ha GpencHHoct (jx. T. 4.3 TIpotusonoxasass). 2Kenn c aereporen norentma 2Kenn c reveponex norexuvan TpsGaa Xa WsTonseaT e*pexTHEHA KOHTPALENINR M10 BPEMe Wa ACHERME CEC Cutntpom. Kepmene (CiHrTpowm npemniana 8 KBpMara, HO B TOIKORa MAIKH KOAHYECTHA, Ne HE CE OUAKBAT HEXETAHM JeKapCTBEHH peaKUHA MPH HOBOPOREHOTO. Peurennero 3a KepMewe TpaGsa 7a ce OBMHCIHC BHHNaTENHO H Moxe Ja Ce MpeAXOXUa OT KOArysIauHOHeH ‘Tect m oyenka wa Birra K cratyca Ha KEpMa¥eTo. Kepmeuuare xen, aexysanl coc Cmntrpom, tps6na 22 ce MOHMTOpHPaT BHHMATeAHO, 3a 2a ce WaBerHe ‘Mpesntuapanero Ha npenopuntemmute PT/INR cToHHoctH, Tlo spene na xepMente nput xereTo, € HeoGxoaHMo sa ce npuslara upodundirasno 1 mg BHTaMmH KK; coamno. epruxnrer Hana xannn 3a mprroxerncro na Cuntpom H sparelicraneTo My BBpXy (bepritaHTera np Xopa. 4.7. Expexru supxy cnocoSuoctra 3a modupane n paGora e Mam He e nsnectio Cuttpon na rlosiiisa cnocoSnocrra 3a wodpupane nM paGora ¢ MauIMHM. BBnpeke Tosa aMBysiaTopnnte nauleHTH TpAGBa a HocaT ce ceGe cH “ak THKoarysIaxKOHNa KapTa” B cmyali Ha TpaBMa. 4.8. Hexenanm sexaperpenu peaxuun Hexenante nexaperacin peaxumn & Ta6sinua 2 ca w36poen no cucteMo-of MedDRA. B panxure Ha aceku cucteMo-opraiten kaac Hemenan#Te 2 HecTora, Kato Hail-weeTire ca TBpsK. TIpH Beso FpynMpane B 2ABLCHMOJekapersent peaxuii ce HS6pORBAT B HHSXONAI pes NO OTHOLIEHNE Ha TAXHaTA CepHosHocT. Kateropuute ‘NeCTOTH ce ONPENeNAT CHrTACHO cnemHaTa KoHBEHWHA (CIOMS III): aHOro YecTH © 1/10), secTH 1/100, 1/1 000, <1/100), peak (> 1/10 000, <1/1 000), scoro pear (<1/10 000). Kprnowsannn Tlosara Ha xpbooiraauon » pasa oprani e OGwialiva Nexeraia 1eKapcTsetia peaKINs Ha TepamHsra exe Cutrpom. Bratinxsatiero ii e cmpaaiio c 0aupOBKaTa Ha AeKapCTBOTO, BEApACTTa Ha NaLWeHTa H ecTecTROTO Ha OcHOBKOTO aGonsBaHe. TaSanua 2 Ta6ansno oGoGuenne Ha HexkenaHITe peakunH Hapyutentia wa mwynnara cucrema Peaku: (Cepoxuysersuremioct (Hanp. ypruxapis, o6puB) Cea08n napymenns Yeon: Kppaowsans, ‘Muro peak: Backyaurn (Cromamuo-ypesuu napyuienns Peaku: Bary6a wa anerwr, ragewe, nospeuaKe Xenaro-Gu-mapan napymenns, Muoro peak: Yepwompo6uo yapexaane Hapymrenns na KoxkaTa H noxKosHaTa THKAN Penn: Anoneuns Muoro peak: ‘Xemoparnuna* Koxwa HeKposa C neuseecra vectora: Kanununaxcns Hapymenns na kpoora w anwduara cnerema C wenseecTua wecTora: Avjemns (sropisita enpaMo xpsBous.tMBa) * OGuxnoseno campsaia ¢ BpOneH AEuNNT Ha NpOTEHH C MIM HerOBHLXT KO~aKTOp npoTenH S wit ‘CroSuiasaneTo Ha nonoapaHH HexXenaHH peakiLHH czten paapeuiasane 3a ynoTpeGa Ha TeKapcTBeHHs poaykr e BaxHo,. Tosa nossonasa a NpOADIOKH HAGMOREHHeTO Ha CbOTHOILIEHHETO NO3A/pHCK 3a ekaperseHus npoaykr. OT MeAMUMHEKHTe CMeLMAMCTH Ce IBHCKBA sa ChOOARAT BAKA MOLOSHpAHA Hexenaia peaxuis pes: Vorenuireana arena no aekapersara ya. Flas Ppyen” Ne 8 4.9, Tipexosupane Tlopaau ¢axra, 4e 2opH H Moro roneMitTe ENHHMMHH jO3H, OOHKHOBEHO He Ca OnlacHH, npexOsHpaHeTo ce Manibectupa KAMKHUKO MPH NpONBTKHTeRHA yNOTpEGa Ha HEBHH AOSHPOBKH NO-BHCOKH OT HeOGxoAMMHTe 3a 7eHeHHETO. Tipusmaum u enserrown Tloasata n Texectra Ha cHMMTOMHTE saBHesT OF HHAMBHAYaNHATA HyBCTBH anTuKoaryaanTH, TexecTTa Na MpENOSHPAHETO M MpOBDRHTeNHOCTTA Ha Kepsexero e raasiusr npisiak Ha HNTOKCHKaWMa ¢ Mepopamiit aHtTHKo Ha6.mogazaHute CHMITOMH ca: NoAKOMeH KPBBOHSANB (80%), XeMaTYp)TactpoutrrecTHHAaNHHa TPaKT, XewaTeMesa, MATO"HO KBPBEHE, EMIHCTAKCHC, KEPBEHE OT BEHLWTE H KEpREHE 8 cragute, JlaGopatopnure Tectose noKassat Teepe Buco PT/INR crolixocTH, ocoGeHO yatBmKEHO PeKaaunuKalHoHtto BpeMe nH MpOTPOMGHHOBO BpeMe Ht HapyileHO raMa-KapOoKensHpane Ha axTopH VI, Xu X, Jesenne HeoGxogumoctra H npenopesirrenwocTra Ha se'eHHeTO Cue CHPOT OT HNeKaKYaHa, CTOMaLes ABB KATO AOMBMHEHHe KM TepamlAs ¢ AKTHBEH BETH H MpHeM Ha XONeCTHpAMMH, € crlopHa. TlonsHTe OF TesH [HeMeHHS Ce CBNOCTABAT ¢ pHCKA OT KMPREHE MPH CNH NalLweNT. Cnewau roamppaxamm meprat Tipu creme cry'an Ha TeKKH KPEHOHSAKBH MpH BC=KO KHAO Ha INR cbaktopHTe Ha KpEocECHpBAHE MOME Jia BESCTAHOBAT HOPMAIAHTE CM CTONHOCTH KATO Ce Rule MIpSCHA KPBB KK MpscHa saMpaseHa 1a3Ma, NPOTPOMOHHOB KOMMLAEKC OT KOHLLEHTPHPAH HTK peKOMOnHaHTeH daxrop VIla c 206aBKa OT seTaman Ky Auraxot Burawna Ki-(uToMenaawos) Moxe 2a attrarontsupa wixuOuTopHoro zelicTaxe Ha CHTPOM BEPXY ‘NepuompobHoTo raMa-KapGoKcHaMpane Ha siTaMin K-2apMeHMMTe Koaryal{MONHH bakTOpH 3a 3-5 Hac, B cayaii wa xannimo nesasnwn xppeows.nsn (INR<4,5), karo ciaGo KBpBeHE OF Hoca Wl MA:TKH H3ONMPAHH XeMATOMIE, HECTO € JOCTATEIHO BPEMCHHO HAMAAICHKE HAH NPOTIYCKAHE Ha OSHpOBKA Ia Cunrrpow. 3 cays wa nomen INR (INR 4,510) Ges snnurremo mepuens, nperveteTe ACNEUNETO ese HITTpOM. B cayuaure Ha nosuuento INR (INR >10) Ges siasitremo kepsene, npeKecreTe newenHeTo cbc Culrpom W npunomere 1-5 mg suramui Ky nepopactexo. ‘Ako iva nanmHH 3a sHawHTeNk KPBBOHSTHB (MPH REEKO HHBO Ha INR), 14 ce NpeKBeHe eHeHHETO CBC CCutrpom, Karo ce npHaoxKn 5-10 mg siTamut Ki Sapte eeHosHo (be cKOpocT, KORTO He HanBMUNABA 1 mg sa mintyra). B cayanre na xppsousius newexneTo coc CuRtpomm TpaGpa 1a ce BbsoGHoBABA, Koraro INR € 8 ueneBHa AHanasOH. 5. PAPMAKOJIOFHYHH CBOMCTBA S.1, Dapmaxormuamwanu esoiiersa ‘Dapmaxorepartestwuna rpyna: aHTHTpOMOOUHTH, aHTArOHHCTH Ha BiTaMaH K. ATC kon: BOLAAQ7 Auetoxywaponaxrunsaracxcrasna ne CiarTpoM © ryuapiiono npoxsnoano x ieleTD8 waTo iTaroHuT fa utannn K. Auraronerire na piraMs K nposesDe® a HOaryAABTHR C8 iupaiixit buTamai K-enoxen-peayktasata ¢ nocmeytpattia PEAYKUUAS HA rasa G enetiHChomenariiTe no-rope KoarysiainHonitH dbakropH ¢ kanlHesHTe HOHM. Bes NpOTHYaHeTO Ha TAM PeaKINHs He Moxe fa Sano¥He KpBBOCKCHPEAHE. ; B sapucumoct of pasMepa Ha navamiara AosuposKa aueHoxyMapon yarbmkaba RT/INR mpHOsusHTeNWo Ha 36-72 waca. Cea npexpatanaie Ha tevenneTo RT/INR O6AKHOBeHO Ce Bpbllia KEN HopMaTa CHE HAKOMKO JH. 5.2, PapmaxoxuneTmaun eBoiierBa AGcop6uns AuleHoKymapon, paneMmania cMec oT ontusutn R(+) 1 S(-) ewattTHoMepH, ce Pesop6upa Sep0 Np epopantio npunoxetine H tali-Manko 60% oT npneTaTa 1O3a ce OTKpHBA B CHCTeMHOTO KPSBOOGpAuLeHHe. Caen ensoxpatua josa or 10 mg ce aocTura nikosa finaaMewa KoHLeHTpALUR OT 0,3 + 0,05 Mixporpaw/ml cnex, 1-3 aca. Tlakonure mmasweHH KOMUeHTpAUMM H OGAACTHTe MO KOHTIEHTpANHORHaTa xpisa (AUC) ca nponopunosain Ha aosata Haz 20308 OGxsar oT 8-16 meg. TinaaMexie konwentpaunn npa oraemmiare nauuenTa sapypar 20 TaxKeba cTemeH, Ye He MOE 1a ce {YeTAHOBH BSAHMOOTHOMIEHME MERKAY AOBATA, Maa MeHHTe KOHILEHTPAMIHH Ha AlleHOKYMAPON M MPHBARHOTO zuao Ha mpoTpoMOU. Pasmpeneacune Tipwroxxemar aueHoKy mapon ce pasnpesiens 8 naaMesttTe paKWNH Ha KPBETa, KbLETO 98,7% ce ceppana c nutasmenire npoTenEH, rmasko c anSymnna. MpwawusT OGeM Ka pasnpesteneHue e 0,16- 0,18 likg sa R(+) extatrnomep 1 0,22-0,34 Iekg 3a S (-) enantHomep. AueHoxymapoz npeMuHasa 8 KBpMaTa, HO caNO B MHOTO MAYIKH KOAHNeCTBA, KOHTO He Morar sia GblaT OTKDITH c OBHKHOREHHTE aHaTHTHUHK MeTOAK. Toll Chuo NpeMHHaBA NTaueHTapHaTa GapHepa (BX. CBIIO 1.4.6 @eprumurer, GpemenHocr H kepMeHe). Buotpancdpopmanus / Mera6onux0M AuewokyMapoa ce meTaGonu3upa B ronama cTenex. OcHoBHHTe MeTaGOANTH ca XHAPOKCHAIMpAHHTe Ha 6 1 ‘7 macro enanTHoMepH Ha alleHoxyMapon, a usToxpom P450 2C9 e OcHOBHHST KaTanHsaTOp Wa ‘oGpasysanero na TesH YeTHpH MeraGomHTa. JIpyrH ensHMM, yuaCTBALIM B MeTaGorHsMa Ha (R)- anjenoxymapoza ca CYP1A2 4 CYP2C19. IIpm peaykusia Ha keTo-rpyniara ce oOpasyBat Mpa pasH4aH kapCuHonosH MeraGoanTa. IIpu pexykuHa Ha HHTpO-rpynata ce oGpasyBa enuH aMHHO-MeTaGosHT. HaKoit (OT TAX He JONPHHCH 5a ANTHKOArYNAMTHATA AKTABHOCT Ha H3XONHOTO JIeKAPCTBO [IPH XOPA, HO TE BCHSKK ca aKTHBHiC npH KHBOTHHCKH Mozed. TexleTHUHOTO MHOrooGpasae Ha CYP2C9 e npsnia 32 14% ot MexxayHHaMBHAyaNHOTO BapHpaHe BL apMakoMHaMN4HAA OTTOBOP KEM alleHOKYMApOn. Eanmmnnpane AucHoKymapoa itwa noayxHBOT Ha exMMHHHpane OT nasmara 8-11 aca. Cac mepopaaHo MpHAOKeHHe BHAT RABBMEH KANPHHC RocTHTa 10 3,65 I¢h. ToraanHaT masMeH KAHpBHe Ha R (+) elaxtHoMepa Ha auenoxyMapon, KoflTo npwrexaba 3HaitTento No-BHCOKa altTHKoary 1aHTHa AKTUBHOCT, € NHOFO 10- ncbx OF TOsH Ha S (-) eHaHTHOMepa, Camo 0,12-0,18% or osara ce exckperHpa 8 Henpomenen Bi c ypuiaTa. KyMynaTHBHaTa eKCKPENHR Ha MerabonuTHTe H aueHOKYMAPOK CHER eAMa ceAMHUA NOCTHTa 60% oF nosaTa mB ‘eweca, (Cneuwaaun rpynu naumesra 10Tlanwentu 8 wanpexua.ta suspacr B xoaa na KanHiHO npoy'saHe NaasMeHHTE KONMIEHTPAMLHH Ha alleHOKYMapoa, ¢ KOHTO Ce NlocTHTa onpenereHo MmporpoMGHHOBO HHBO, ca GHLTH 10-BHCOKH IPH NauLHeHTH Haxt 70 FORK, OTKONKOTO NH O- MAA, BUAIPEKK He MPHROXKeHHTE AOsH He ca SHAN MO-rosEMHL BeOpesno yspexaane Hawa wansin dapwaKoKHHeTHYEH saHHH 3a a1leHoKyMapoa pH G»GpesHo yapemaante. Bb3 octHona Ha \YPHHHATa eKCKPeUHA Ha ALeHOKYNApOH, He MOxKE Aa Ce IKON BL3MOxHOCTTA 3a HaTpynBpane Ha MeraGosHTH npH HapyieHa OnOpeuHa yHKIUNR. 3aTORA HaMOMABAHETO Ha atleHOKYMapO.l € NPOTHBOOKASAH TIpH MaLIHeHTH © TEXKO GEOpeuHO yapexraHe H TPAORA ja Ce BHMMABA TPH TaLIMeHTH C EKO JO YMEpEHO GuGpeatio yapexctane (Bx. cbitio T. 4.2 Jlosmposka H HAHN Ha NpHAOKeKHE, T. 4.3 [TpoTHBOMOKAsaHHA HT. 4.4 Cneu#anin mpenynpexstenis # npeanasin Mepxn npx ynorpe6a). YepnoxpoGuo yapeanane Hawa asus dapwaxoxnieTHMHM aH 3a auleHoKyMapon NpHt 4epHoapoGHo yapextane. BYs ocHona Ha NeTaGoaNSMa Ha aleHOKYMapoa H BEIMOAHOTO HaNaLTeHHe Ha eHSHMHATa akTHBHOCT Ha CYP2C9, CYPIA2 a CYP3A4, e neposrio kaupptica 2a Cae HaManeH. 3aTOBA HanOASBAHETO Ha alleHOKYMapOn © npoTHsonokasawo pi MallMeHTH c TeKKO NepHOAPOGHO YsperkitaHe M TPxGA ja Ce BHUMABA TH NaLIMeHTH C steko 210 YMepeHio YepHOIpOGHO yepexnaHe (RK. chin T. 4.2 JlosHpOBKa H HAYHH Ha NpHAOKeHHE, T. 4.3 Tiporusonoxasanna mT. 4.4 Creutaann npeaynpexmenns x npeanasiit Mepku mpu ynoTpeGa). Ernoc Exenpecusra na CYP2C9 ensnwmure cHcTeMm € nlommwopiia H YecTOTaTa HM € pasMHYHa MPH OTAERHHTE nonynaumn. B xaskaskara paca wecrorata Ha CYP2C9*2 CYP2C9*3 ¢ chorserHo 12 8%, Maunewrute eAMH HAM MoBeve anes BapHanTH Ha CYP2C9 HAT HaMAzeH KAMPBHC Ha S-aueHoKy apos. TIpw TanweHTuTe OT aippukancKara paca CYP2C9*2 u CYP2C9*3 ce epeuiar ¢ MHorO Mo-#H1cKa YecTOTa ~ I~ 4% 1 0,5-2,3%, choTHETHO, cnpsMO KaBKaskaTa paca, AMOHCKATA MONY.AALHA HMA NO-HHCKA aTesHa ‘ectora Ha CYP2C9*2 u CYP2C9*3 - 0,1% u 1-6%, choTBETHO. Tlonepxauara 1032 Ha aueHOKyNapos e pasaMsna B sasicHNocT oT rexoruna, Tloapo6ita muopwanus orHocuo cpeasara 03a H MeaMaHaTa Ha n03aTa B sasncuMoct ot CYP2C9 revoTuna npenctanena s Ta6amuata no-2029: TaGanua 3_CYP2C9 renorun u nomepxaula 03a Ha aueHoKyMapor. Tenormm = N Cpennanosa = SD Menwaria wa aosara Vinrepsaa (mg/ceammua) (mg/ceamnua) cyp2ce*l 169 17,1 87 15,8 23-61 CYP2C9"2 90 144 63 13,5 3,5- 37,3 CYP2C9"3 48, 110 Su 10,5 23-22 Keanu npoyssannst He ca nposeavtaHy HOBH KAMHHYHH HsmMHTTBAHHA CBC CHHTPOM. 5.3, Tpeakammmsiam aaan 3a Gesonacnoct Toxewsnocr Caea eawoxpatia (sitcoka) nepopania n/n peHosia 2058 atleHoKyMapon ic Ha TOKCHHOCT pH MHIIKH, TuTEXOBE H salu [Ip KyNeTa e HaGmOMABAHA BH ToxeMsHocT npit nepopaex mpi. nTipz a3cneyaaHns Ha NOBTOPHO NPHAO-KCHHE Ha AcKAPCTBEHA NPOAYKT Ce CHHTA, Ye MCPHHAT AOS € OctiopesTapretex Opral 3a TOKCHSHOCTTa Ha KYMapHHOBHTE MPOHIBOAHH, BKMOYHTEIHO alleHOKYMSpom. TIpsioxeuneTo na Team neulecrBa B npeKoMepHH dbapMaKONOTHYH OSM MOM Ja IPMS XeMOparHH. 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Kapmanorenxocr ‘He ca nposexcaaHn npoy'Balita Ha ZORMBOTHO MPHAOKeHHIE Ha aNeHOKYMaPON PH KHBOTHE, Kywapurrst ropmurasa saGozesaeMocrra oT GenoapoGal # YepHoapoGHH TYMOpH MPH MHILKH NepHoapo6Hu W GLOpesHH TYMOpH MPH TuTBKOBE, es a BAMA Ha MpexHBAeMocTTa, Cosa ce, He NepuoapOOsuTe TYMOpH pH T-TEXOBETE H GeOApOGHHTe TYMOPH MPH MHIUKHTE ca CEEpEAHM CoC crenwepsnnre 3a BHza MeTa6omHTHA nbTHua, XenaTOTOKCHNMOCTTa Ha KYMapHna H HerOBHTe TNPOWSBONH NH ruTbxOBe Ce CBDPSRA C CHSHMNATA KHAYKLA M HaHa Ha TAXHOTO MeTabOIMSHpAHe, HNpUCbUL Ha TosH BHI rpHsaM. 6, OAPMALLEBTH4HH [AHHH 6.1, Conesx Ha womommmuTe BemecTsa Cosmues anoxci aeporen, 1axTOsa, MarHesHes CTeapaT, lapesHsHo HKIECTC H npeKenaTHRNSApAHO apesusno nnuecte 6.2, HecbemecramocTa He ca uspectan. 6.3. Cpox ua rognocr 5 romman 6.4, Cnenwaran yenonus wa coxpanenue ‘Tosn aexapcTeex npouykT He HOHeKBA CHELWATHH yesIOBHA 3a Coxpattettite, Ja ce cexpaiiasa na acto, HezocTemHo 3a zeua. 6.8, Bug u chsqbpacanue wa onakonKaTa(Cinrpom raGnerxat 4 mg x 20 6.6. Cnenua.anH npegnasiH MepkH mpx maxBEpaRHe Hawa cnenuanau wsucxt 7. IPHTEXKATELI HA PA3PEMEHHETO 3A YIOTPEBA Merus Labs Luxco Il Sa R.L. 208, Val des Bons Malades L-2121 Luxembourg, Thoxcen6ypr 8 HOMEP(A) HA PA3PELIEHHETO 3A YIOTPEBA 20000293 9. ATA HA ITBPBO PA3PELIABAHE/TIOJHOBABAHE HA PA3PEIMEHHETO 3A YIOTPEBA ‘ava Ha msppo paspeurasante: 05.10.2005 r. Tava wa nocnenko noaHoBapaxe: 08.12.2010 r. 10. JATAHA AKTYAJIM3HPAHE HA TEKCTA Texewspu, 2022 r. 13