METHOTREXAT "EBEWE"
`
`10 mglml and 100 mglml
`solution for injection 8: infusion
`
`Composition
`Elilrrrgrrretlwrzrlnecrrate
`1rriioi5n'loorrtai'rs:
`flrrrgrrretlrcrtrteiraate
`trriioi5n'loorrtai'rs:
`ttridoitfl mlcontairrsztfltllrrgmethrzrtreirate
`ttriioifillmlcontairrszmrrgnietlrcrtreirate
`
`Clinical Particrlars
`
`irlr-dicatiorrs
`
`lrlirnn-phstir: Cltllrriillapy: Treatment of gestational cItr:I'iocarr:'norr1a, chr:rrioar:|enorna clestnrens and lrydatidifonn
`mole. Paliation ofacute lyrrplwoqrtic leLIterria. In the treatment and prophylaxis of rneringeal |eLIterria. Greatest effect
`has been observed in paliltion of acute Iympholzrlastic lstem cell] leultenias in chilr:I'en. In combination with other
`arlicanoer agent:s_ rrrethotrenrate rrury be I_rsed forthe i'rdLrctiorr oi rerrriorr_ but is most comnirzrnly used in rrairtenanrne
`of i'rdLrr:ed rerrissicns lulethotrexate maybe used alone or in crzrrrbirurtionwidi otherantineoplastir: i1 the rrwiagernent
`of breast cancer, epiderrnoid cancers of the head and neck, ILI'rg canr:er iparticuIadysr:p.iarnpLrs eel and srrral eel typesl,
`bladder carcerand osteogenic cancer. llilethotrerrate is effective ii the treatrnent of the adrranced stages {III and llr",
`Peters" Stagirg Syeteni of Iyrnphosarcorrui. panicularly in cl'I'Ir:l'en. and in advanced cases of nrycosisfun-goides.
`
`Fsoriiz Because ofthe high I: attendirg its use, methcrtre:-rate is indimted only it the syrrsrrtorrratie control of severe
`rersicilrant. disrtrling psorhs wlich is nrzt adequately rerporrsirreto other fomuol therapy. and rzrnlywhen the ring‘:
`has been established. as bybioprsyanrzlrlbr after derrnatolorjcal cronsr.rltatir:rn_
`III-rntoirl
`Mediotrerrate can be used it the treatment of selected adults with severe rheumatoid arthritis.
`only when the diagnosis has been weII—estd:rlished ar:cording to rhewmtological standards. with iiadevrzpate response
`to other forms of :I1tid'reurnatic therfizry, inciiding full dose H5.r|5r.I|Ils and Lrsmily a trial of at least one or more disease-
`rno-r:Ii‘yingarrtihe:r.rrrI3tic chrgs.
`
`Dosage ar1r;Lr|l.dnn'r-ristr-'aticrn
`FEED?
`Higrurt trrlrlrrrsurd Itllrobhltosla:
`In polyclrentotlterqoy oi rruiigruI1ttLI'nr:rrs and hemobhstoses the dosage cl‘ methotterrate hastobeadjusted accrzrnzing
`to the irdication, general condition and the blood counts ofthe patient- '|'Ir~eadrri1'ntered dose in cclrrrerrtiorui lowwdose
`hl'|'J{then1:Iy {single dose lr:rwertI'En1DIZI
`rner:iLIrr-dose l|uIlT.'!ltherapy [single close IDEI n'gri'rr3—tDlI| rnglrnzl and
`high-dose l|rl'I'}{therapy lsirr-tie dose higher tluar 1[l0l] rrrglrnzl depends on the respectirretherapy protocol.
`The follor.-.ri'rg dosage i'rstructrorrs are only guideines;
`Eorrrrmlional r'.'i:Is'e ofmethotrerrate tlrerap-}r— no calcium iolinate rescue required:
`rs—2o rngrmi M —twice weeltly
`3D—5l] rnglmi l'I.l' - once weekly
`15 rriglr'n!dayltFilIrl-girenat2—3we:el:sirtena|s
`intennediate drose ofmetlrotrerate tlrerapy:
`513-151] rngfrrr? |'rr" irjection; nr:rcal::iLI'nfoimte rescue reqLi'ed_ giyenat 2-3 weelrzs intenrals
`2:1-l] rngfrn |'|r|'inlLrsir:rn merit! h: cdciurn folirate rescue required. given at4—II" days irterwis
`EDl]—1lIlfll] rrgrirrri |'lI'i'rfLrsir:rr1 or.rer'3E—-IL’! h; rarlciimfoliiate resuie recpied, giuerr at 2-3 weelrs irteruals
`l'-Hg-l'r-dr:Is'e methoaercfie them —caIci.rm foimte rescue re«r:pi'ed:
`1-12 grnlrrr: l'|rf'or.rer1—Ei hours, rjyerr at 1-3 weeks intenrals
`For intzrathecd or intrarrerrtricarrlar methotrexate therapy amarrrirrtrn dose of 15 mglrnz is ar:I'ninistere«d.
`Irrtrathersal route of adniristration: l].E—l.‘r.5 rng.'|=;g or 3-12 rrrgfrnl rrretlwrrrtrei-rate is athinistered errery 2-3 days. after
`disrqapearanrre oi the syrrptorns at weeldy irterrrals. and sI.trseqLrer'rdyat rnorrthly interwis until CSF linrzings retunr to
`nomad. F'rcpl'ryhcti: i'rt1aIheca| irstilbtion should be erI'ried out every E-«'Bweelr.s.
`In patierrtzsrrlrith
`rerud fLIrctiontI'rethenqJ1r risk shr:ru|r:l l:recarehIIyc-rzrnsidered and the dosage should be reduced
`oor'req:ronr:Irrg|y If rerzpled.
`
`
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`MEDAC Exhibit 2018
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`ANTARES v. MEDAC
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`IPR2014-01091
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`MEDAC Exhibit 2018
`ANTARES v. MEDAC
`IPR2014-01091
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`hlnunynllizudfiuqu-Iifihrtpmifinhiiithiupufliufllihudnflwmhiunnwdlfim
`Generally 10-25 rng rriethcrtre:-ulteaur:lri1istered puenteralyat weelndy ittenlals. Dosage shcLId lzieadjusted aceorriig
`totlregerierzlunricitisricrttliepafient
`htllrlplr-ml-ilbtlhl-1utoidn'|I1ri1iI:
`Generally 5-15 mg rnethotleade anlriristered IM initially,
`iru:'easedby5rrgweelclg.LtoarI'a::i'rIJmof25rrigwee|:lg.L
`flEI:ll:IdI:Il'.illl|lI.iI.'llI'?a'Ill::I|l
`
`a rrnssilre-dose therqsy once weekly. Dclsage can be
`
`*IZl'fl'll'IIlI‘ 'ElEIE' H my cat be administered IM. W las lJCIll.IS iijection or irllusicnl. irltla-arteriadly, irrtrathecely
`and intrave-.rrI1'i::ul:aItg.r.
`Hflltotrnd 'EBE'IE' 5110 mg. Illlllt my ad 5l1l‘.|l‘.tIIg — r:or1eentrsle for itfusien hm. to he ciluted with stanizhrd
`solutions for infusions before aiiriristnticn aeoording to therary proteecl and i:I.iration of irfusicn. Use 5'33 gheose
`soI.ItiorI. Hingefs lactate or pmielofiml saite solutiorL
`:§eneI:ll*!'r ‘I-255 rnethotremte solution is adrritistered lin ocsteorsarooma ligher nconeentratioris are elescrizied in the
`rterature .
`These rnethotreszte solLrtions for iifusioiiziemat rocnrterr1:rerzl1Ire over 2'|Il1DLI3\'d'lBl1 emposedto ight orprotected
`from lflit. ll lorqer itlusion period is reqlired. the infusion hagslziettle sheLld he t:l'u§I1g-eel.
`Dosages highertlm 1110 rr1gI'rn1£Ie ger1er£Iyai:l1iristered as W 'rrfLrsion.
`Use only clear md freshly prepared sohhons.
`Amid contact with skin or rnucesa.
`For ifllu ill-ally!
`
`Cor-rI!r'a'i-nieatiou-is
`
`I lirroanrrr hyp-ersensiiyityto my eorrponent of the drug
`I %ere liepaficmd renal llI'|J1ll|'1'lEl1t lserum crealirire :- 2 rng"L:ci:ir1Iraini:icati::IrI: serum creatirine 1.5-2 rngfl: dose
`tohe|erh|eedto25'}IE otthestateuldorsel
`I Alooliolism
`I Diseases of the hematopoietic system I:icnne rrflrow liypoplseii, leu-::ep-enia. threrrtiocytoperia, anerlial
`I Existing infections
`I Ulcers ofthe oral eei.rityarI:l gastroittestinal test
`I Fresh sLrg'oalwounds
`I Preg|1£I1cy2I1d lactation luse of reliadnle metho-cl of eontlaoesption is manrhrtory before, rhrrhg and after methotrenoite
`therapy both in men md y.romen.l
`ParticLI&I care should be taken in i'rpain'ner1t of bone marromr alter an intensive ratii:ithera|:ry_ clremorlherfizi-y EI1tl:|liEl'
`prolonged pretreatment with dmgs i1|:iairing hone rmmzryir lsu|:il1enarrI'des_ chlorsnqziltenieol, |:Py1'a:c|e
`iridcmetlracin. ciziliertyltydantoinlt palierrtswilh poer generd health. clildren aid the elderly.
`hlelhooerrateslworid not be Lisedforthetreatrrientof rl'ieLI1'EIoii:la‘thriis orpsorirsisyulgiris in patierltswith preeihfiru
`severe ting disease.
`Caution should be exercised it patients with thi'd space fhid collections lascites. pleural effusion. seroma at site of
`opersliee wtiurids}. sitce e1roI'etion of rriethotreirate may he reizhced resulting in iicremeof
`
`Hhnrirrgsand Hecailtians
`Methotrexate should be achinistered only under the supervision of a cpdified physician e:q:Ierienr:-ed in the use of
`arltineoplastie therapy.
`fies! care should be taken y.rher1 methotreziiate is ec—ai:hi1isteIet:l with non~stereii:H mtiinllammaory drugs ll-l5r1l[lsl.
`Seyeresi:leel'le::tsi1chdingfatEitieslafterliIj1closesof methcitreaoltelhayebeenreperted.
`ConsLI'r|:rtior1 efslinnlicleveninlcnlniesesslunirldheawzided.
`The patient should he itlormed Ituziut possinle rislcs lsicle effects}. Corltrainiziesiioris and precatltions for use must he
`stliclly observed because ofp-ossi:rl-e severe {under paticulai circunutanees lelhalltonic reactions.
`Plmrm eonoerrlralion of methotremte
`I l'llgl'El'Il'II'|'l-2'lirl1E5IU£ molull l2-I hetls alter iritiating rneIho1Iea:etetl'ierfi:vyl
`I Twine 1045 molill l-1:5 hoLIs after irithting rnethctIe:atetl1er:1:ryl
`I 10"’ Inolll l'.-'2 hours after iiitiatirg rrietliotrearateflterrzfirl
`indcslean hcreasedriskof
`h11yelc:sL|:I|:ressiori, n'uoo:sit'sl and reqire a brig-lasliig and high dose olca|ci.im
`folinate rescue tl'IE.'tfl2Pj|'.
`In patientsvrith impaired rend fmctiorrs rnethcrtreirate elesage has to he reizhced ac-oonzirfly.
`In the
`dose of melhotremhathe creatiiirieeleamoe sliouldheat lie-mT5‘L tithe rion1ui'u:iI.ie l5U rri'min.Iin:
`.
`resp. 9|]
`An intemiedhte dose of rnetl'iotre1oztel:- 1m
`3| should not he prescrizied if the rreatirihe cleaanoe is reduoed
`l:ielow 50% of the nomial yahe lit 35 nl.I'm'
`resp. -: EU rrllrninl, unls ehily deteminatiori of serum ereatitiie.
`metholrecrrate levels md calcium foimte rescue perfonnedtill the methotre:-ate levels decrease below 10'? molill
`Eluritg the eomrerrtiortd close of metl'io1re:-uitea dose reduction of 50% '5 reoorrlnended ilthe serum crezliririeyfli
`are 1.2-2 nultl and cessation of therapy reoornmended il serun1 cr-eatinineyzltiesex-oeed 1 rrgltl
`
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`Preretpieitesfnrs rnei:ILI1i nr high-dese rneIhetre:uite aehitistrstiert
`I Adeepate atleiiiailiy nf I:alt:i.Im folitflefni suhsecpent rescue therz1:rI_.r
`I Flaoizl deteirriration nf rnelhetleimte serum levels
`I .I5nIaH:riit'.r nf hentmiijsis
`I Autelegnns hnne rrutrnw er blend sqopies. leultneyrtes and platelet eonoentlstes
`
`Pretreatment e:IeI1irntiene and safety precautions:
`I Exnhisinn of renal and liver irrqoeinnent and Iisturhmees of the herno|:-nietic: mtem {nerd and liver function tests.
`non'|:I|ete hlnnd nountsl.
`I Before trmtrnent of rheLI'mteid artlritis with rnethnlrehaate ii palients with hepatic diseases liver Iziinpsyr sheLId he
`perfnnned.
`I Pregtaicar should heexeluded.
`
`Fnr pre=|.rentinn nf intrarernl precipitation of rnethntremte or its rnetiiovnlites EI1dftJF pr-Ionh-.rlaIis and treatment nf
`hypemlinemia resulting from destn.|t:tinn not the cell nucleus. fnn:ed hydration and alluiization of the Lrine I:r.r infusion
`nf Md'l'I:l:l33l2|hlli1Ifl. 1D—..'T!5 mrnolll in II1 Ilnouri ef3 LI'rn1.l2-I houml 24 hoursI:|-eferesnd Lute 14 hoursafter |"l'lE:ll'I2Fl]'E’.'IlflZE.‘
`ei:hirI'etIstion
`retpiesl
`It FEi:E!SSfll'|_I' 1511-224] nglmhlthy snetazelalride nrallopuliruol: E! rI1g.I'l'.gl:h1,r can be used.
`.I-'l.n itterrnediste aid hiflrdose rnethntremte thera:-1r should not he initiated '.I'||lI-E:l1 uritay pl-I u-eluess as helm-.r ID. The
`allcairle status nf the Lrine must he nontmlledd least -thlirug the first 24 h nftei irithtinn nf I'I'I3‘li'l-|J'lrI.EllflIlE.‘3:lrl'|lI'Il5ll1Itl-[I1
`{pH 'I.aiue 2 EB}.
`hlenitoling nf rnethotrei-tale serLI11 levels is manthtnnr inrneaniatelmr fll'lIEt neuntiizin not rnethnlremte as
`well
`24 h. 43 h and T2 h sftenl-aari:|st fln the basis nl‘ methotresste serLI11 levels. the eneI.Irrenee ef signs nf texieitr
`can be inferred aid the edeium folnatedos.-age can he etfilst-ed.
`[lLI"I|-g the ittmthenal administration systeirit: side-eHe1:ts rm? III-CJ:I_.|l_
`.I-'I. i:I'etulcirioale1aI1'i1stinn nf the patients. |:|ati::I.Ih'l1r ilspenlinn nf the 1]‘-lllI.':3'lI'lI'||'_. ph5r,rn:rt md lEl1_fTIJI fnr raharuges i1
`rnuonfl. regphr rnonitnring nt h3l.IDD-|J_||'I2E5 md thnzrltlzinqrtee lthihr up to Ettirn tueelzlfl. noI1'1:rlete blond eemt lnnee
`WflEH'j|l. lend md Iiverfunetinns should heperlenned
`|JLrirg|loI15]-te|'mcI'lI'gI1-dos::getiie|'i1o'y'.hnneIruI'rew hiepeiesnnyhe rleeessznr.
`In sueueie leut:n-peria the Iislt nf at i1fe1:tinn shnLId be borne i1 nirld In case of infection. therzq:-1r should he stn-sped
`and
`therzqnr should be instituted In suevele nas of nI'y~elnsuppression the trmsfusinn of hlnnd.
`lEI.|I:l2l(."||'l2EE'.-fl'Il2lt tray he nnr.
`
`Ihlg interactions
`S-eueial chm. tray cause intersetierrs Ilrflnly p|':arn'aonl:i1etii:l dLI"ng ennenrnilmt eehriiistrstien ef Inethntreiete.
`
`The Ieliaitf ii l1n|:I1:Irante ‘I itulelnil Int:
`Inhibition ofthe rerfl e.1o:|'etinn nf rnetholie:-rate with nnn-steroidal arli-i1flan'Irat4:I'I_.r-tI'Lg=.. seinfhtes.m
`pr-ol:-ene::iI:l. -oephalnrlhin, |JerI'niIirI. eiihenieilil. tiazasilin, |1a"a-n1inohin:urit: acid.
`Drugs tlahieh are imiohred in the et:tiuetLI:IuIaI secretion i'r|:ei'the elirritatien nf methntresste mdtherefnre mus-eel":
`irumsed plsslra eeruoentnatinn.
`The displacement nf the rnethntrexete whit:h is hnund to phsrre prnteins lesads tn :1 higher free noneentration in the
`phnrrIi,e.g. wih E E sullEI‘um1'nle. t:l:no::nrI.I:iiein. I:rleI:IIrI-.n::in. t:5rt:|ncpl1-ospl'IIride. |:|l'l.‘3|'I'||'lI|-In. Izieihituates.
`tianquiizels. tehaqnsilies. nhlorarrqnheninol. p-nrnirlnloenzioinz: acid. nrel entidiatieties lnhlnlprnpaltide. amit:lo|:I1rI'i1e
`deri-Irati-u-es}. 1:iLreties.
`Inerease nf the ijnaeehlar ai:~_::LI1ILiatii:r|1 ef methntrea-Late md Inelhntreiiate pohrglutamtes. ed. with since dlaileith.
`eplpndoplnrlotninrrs. prnl:-enesid-
`
`TI1n lcliuitf Iil1nlI'|:IrnI:Itn i Ill-cllnll-ll I11:
`Inhibition of the iitrsneldar uptsloe of rriethntiecruate lnn|1ioosternit:h.. L-es|:|nrmi1s-se. IJI-enm',rein. perisilinl; insreme nf
`the dihjrdrotolde reuthntas-e ennnentratinn lhiamteienel er i1ereas-e efthe intmoellular |:Iuri1e enneentlatinn HIe|:II..IIirIoll:
`'I.rita1in preparslioltswlinlt eontfii foil: acid or its dethelivee {esp-e:t:iaI|1.r fnlirinneidl-
`
`Drugs with Icrlown hepetntexieityr should not |:I-esi:I1'i1istered nnnen|11ita1tl5rvaith methotrexate due to iiereasesd risl: of
`hepatoxieity.
`Drugs with fnisneid antng:I1'n.tec:liIiit1rIp'{.Iri'IIethaI1irIe. tiimetho-pr'rn} lI'li'§I' iieiens-e the toxieitynf rnetholreiuate.
`
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`The n11re|esuppressiire activity em insrease due te lung-lasting pretreatment with myelesmpressiire substanees leg.
`sLfi:iheruI1ii:|e. eHeIamphenieeL pytazeledelivatives. i1di:irnet|'Iit:in. aid i:fi:Ifrer11rInrdanti:iiri.‘r.
`Melhetreiiate can enhanee the aetiuityr et eeumarin-Ike eia|sI1tieeag.ih'it:s lthe pnzithierrliit time is prelenged the te a
`rechieed deeenqiesilien efeemnin
`Eluritg sittuftalteeus parentend admin'e.tratien ef til:-j|'t:f-IZI'|:I'ir' md ittiathessd
`iisenzlueis (:11 net be e:ii:i:|L|ded.
`
`ef methetre:-ate. neumt-eg'sa|
`
`Methetreaeie fl1tl‘||' irruiai the imnuneteqje reaetieri te ireecinstierrs slid trey leed te severe eerruiiestiens. Thelefere
`i.iai:iei'nItii:ii1ssheI.i|i:| net be eanied eut shiritg n'iet|'ii:iti'e1-site therapy.
`.f3ui:eerdingte the typemd ittensihrefthe l'lI'y'EiI'.3I5|.|Z|II'E=55i'|uI'Efl'IElfiIF||'IEIf the ti-E553-E:fl'IdIEItf‘IE.'ffB:ltJl3'IhE:HI|ii-I1'§|"I1D respend
`nenrelyte i.iaei:'I1sIien rm',itslr.e 3-11 merrlhs. Leukerrii patierlss ii reltiseien sheuld net beti'aeei1£tedwith iiieu-aeiines
`at least 3 merithssflerthe last dese ef rnethetre:ete_
`
`The use ef nitreus exide sltesthesia peteritiites the effect ef methetreiiate en felate met:i:ie|isn1_ i_.riet-ting severe
`ur|:irei:ii:tfl:I|e I'I'|1flE'.i-EI5l.J|:|:l'E=SSit1Ir1fl't-Ef sternatitis. This effect can be recheed birthe useef felitisaeid rescue.
`Arriedareneandmiristiatiente patients receiving metliizitreciiate treatment fer |15fl-|'tfl5i5 ins iidueed uleelated sliit I-esiens.
`An inerezeed risk ef |1epatcituiIii:it'ir has been reperted when rnethetlesstesltizl etietinateaiegiuien I.'.!CIrl1l..|lr'B|'Itf'||'.
`
`H'eg-naisjraid Lactation
`Methetiiesete is a tetateg-enie dni-5; :d:iertien_ fetal death and'er eergeritzd :d:inern'iaiti fume been repettesl TherefeIie_
`it
`net reei:i|1imendei:| in wi:irnen ef efilileezriig petentii uri-en the petentiil benefits eat be eiipeeted te eutweijt
`the rislcs. If the -i:l'ug
`used -izhring prei;I1£'ni::1rfera1tiIieeplastii:iIr:iedieris. er if the patient heeemes. ptegnant while
`tflzitg th -izhig. the pflierit sheLId be infermed en the petential |"a::.=Idtethe fetiis.
`Fer the rrfltagernerit efpcseriasis er rlieurmtiziiizl sitfritis, methetieaerte thers|:n_.r in wernen sheuid be started irrlneiziitehr
`fellewitg a menstrual peried.
`Apprepride measures sheuld betflzen in men iziriaremen teaireid eeneeptien dLI'ii-g and feral least E rnenths fellewing
`t:vE.'!5fiit-I]-|'I ef methetIe1iatethen1:ry-_
`
`Effect on the Atiflitf to [hire and Use Machines
`The dziiity ef patients te drive er epeiate nni:|'inerii tray be inpaired.
`
`Adverse Efleets
`
`Mani side effects ef nietfietre:-ateflterqeirare uruweiiflzile being dietefltepltatrneeieqjedadiereefflte drug. HEH'I'Et|'E!F.
`tlieseaduelse effects are genelally Ie=i.reIsi:i|e if detected esiht The majerteiti: effestsef methizitiexate eesur it nern'ia|_
`fifllitifjf prelifelatitg tissues, puItiei.Il£It'I_.r belie I'I'EI'|"CI"I'I' and the mlstreintestinal tract. LI-eefiliens ef the mid rnueecsa are
`usufly the eariest si-ms eftexisitylz The mesteemmenly reperted adirerseeffeetssre diffieuit'.i it swallewitg, uleeratiire
`stentslitis, p|1EIt'Tl;itis. feueepenii. thrembeeyitepenia. nausea, tremiling md sbdenirud distress; hizsnetrer. in fer ether
`eiffeierit texieities rrIr,r eemrwith different frecpiertcaufinteirsitjraissiltiig te different desesfreutes ef
`C|'ther|e|:i4::«|'tedai:|-irerse e|fei::tsirivi:i.ii:|eri&5se. unchefsligie. ehilsandfeirer. -Iizziiees. decreased resistateete i'ifei::|ien.
`titritus. tihirredvisienslid e1re i:iseemfi:irt_ The ineideneeand seveliyrizif mile effeetzs :1:ipearteI:ie de:se—rehted_
`
`rlstiatlen.
`
`flllrflt elfeets emheetassfled asflttlnm:
`
`eeshirntesis. acne. furunt:LIesis. Severe tea-iie n'ianifest:atiens Ike iraseuflis. sevele herpetifelrn sliit enqetiensatd Ljrels
`simiiente niaijqapea. F's-erislie lesiens em itereme by simLdtsIteeus I.f'|J'I:ai:iatien therqey.
`
`Ht-et£'Bene rruI'rew depiessien. Ieueepeltii. neutrepenie. thrembe-eirteperifl. anenii md |mnh are
`e1qieetedfet|e'iii.ring rnetfiiitre1£Iethers|:n_.r. The nadir ef eieulsting leulceeyrtes. neutrephilcs and phtelelss Lt5LIIff'§I' eei:LIs
`bet-.iiIeen5aru:l1Z3i:h-ilsafteriri f'I.I'be|L|sdese I'.iiIithrei:ei.reni'bet'.iiIeen1Itte2.‘-Zttiiw'l_ f_t¥|.i£t]I!.‘|f'ftE.'=5tir'dlIEl.J'I]'tI|-f1i5I'I'ttl'|_||'
`eesasiensljr sltewtwe depiess. tfietisteeeilning it 4-—?iih'.rssItdas~ei:i:I1d ned'rafteI12—21i:h',-s,feIewed by
`reeetieni. Cliniesd sequehe such as feiret, infeetiens, septieeirii md henienfnge fI'tJIl'I"|Efl'frEl.|5 sites rim be e:iipei::ted.
`Megiieblastiesiivenii has alse been reputed. nuirly it etdedrpatierts reeeiiriig Ierig-tennweetdii Inethetreiiate thers|:n_.r.
`Felste sI_|:ip|ementElii:in may permit eentiiuatien ef met|'I:itie1iatethen1:rir with rese|I_Itien ef anenit
`
`Ahineiihryfiystnn: Eingiuritis_ fl-e:ssitis_ pharyngitis, stermtitis, anerexix ventiting, diarhea, heniatemesis, rnelena.
`gastmintestinad uleelatien slid bleeding, enteIitis_ intestitad perferetien, itidemini eistiess and aneresii rrny eei:I_.ir_
`hIeIhetre:ii:ate
`has been asseehted with acute fltd ehrenii:
`aeute liver atreph1i. neenisis.
`fzltyr metarnerphes-is. PE|'iDeI't:d fibresis er hepati-::i:in'hesis. Afteiatien ef liurerfuniztien tests tinereases int
`md LEI-I h3't|'Bf5f is eemntenljr repeated but Lnually resizilueswitfin ene miinthsdtereesssliizin i:ifthen1:r,r_ A mete irqiizltsltt
`hepatiefliresis DI eithesis filiffdiflw Ierg-tenn threats er Ierqert tieelrnentssltizl higlt ::imLdatiirei:I1.u;Ideses_ The risk
`ef -izleireleping ehrenie Iiepetetexieity in prseridie patients seerrete be eerrelated net en|'.i te the eurnuhtiire dese efthe
`iiL|g|:iut Iise tn the presenee ef eeneurrerit eeniitiens sueh sesieehe|isrn_ el:inesit1_.r_ diabetes, adiisiieed age and the use
`ef Iiserieal een'|:ieunels
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`Hroymimffiystenn Hened t‘aiLI'e, azoterria. cystitis. hen'utturia_ tlefeotiire oogenis or spenmtogenesis, tnitsient
`oigospenrit. urogenialfmeristnial dysfunction. yagirnl iischsrge. iifertity. daortion. fetal defects. severe nephropathy
`have been reported
`
`Ftidincstaryfiysharrrz Interstitial pneuntonitis. itterstitiad flarorsis. reyersisle eorsino-philic pulrnornry itfiflrates rrny on:::ur.
`I]-eaths fa-ire been re|:iorteda'rdct'It:inici1terstitid-ol:st1t.it:ti-ire piirioruiydsease |'m.occmii:irflyoi::o1.Ired. Marifestations
`of niefltotre:-ate-iruh1oedpIJkmmrytoxicityuJrI11'nrlyiru:hidefeireL ooLgh leap-eoelyoly md non-prochcliyel, clyspnea.
`chest pEi1_ hypocientia andilhr ratiologicad eiriclsnceof puhionary itfifbates lusuzly tiffuse anifor alveolar}.
`
`C-'attrrd' Menmusfimmn: Hearhches. drowsiness. b|LI'red yision. apfnsia, hemipareshatd conIn.dsions Imre oocuned.
`Cornrulcsions, pEI'esis_ Euihirrflane syntiorne and increased oerebrospinad fluid pressures lwre followed iI'I‘I]'EIf‘I3fiif
`adntitistration- hleurotoidcity is repolted it patients reoeiying intrathecad or figh-doses of ntethotreirate. Chernioal
`arachnoidilis is niarifested by
`pain. nocad
`A subaoute form of toxicity rrny be chaIactenzed_by
`ynytruydegtees of pores. Paml-em and Itcresased CSF preseure hauvealso been reported. flu.-I:|eLeI_.e:dsyItn:h:iI'rie, oocumng
`I'I'lJI'I'Ii't5'I1t2|-j|E'fl3H'fIEl"I]EIif]TflE.'l'II. is chaiacterized Iziynecrotizitg |eukoenoe|:ihfl:pa’d1y: The synizlorrie may begin 'nsii:Ious|y
`and progress tooorrfusion_ sttpor, seizures, ataxiaanddsnterttii The effects are doserelatedatdoinir particthtyyirhen
`intfithecal rnethotreniate is given at closes greater thin 50 mg in oorrdziirntion with ottltial irraiiaiion and systerric
`rriethotreloitethenqny. Eo-,g'iti'i.re i'r|:iaim1ent has been reoonded it c|ticI'enviho reoeiyed ittlatheoed ntethotremte together
`with orarial iradizlion.
`
`firoinogeifitycflytotoriic dnm. fare been reported tobeamoitedwifltm itoreasedrisluzi dE.-i.reiopn1errtof s-eci:ir1v:h'y
`tumors. it hLI'nans- Evidence of uchrornosorrd rhtagetoatitud somatic: cells and hLI'mn bone rrurrow oells has been
`reportedyirith methoI1e1I;ate_
`
`ofcId:i-etJes_ osteoporotic
`fl'tfifiHea'.'tion:crefatedtoniett'iciIremteuse ini:h.ii:|epneLInor1'Iis_ rnetdaolic
`effects. itchizingmeptic necrosis ofthefernoral head.:d:ir1onrEdi:|t.snges i1tissL|eoe||sat~de'iren sudden dezlh.
`
`Elva-‘close
`
`Cflciunfoiiateistf£amflmefunemrfingflehrIHiamtmdcefiedsofmetmbeidemflEf£n'flopiHtsgmmm
`When large doses or EF|:|'E|"d'EI5'EE5 are Ijytelt. -cdciLI1t foliide rray be aizhtiristered by intrayertous infusion in doses up to
`T5ngwiflin11hours_foIcnIredby12ntgitbEII1|suJbItyeyEsyEhmrsfcI'4 d:ises_".|'It'|t~ena1iiermet|:t:sesofrristt'icit1te:Io:Ie
`fispear to hayeat ad~.e|seet'feot_ B-12 n1gcifoa|oiJmfcdiriaterrIaI-ybedjyiert itlnlmsotllaty eyeryfi hours forltdosest
`|ngener£d.vihereoyeri:|osme sLispe«ctocLthedoseofoa|ciJmfoirnte shoLddbe eqmdtoorhflierthan the offeniing
`close of ntethotreiizte and shodd beadmiristeled soonm.poesiJ|e;preferfl:I|ywihi1thelist fl]-LI'fl'|d certainlywihit
`dhoursafterwlichit n'iayni:Itbeef'fet:Iiye.
`flther supp-i:irti1gther:1:iy such as blood tratsfusion and renal tialysis maybe reI:]Li'ecl
`Effective eiearznee of rnethottetiate has been reportedtnith acute. ittermittent hentoiidysis I_|sing a highfltlxiialysec
`
`Phamtaceulioii Properties
`
`H-'t.'per'tfesand Effisasy
`Melhotretiate is a folio acid antmorist with cytotoxic activity belonging to the groin of anti1ietabo|'rtes Melhotretiate
`acts rrninly it the S-phase of the oell division. It irltisits oonuzielitiirely dihydrofolete rechictase and the reduction of
`titydrofoic acid
`to tettahyiiofoicacid Fl-I4}.
`_
`_
`_
`_
`_
`_
`_
`Activated reihoed
`-derlyatnres tie neoessary forthet1ars.rrIsI|o|t of E1 urits fltd the syrlhis-Ii pymlcite. |:unne
`and anino acids- Therefore rnethotretcate ini:h.Ioes EI1 inhibition of the |]t"v|.i!I._. HMA and protein syrrlhesis through the
`intraceILdar decrease of FH, andactiyated rechoed fohte deriuafiues
`The vcytotoxic activriyof methotretiate oorreletesfn ubct with the in|'i:iition ofthe DNA synthis.
`more
`H:1JI.'_l|ypIt:drferatIruhssLIes lite ntaligruitt oefls.
`rrurrotr-L
`eels. shn opltheiimaid rnucomare
`sensltnre to rneIhotre:Ir'.=Ie. The oell pnoiferation
`aocelerfled |I'I niaignontas and rnethotleirate oan therefore Influenoe
`persistentlythe rrudigptaltt growthwlthout i:i_I..IsItg Ineyersitle i_:hnta-geto
`nornialtlssue. it psoriac:-is_oeI profrferabon
`of the eprtheiLI1t as oi:irr1:uI'ed to nonrud ski‘: is Increased. Th difference It the oell proliferation rate is the reason for
`the use of methoIre1i:ate in severe randciltant iisrdaingpsoiiasisand atfrilis psorhtica The actiyityof rriethottexate out
`be neutraizodtnith the
`of folirieacid las oaloiim tolinatei. Foiric acid is rnctaboizod ittIaoeILhr|y througlt
`H5-nietiryl-tetridtyciofcdio acid itto tehahyiiofoicacid and
`m-Irietityteit-tetriit-.I1:lt:rfi:ilic acid and causes filing of the
`intraceILdar pool of reduced folate delhslives ayoiiitg the ithi
`ition of the iirydrofolate reiductane by I'lI3fl‘lI:}|1]'lE.‘:|t?fl'ftE.'..
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`Hnrmarrafineties
`
`After
`In high-i:|I:ise rnethehercate 'fl'|ElfiJ-'§I' phsma epn-::entratii:ins ef ID“ mi:il.I'l were reached immeiziately after
`lifaiiririslnlien ef methutremte the eirtraeelhihr nistrilautiuri is very rapid: ii the total fhiid eentent til‘ the body the
`iistrhitien is in volume of q:iprmL THEE. efthe bu-i:|'.r '|:|'IElfll'I'lZ. With parenteral admiiistratien. t|'rerq:ieulieaI'ir irrsultieient
`r:-izirieentraliizins are readied ii the CSF lire te an i1|:uired eressing ef the bleed-brain I:rarrier. Hiijt eeneerrtratiens ea‘:
`|:ie ehtiined by irtrslheealadrniiistrslicli. if remired.
`After I".I'ai:hirI'stratienaIIiplu:sie pattnnmr is assumedferflie phsnn euneenlraliuns ef nrethetreciurtewifli n'ieii..Im hit-
`Iifetimes of D35. 1145! and 2599 hours wherel:n_.rthere are wide fluetuatiizins in thetlid phase {B-59 |1eLIsl.
`Mterttieadminislratiun tit rnethizitremte |'|i|'|:ie|us iijeeliuri ershert-term infusiun BI}-B555 ef rrrethiztremte
`uia lcidneir undimged within 24-31] huurs with ruzirmal renal function.
`Partierrlaulyrvaifli irrpaired renal funetiuri andslse with gaslnziintestiirel ehshtretien li|eLrs}5I1d ifa '1t1i'd space‘ "E. present
`as a reserve eizirrqzirltlnent i1 wlieh hIIT.K ean aeeumLIate lsueh asas-i:ites5I1d.I"er p|eLIa| efiusiensl. the tetal elearzuiee
`is recheeduidanirtensifiedsndprplnngedatdinriefhfiitisehserued.
`After irtralheml n'iethi:iI1e1i;ate ai:hiristIatiena slew Iesurptiun ii the phsnua r:prr|:artn1er'rt eeeursmd leads to pussizile
`prelizinged texie plmirn Ieirels. Ir‘-Irirdrerr-mefliutrea-site and 2.-I-dialriie-Mm-nredwl-iziteruie ai:id lD.I'-'l.hIP.'l-'l.| werefciund
`rnetflzielites in the planner and urine. lulethutreaete. T-h1rr:h:a:yn1et|'u:ihe:elearI:| D:|5ihII3A£Ies|i5d1flysuhIJ|einaeiri: Lrirre:
`thereiereaeenespuridirrg hjliiatiuri md allzzirisatien l]f'fl‘|E urine aredasuhlnely rei:|.ired dLI'ing high—dese rnethetremte
`therqay te auciclaeute rerui insLrl'|ii:ier1e1r duete intrarerud prei:i:iitElii:in.
`hlelhetreszte is |:ieLI1d te serun1 protein in a latent 5D—?l]'I..
`
`excreted
`
`Pharmaeeulieii Preeautinns
`
`lrreenrpatihflities
`I‘-IrriJI.r.I11ir'ri:prr1:iatibiliiesinelLIdIe streng u-xidants flidaeith. lrrmeiiate preepitatiuri er illfbltiijf ueeurs with eli-urpn:rrrer3:irre
`hyirhzieliluride. dru-peridul, idamlnieii. rrietueluprmiide lrirdnziehleride. l'IE|JEIin sizihrtiun. prerhisizilizine seriim phesphate.
`prerneltiazine h1.Ii:l'erel‘luI'ide. I::'irl:arsl:IirIE. El-dlll.I-EII1Jl.IlB[:lI.
`
`Storage
`Store at ruerri terrperature. de nut e:eeed25”C. preteetfnzim light.
`Keep inasafephi:eeLrteftheread1efel'i|dren
`
`Hesentatiars
`
`5Dn'ig—1uia|et5ni
`hIeIhetre:el'EBE'r"|iE'
`flni-g-11.:-ia|et5n'l
`hIeIhetre:Et'EBE'i'JE'
`hIeIhetre:Et'EBE'i'JE' 1Dl]Jn'ig-1uia|et‘|l.'in'l
`hIeIhetre:el'EBE'r"|iE' 5DEI1|n1-g—1uia|et5Dni
`
`filrstrsrntiarrs hr r'..Be.i"l-hndfirrg
`I Parenteral methetrencate prepusliens do: not eeritaii an antimierel:iia||:I'eseruati1e. Any unused si:ilI.Itiur1 shuuld he
`rismrded.
`I Parenteral rrreflmrlreauite prepelalinns are stable for 24 heLrs when diuted with the felewiig i1Imirenuus sulutiurrs
`fer idusiun: l]..‘J'I. seiirrn ehluride. glueese. suIi.Ime|'i|erideu1d glI.ri:ese. eurrp-ui.I1d seriim ehl-uride lHirrger's irieelinrll.
`eurmeund sudium lactate llaelsrted Flinger's iijeelinril.
`I Be not mix rrreIhetre:Iele with ether rings in the seine intusien hm.
`I C1rtete1i:ied1.|m. shi:iu|i:||:ie hannled cinhr l:n_.rtIained personnel md in a desigmtedaea
`I Thewurl: sLItaee shi:iu|i:l|:ie preteeted lzrir dispesmle plmtiehaeliedsbsiziltient pqa-er.
`I Preteetiire elething lguggles. gizi-.I-ms and dispesahle gleues and rraslrsl sheLId he wem by fl halidliig parenteral
`rrieltietrexate.
`I Methetreirate is netvesiemtandsluuHnetmL|seham if iteemes i1 euntaetwifli theskin. I-Imlreuerz it shi:iLId|:re
`washed I:Ifh|r'lfl'I water ilrirreciatehr. .l-'l.n-.rtIarrsient stinging rm-ir betreated with blind ereu11. if there isaw danger ef
`mtemiesbsurptiuri ef sigriifieslit gmirlities of rrrethetrexste byrany n:iI..rte. ealeiimfuirnte emrer sheLId be given.
`I Cvtetmdeprepaafierrs shuuld not be hancledhyr pregrnrt staff.
`I All iterre. used fer_reeerrsti|1rIierI. fldrriinistratiun er clearing. including glmres. shuuld he pheed in hifli risk. waste
`rispesal bags fer h-EI1 temperature ineineratruri.
`_
`_
`_
`I Amrsprlhge izir-.I-irate rraterial rray he iispesed ef i1|'f|rI:||’El‘fltIJ|'I.
`
`Harrm‘ar:t1Irer
`EElE'r|'|r'E Phelrrn GesIn.|:i.H.. A-4ElEE Urrteradi. Austria
`
`Lieenee Holder
`
`Plurrreiugie Ltd.
`P.[l. Buirn1:3IJ2}'. Tel—A-iriu E14323
`
`WA
`
`FHARMA
`
`SH1l]'l1‘.i
`
`
`
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