EDITION
`
`2003
`
`PHYSCANS'
`DESK
`REFERENCE®
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`PRODUCT INFORMATION
`
`&idovudint doS(' and the pr~li'ntf ofintcrcurrcnt infectious
`tit iOfla.mmator~; cpi!-Odl'$, lf thtt h('mat<w;rit eX«'«~~ 40'1,
`the d~ should be- di$COnlinuOO until the hematocrit drops
`W 36q. Tht>dose$hould be redut:ea by2St.i when treatmenl
`it re.~me-d and then titrated to m~t-int~in the de~Si.red hemal·
`ac:nt.
`C.nc.r P•tl•nt$ on Ch•motherl.lpy
`Ba~!ine endogenous serum erythropoietin levels v-~~:ried
`amona pati~ot.! in the:se trio.ls with approximately 75';\ (n o::
`83/llOi h~wing endogenou' &erum erytl\ropoictin le\'I!'IB
`132 mUnitYmL, and approximately 4"' (n ""411101 of pa·
`ticnts ht\\'ing endogenous serum erythropoietin lC\·els > 500
`-mUnit.s/mL ln g~enl, patients with f()wcr ba5t'line ~rum
`e:rythropoietin
`levels resportdcd mo~ \'igoroU!ly
`t.o
`EPOCEN-!1 than pt~lient& with hlghl!'t l!'t)'thtopoietin lt .. ·~lf
`Although no specific sertJm el')'-thn>poietin lev-el can bt ...up.
`ulattd aba\•e which patientf would be unliktoly IOrt!-pood to
`EPOGEN® thl'rapy. trtatmcnt. of pabt'>nta with IJOII-~l~ ~r.e..
`vat.ed serum er)•thropoil"tl.D lf'·cb ~ft', 200 mCn.;~ .... 'mL i·
`not rf'COromended. The he~tomt ~Wd lx- moW1wed OD a
`-.-~kly b<Uis in patW:>ota rtu'.i'nn_;t EPOGE.."\'11 tb.:npy uat.d
`htmatoerit beeomt-J. at.
`l'«(lmJnt'ttdt>d st.utinlil d~JM' of
`Stlrting Dose: Tht-
`EPOGEN~ for adlllt. u. 150 l'ni~ SC TIW. For pEdiatric:
`P<tti('nt$. "* PRECAt."llO~'S. P«l.iatrie UM.
`If ~ tbponse I., nol satb;(aetory in
`Cose AdJUStme-nt-
`ttrm" ( ft>-i~.~QDg tran..,fusion nquu·~~nts or increAsing
`n '"'rl.at<·"ril J\n ~ wet'k.'> of therapy, the dose ofEPOGEX•
`t&D. t .. ~~~~m~ up to 300 UrtitNkg TIW. If patienu ha,·t>
`oot ~ .Ntitfact.Orily to M EPOCEN® d~ of 300
`l"Ms.o\.gTI\\. n ~..~unlikely tho.t tbe)' will respond to higher
`dOM-;;.oCEPtX:E..~ •. lfthe hf.matoc:ntt>xccedt 40%, the do-st
`of £POGl!\l- tbol..kl be "'ithhekt \llltil the hematocrit. faJla
`to 36Cf n. d'* Df LPOCl:N® i;hould ~ redured by 25St(cid:173)
`w~n uwtmer.t ~ JHuJIMXl and titrated to rualntail\ the dc(cid:173)
`&tftd lwala.t.omt lfthc miual d~ ofEPOGEN® includes a
`\'f.'f} rapid b~.matoait Napoo.se fe:g, an incruse of moro
`thn.n 4 petttntagto points rn any 2~week period), the dose of
`EPOGE.'V~ >hould be rodu«d.
`$urg1ry P•ti•nn
`Prior to i.mtia.tl.ng treatmenL with 'EPOCEN® n hemoglobin
`,:hould hl> obtained to etit.ablish ~hat iL is > 10 to s 13
`gtcU.. '" The recommended dose of EPOGEN® is 300 Unit!/
`k;'dlly subcutaneously for 10 day& befQn: surgtry. on Lhe
`day of surc:~ry. and for 4 d~ af\er surgery.
`An aUernate dose sebedulei8600UniWkgEPOGEN<Dwb-
`:~~~l:~~!~ ofu~rt'h~~ :~:~~/!r~!~},, before
`All patients ehould receive adequ&.ts in:n1 &upph.•Jruontatlon.
`Iron supplMnentation should 00 initiated no later Lhan 1ht!.
`bf.'gi:ftning of t~a.tmont with EPOCEt\® and should con(cid:173)
`tinue thnma:bout the course of therapy.
`PREPARATION ANC ADMINISTRAT10N OF EPOGENo8
`1. Do not Wke. It 1s not ftO(ft!nty to ahakc EPOCEN®.
`Prolonged vieorous &hak:in~; may denature any glycopro(cid:173)
`tein. rendering it biologically inacth .. -e.
`2. PI\J'tnterol df\l.g products shauld ~ iru;pected vitn~ally for
`particulate mt~tter ru~d discoloration prior to administra(cid:173)
`tion. Do not. use any \ials e~ibiting particulate matter or
`discoloration.
`3. Using aseptic techniqua, BtUich a sten1e needle toa ster(cid:173)
`ile t )TingEI. Removt: tbc ftip top from the vial contalnin~
`EPOGEN®, s.nd wipe the septum ""ith a d.i!:infcttant..ln(cid:173)
`urt tht n«!dle into the vial. and withdr;1w into the Sy(cid:173)
`ringe an appropriat(l ,-olume of tOlution.
`-4. . .Cingle---doae: J rnL vial C:OI'ltaina no pl"e8oCrvillivo, UK
`one dose per vial; do nol re-t-nter thfl vial. Discard unused
`portions.
`Multidose: 1 mL and 2 mL vials contain p~rvative.
`Store at 2• to a• C af\.er initial entry "nd between doses.
`Discard 21 da)'t afte,r initiaJ entry.
`5. Do not dilute or administer in conju nction with other
`dru; solution.s. Howe-.-or, at the t:i.me of SC administra·
`bOn, preservfttive-free- EPOGEN® from single-use vials
`ruy be admixed in a syringe witll bacteriostatic. o.n &O-(cid:173)
`dium ehl~ride inj«lion, USP, with benz.yl "loohol 0.9Cl(cid:173)
`~astatie saline) at a 1:1 ratio using aseptic tecb·
`ruquto. Tiu! bt!nzyl a.lrobol in the bacteriostatic !'!aline acts
`u • local .pn~sthetic which may amellarate SC irUection
`1101b1o digomfort. Admixirtg i1> not n~ry when uaing
`the multidoae viab ofEPOGEN® containing benzyl alro(cid:173)
`hol
`ROW SUPPLIED
`EPOGEN®, containing Epoetin alfa, is available in the fol(cid:173)
`lowing packages:
`1 mL Single-dose, PrKetYitlv•frte Solutian
`2000 UnitslmL (NDC 55513-126--JO)
`3000 UniWml..CNDC 55513·207-10)
`4000 UniWmL(NIJC 55513-146-10)
`10,000 lTniWmL CNDC 55513·l f4.10)
`40,000 UniWrnL (NDC &5513-828-10)
`Suppli~ in dispensing packe containing 10 ~tingle·dolie
`vials.
`2 mL Muhidose. Preserved Solution
`10,000 UnlWmL (NDC 65513·283-10)
`1 :mL Multldose, PtesetYed Solution
`2Q,OOO UniWmL (NDC 55513-478-10)
`Supplied in dispE>ns:ing packs containing 10 multidose vials.
`STORAGE
`Store at 2' to 8'" C 136" to 46" f). Do no1 freen or shake.
`
`REFERENCES
`1. Egrie JC. Strickland TW, Lane J , (!tal Chantci.('rization
`and Biologi~l Effects Q( R4?WmbinMt H~,~man El'}-thrc·
`poietin. /mmuntA>iol. 1986;72'213-224.
`2. Grabe:r SE, Knntz SB. Erythropoietin and thl' Control
`o-f Red Cell Production. Ann lku Mcd. 1978:29:51-66.
`3. Eschbach JW, Adamson JW. Anemia of End-Stage Renal
`Dlsease (ESRO). Kidney btl/. l9S5:2S:l-5.
`4. Esehbach JW, Egrie JC, Down.inl MR. el 3.1. Conection
`of t.he Anf.'min. of End·Stagto Renal Diuae-e with Reoom·
`bimrnt Human Er)'tl'lropoi.~tin .VEJM. 1987:316:73-78.
`5. Esc.hbach JW. Abdulhad.i MH. Brown(! JK. MaL Rwun(cid:173)
`binanl Human Etyt.hropotf.'-ttD m Am:m~ Patil!nt.,. .,..;th
`f:nd.Stage Rerud D1..._ Ann I• n. .Vrd. 19~;111:
`992-1000.
`6. Eo<hbo<h JW. £eno JC Oow1w\c MR.« a! Tho IJt< of
`Recoalbtnan~ Rlltll4n Erythr-opktm r·HuEPO Efr«t
`m :r;~-StAC" ~W PrHue ESRD
`lo Frilfdman,
`Bf~"f'r, O..Santo. G~ ~ ~wt. o(Ch~
`t'rtmia. Pbil&deo1pha. PA Fitld ODd Wood 1n.c, l9S9
`14~155.
`i. EgneJC, EschbachJW. ~t~mrPT ... \da.ruAOnJW. Ph.a.r(cid:173)
`mncokinl!tie1! of Rtcombmant Hutllltl'l ETythropoietm
`{r·Hu£P0l Admini.&tered to Ht-IDQc!ial)'!<is 1H01 P:~­
`tie.n~. Kidnt)' Inti. 1988;33:262..
`8. E'•nn' RW, Rader 8, Mnnn.int'n Ill., t::t l\1. The Quality of
`Life of Hemodialysis RccipWnU Tn:at<"d with Recombi(cid:173)
`nant Human Erythropoietin. JA.\lA. 1990;263:825-830.
`9. Pnganini E, Garcia J. Ems P, et al CliniC'&) Sequtlae of
`Comction of Anami.a witb &oombinant Human Eryth·
`ropoietin (r-HuEPOr. Urea Kineties, DialyzC"r Function
`-.nd Reuse. Am J Kid Dis. 1988;11:16.
`10. Delaoo 80, Lundin AP, Galansky R, et at. Dia.l~r Urea
`atid Cl1!atinine CIMtanoea Not Significantly Changed in
`r·RuEPO 'I'nmted Maintenance H~odialysis (MD) Pa·
`tient$. Kic/Jtey lnJL 1988;33:219.
`U. Stivf!lman J, VanWyck D, Og:de.o D. Use of Recombinant
`Erylhropajetin (r·Hu£P0) wilh Higb Flux Dialysis
`(HPD) Doos Not Worsen Alolcmia or Shorten A«ess
`Survival. Kidney lntJ. 1988;33:289.
`12. Lim VS, Deeo"''in RL. Zmrala D,etal. R.t-tornbinantH\.1-
`man Erythropoietin Treatment in Pre-Dialysis Patients:
`A Double-Blind Plaeebo Controlled Tril'l. A11n lnt Mtd.
`1989;110:108-114.
`13. Stone WJ, Gmber SE, Krnnt.z SB, et. aL Treatment of
`the Anemia of Pre-Dialysis Patienta with Recombinant
`Human Erythropoietin: A Randomj:a::ed, Placebo-Con·
`trolled 'niai.Am J Med Sci. 1988;296:171-179.
`14. Braun A, Ding R. Seid<'!l C, FiesT, Kurtz A, Scbarel' K.
`PhPrmacolcinetiaJ of reoombinant. humat~ erythropoietin
`applied subcut.anoous.ly to children with chronic rt>n.a\
`failure. Ptdim,. Ntpltrol. 1 993;7:61-64.
`15. Ge\·a P, Sherwood J B. Pharmacolti:notics of recombinant
`human erythropoietin (rHuEPO) in pediatric patients
`on chronic cycling peritoneal dialysis (CCPDl. Blood.
`1991;18 (Suppl 1):91a.
`16. Jabs K, CrantJR,. Harmon W. tt aL PbtJ.Tm<I(Q\Unetics of
`Epoatin alf11 (rllu.EPO) in pediatric hemodialyajs fHD)
`patieni$. JAm Soc Ncphrol. 1991;2:380.
`1i. Kling PJ. Widnes$ JA. Guillery EN, Vf.'ng·Pcd~n P,
`Peten. C, DeAlllt'COn PA-Pharmacolcin~~ and phlu'ma·
`oodynamics or ('rythropoietin during therupy in lln in·
`fanl with rtnal failure. J Ptdiotr. 1992:12l:S22-a25.
`18. dt'And~de- JR and Jove M. B~lineo Hemoglobin as a
`Predictor of Risk of Transfusion and Reipo-nae to
`Epoelin alfn. in Orthoptldie Surgery Patients. Am. J. of
`Orlhop<XL :JetK;2S (8}:633 6-12.
`19. Goldberg MA and McCutchen JW. A Safety and Efficacy
`Comparison Stu:dy of Two Dosing Jle&imens: of Epoetin
`alfa in Patients Undergoing Majol' Orthopedic SUJ'it.f)'.
`Am.. J. o(Orthoped. 1996;25 (8}:544-552.
`20. Faris PM a.nd Ritter MA. The Eff~ or Recombinant
`Human Erythropoie~in on Perioperttive TrttnsfuJ.ion
`Requirements in Patients Having a Major Orthopedic
`Ope:rat.ion. J. &m~ and Joint Surgtry. 1996;78-A:Gz.-72.
`21. Lundin AP, Akerman MJH, Chesler RM, et ::.1. Exercise
`in Hemodialysis Patients after Treatment with Recom·
`binanl Hum11n Erythropoietin. Nephron~ 1991;58;315-
`319.
`22. Amgen l1.1e., data on file.
`23. &c.bbat.h .rw, Kelly MR, Haley NR. c' et. Treatnlent of
`lhe Anemia of P~iVEI Renal Failure with Recombi(cid:173)
`nant Human Erythropoietin.NEJM. 1989;321:15s-163.
`24. The US Recombinant Human Erythropoietin PrediaJy.
`sis Study Group. Double·Biind, Placebo-Controlled
`Study of the Therapeut.it Uae of Recombinant Human
`Erythropoietin for Anemia As&OciatOO lil.'lth Chronic Re(cid:173)
`neJ failure m Prcdi:dysii P<~tients. Am J Kid D~.
`1991;18:50-59.
`25, Ortho Biologics, Inc., data on ftle.
`26. Dann.s RP, Rud.o.lck SA, Ab@.ls Rl . .£rytbrcpoietin n1er ..
`apy for the Anemia Associated with AJDS and AIDS
`Therapy and Cancer. Jn: MB Garniek. ed. Erylhropoict.ill
`in Clinical Applications-An lnternt;Jtional Pcrspcctit-e.
`New York, NY: Martel Dekker: 1990:301--324.
`27. Fi$COhl M, Galpin JE, Levine JD, et al. Rf!.combinant Hu(cid:173)
`man Erythropoietin f(lr P<1ti~n~ with AIDS 'ITeated
`w.ith Z.idO\'Udine. NEJM. /990;3:2:1488-1493.
`28. Laupaci&A Efl'ed:iv~ess Gf Perioperative ~mbinant.
`Human Eyrthropaiotin in E\{'!ctive Hip Replacement.
`Lan~L 1993;341:1228-1232.
`29. Kerr DN. Chronic Renal Faih.ire. In: Boo&on PB, MeDer·
`mott W, Wyngaarden JB, edt. C«il futboo-" of Medi.·
`tine. Ph.iladeJph.ia, PA: W.B-. SAunders; 1979:1351-1367.
`
`AMGENi!i81
`
`30 Campos A. G:;1rin f.:H. Therapy of renal anl!:mia in chi!·
`drcm and adol~nt.s v.'ith recombinant human crythro·
`poi.etin CrHuEPO,. Cli11 Ptd.1t1lr (Piula). 1992;31:9-l-99
`31. Montini G. Zacchello G. Baraldi E, el al . .8cnefiti and
`ri11ks of anemia correction with r{'!((lmbinanl human
`erythropoietin in children majnta.ined by hemodialyai.!l.
`J Ptdiolt'. 1990;U7:556-560.
`32. Offner G, Hoyer PF, !Alta K. Winkler L, Brodehl J.
`5eigalla P. One year'$ experien~ with recombinant
`erythropoietin in children uT.J.d~TgtJin&cont.inu(luS ambu·
`le.tory or cycling peritoneal dialysis. Pediatr Nephrol.
`1990;4:498-500.
`33. :\fuller-Wiefel DE, ScigaJia P. Spteific problems of rtmal
`anemia in childhood. Conlrib Nq~hrol. 1988:66:71-84.
`34 SchaJW K, Klare B. DrC$-sel P. Gretz ;.:. Treatment of
`rtna! ant"mla by wbeutanf:Ous e-1')1hropoiehn in chil·
`dtt-n .,.ilh preterminal chronic: renal railure.Acto Pt;Jedi(cid:173)
`au: 1993:62:953-95-S.
`35. ~1uell~r BU, Jaco~~n RN. Jarosinski P, ct. a!. Erythro-(cid:173)
`poietin for z:id0\-udine-as$0clated •nE!.mia in childre:n
`with HJV infection. Ptdiatr AIDS ond HTV lnfc.ct: Fttus
`toAdol~sc. 1994:5:169-173.
`.36. ZoCUitti GV, Pleb.ani A, Biasueci C, et al. Cmnulocyte·
`colony stim\llaling facklr and erythropoietjo therapy In
`childlt'n with humo.n immunodefici~:-ncy viru!J infection.
`J /rat Mtd &t. 1996~:1JS--121.
`37. Be<:k MN, &C'k D. RC"(Ombin.ant erythropoietin in acute
`chttmotherapy·induc:ed a.n~mia af c.hildrtn with rnnocr.
`.\ltd PtdjatrOnc.oL 1995;25:17-21.
`38. Bennetts G, Bertolllne S. Bray G, Oinndorl P, Feusn!r J,
`Cairo M. Erythropoietin red\lcts volumea of red cell
`tranri-osions required in some subsets or cbildren with
`aeu~ lymphocytic 1!uk(lrnia. Blood. 1995;86:85&.
`39. Rask;:n NJ{, FiEb.man IV\. Neurologic Di$0rde~ in ~1
`f ailure (fim of Two Partt). NEJM. 1976;294:143-148.
`40. Raskin NH and l''ishman RA. Neurologic Disorders in
`Rt'nal Failure (Serond of 'Two Part$). NEJI,f. 1976;294·
`2:04-210.
`4 L ).!c-ssin~o; RO, Simon RP. Sei~ures as a Manife$talion of
`Sy$teroic Di....'(>.a....:· .Vc-/lmletgj.c. Cl111iC1J. 1986;4:563-684.
`Mo.nufactul'td by
`Ar.o.gt'n loe.
`One Amg10.n Ct-ntttr Dm·t>
`'Thousand Oaks. Califomi3 9tm..1j99
`l51tuC Date: 07126199
`C 19S9-1999 Amgen. lnc. All right$ nw<e"n·C'd.
`Show11 in Product ldtllti/i«JtiOit Ot4id4', pogt 305
`
`KINERET"'
`l/<tn·4-*l
`(Anakinra)
`
`H
`
`DESCRIPTION
`Kiner"tnc (anakinra) is a recombinant, nonglycOf.}'lated
`form of the human interleukio·1 receptor ant.agonlst IlL(cid:173)
`IRa). Ki.neretn1 diff'en..fromnative human JL..lRa in lha• it.
`hM the addition o-fa Jl.ingle methion ine ret~.iduc at iu amino
`Wrminus. KinerctT'-~ consista of 153 amino acids and haa
`a. mol~lar weight af 17.3 kiladallon.s. It is produted by
`reoombinant DNA tt!chnology using an E. toli bacterial
`oxpn!Uion system.
`Kineret'M is supplied in s ingle use l mL prefilled glass sy~
`ringea with 27 gauge: needle$ as a 'lleril~, ehmr, oolor1ess·to(cid:173)
`wllilu, )ln:~Wn>lllin:-f..-...:: ...,liiLi\lu r ... daily aubcutaneou~
`(SCl odmln.istrat1on. Each l mi.. prc61led g lass syringe eon·
`taint.: 0.67 mL (100 mg) of anakinn. io o eolution (pH 6.5)
`c.o!J.taining &Odium c.itraU! (1.29 mg), &Odium chloride
`(5.48 mg), di&odium EDTA (0.12 mg), and palysorbate 80
`(0.70 mg) in Water for Injection, USP.
`CLINlCAL PHARMACOLOGY
`Kinerettw: blocks the biologic aetivity or IL-l by competi·
`tivcly inhibiting JL.l binding to the int.erle\lldn-1 type 1
`rceepklr (II,IRI), which is. expressed in a wide variety of
`li!J$u es and organs.1
`JL..1 production i5 induced in re~rponH to infi<"mmatory
`stirou.U and med.iare& various physiologic. responsos indud·
`ing inflammatory and immunological tc~ponAeS.. IJ...l has a
`broad range of Pdivities inc1udi,n& cartilage degradation by
`its ioduct.ion of the r~tpid loss of pl'Oteoglytan!;., as well u
`stimulat.iaD of bone raorplion.2 The level$ of the naturolly
`oc:curring IL-lR..$1 in lynoviurn a.nd tynovial fiui.d from rOOu(cid:173)
`m&«rid arthriti.!l (RA) patients are not sufficient to oompcte
`with the eleva tOO amount of locally produced IL-i.1··U
`Pllarm•cokinetics
`The ab&olute: bioav.t~~ilabllity or Kineret,.,.' 8.f\c a 70 mg sc
`bolus iriject.ion in healthy subjetls(n•dl) is 95~. Jn wbjects.
`with RA, mtJ..Ximum plasma concentrations of Kineret.nl oe(cid:173)
`curred 3 to 7 hours afte1' SC admmi~trati<ln ofKineret1 "" at
`clinka.lly relevant. doses ( 1 to 2 mgllcg; n "" 18); the ten:ni.nal
`half-lifa ranged from 4 to 6 hourt. lo RA patient., no unex(cid:173)
`pe«:ted aoc\lrnulation of Kinert!tJM wu observed aft.cr dalJy
`SC doses for up to 24 weeks.
`The infl.uenal of demagr8.phic covariates on the pharmaco(cid:173)
`kinetics of Kine:! ret'"" was studied using population phanna(cid:173)
`c.oldnetic an alysis encompassing 341 p~ttienl.$ receh·ing
`daily SC il1,jeetion of KineretTW at d~ of 30 "o;
`d
`150 mg for up to 24 wHu-. 1'bt- t!fC1:
`ance increased with in~1 1.1'
`
`_.
`
`

`

`582/AMGEN
`
`Kineret--Cont.
`
`body weight. After adjusting for creatinine clearance and
`body weight, gender and age were not significant factors for
`mean p)asma clearance.
`Patients with Renal Impairment: The mean plasma clear(cid:173)
`ance ofKineretTM decreased 70-75% in normal subjects with
`severe or end stage renal disease (defined as creatinine
`cloor ance Jess than 30 mUminute, as estimated from serum
`c:reotinino levels6
`). No formal s tudies have been conducted
`examining the pharmacokinetics of Kineret TM administered
`subcutaneously in rheumatoid arthritis patients with renal
`impairment.
`Patients with Hepatic Dysfunction: No formal studies
`have been conducted examining the pharmacokinetics of
`KineretTM administered subcutaneously in rheumatoid
`arthritis patients with hepatic impairment.
`CLINICAL STUDmS
`The safety and efficacy ofKineret"' have been evaluated in
`three randomized, double-blind, placebo-controlled trials of
`1392 patients ;,: 18 years of age with active rheumatoid ar(cid:173)
`thritis (RAJ. An additional foUrth study was conducted to
`assess safety. In the efficacy trials, Kine ret TM was studied in
`combination with other disease-modifying antirheumatic
`drugs (DMARDs) (studies 1 and 2) or as a monotherapy
`(study 3).
`•
`Study 1 evaluated 501 patients with active RA who had
`been on a stable dose of methotrexate (M'l'X) (10 to 25 mg/
`week) for at least 8 weeks. In addition, they had at least 6
`swollen/painful and 9 tender joints and either a C-reactive
`protein (CRP) of ;,:1.5 mg/dL or an erythrocyte sedimenta(cid:173)
`tion rate (ESR) of;,: 28 mmlhr. Patients were randomized to
`KineretTM or placebo in addition to their stable doses of
`MTX.
`Study 2 evaluated 419 patients with active RA who had re(cid:173)
`ceived MTX for at least 6 months including a stable dose (15
`to 25 mg/week) for at least 3 consecutive months prior to
`enrollment. Patients were randomized to receive placebo or
`one of five doses ofKineretTM SC daily for 12 to 24 weeks in
`addition to their stable doses of MTX.
`Study 3 evaluated 472 patients with active RAand had sim·
`ilar inclusion criteria to Study 1 except that these patients
`had received no DMARD for the previous 6 weeks or during
`the study. 7 Pntionls ' vere randomized to receive eilber
`Klneret""' Clr placebu. Patients. were DMARD·nal\re or had
`failed no more than 3 DMARDs.
`Study 4 was a placebo-controlled, randomized trial designed
`to assess the safety ofKineretTM in 1414 patients receiving a
`variety of concurrent medications for their RA including
`some DMARD therapies, as well as patients who were
`DMARD-free. The TNF blocking agents etanercept and in(cid:173)
`fiiximab were specifically excluded. Concurrent D~Ds
`included MTX, sulfasalazine, hydrochloroquine, gold, peni(cid:173)
`cillamine, letlunomide, and azathioprine. Unlike studies 1,
`2 and 3, patients predisposed to infection due tO a bistocy of
`underlying disease such as pneumonia, asthma, controlled
`diabetes, and chronic obstructive pUlmonary disease
`(COPDJ were also enrolled. (See ADVERSE REACTIONS(cid:173)
`Infections).
`In Studies 1, 2, and 3, the improvement iii signS and symp(cid:173)
`toms of RA was assessed using the American College of
`Rheumatology (ACRJ response criteria (ACR,0, ACR50,
`ACR,0) . In all three studies, patients treated with KineretTM
`were more likely to achieve an ACR,0 or hlgher magnitude
`of response (ACR,;0 and ACR,0l than patients treated with
`placebo (Table 1). The treatment response rates did not dif(cid:173)
`fer based on gender or ethnic group. The resUlts oftheACR
`component scores in Study 1 are shown in Table 2.
`Most clinical responses, both in pa,tients 'reCeiving placebo
`and patients receiving KineretTM, occurred within 12 weeks
`of enrollment.
`[See table 1 above]
`[See table 2 above]
`INDICATIONS AND USAGE
`KineretTM is indicated for the reduction in signs and symp(cid:173)
`toms of moderately to severely active rheumatoid arthritis,
`in patients 18 years of age or older who have failed 1 or
`more disease modifying antirheumatic drugs (DMARDs).
`Kineret n< can be used alone or in combination with
`DMARDs other than Tumor Necrosis Factor (TNF) blocking
`agents (See WARNINGS).
`CONTRAINDICATIONS
`KineretTM is contraindicated in patients with known hyper(cid:173)
`sensitivity to E. coli-derived proteins, Kineret"'', or any com(cid:173)
`ponents of the product.
`WARNINGS
`KINERET"" HAS BEEN ASSOCIATED WITH AN INCREASED
`INCIDENCE OF SERIOUS INFECTIONS (2o/~) vs. PLACEBO
`(< 1o/o). ADMINISTRATION OF KINERET"" SHOULD BE Dis(cid:173)
`CONTINUED IF A PATIENT DEVELOPS A SERIOUS INFEC(cid:173)
`TION. TREATMENT WITH KINERET"" SHOULD NOT BE INI~ : .
`TIATED IN PATIENTS WITH ACTIVE INFECTIONS. THE .
`SAFETY AND EFACACY OF KINERET"' IN IMMUNOSUP(cid:173)
`PRESSED PATIENTS OR IN PATIENTS WITH CHRONICJN(cid:173)
`FECTIONS HAVE NOT BEEN EVALUATED. THE SAFETY OF
`KINEREP" USED IN COMBINATION WITH TNF BLOCKING
`AGENTS HAS NOT BEEN ESTABLISHED. PRELIMINARY
`DATA SUGGEST A HIGHER RATE OF SERIOUS INFECTIONS
`(7%, 4/58) WHEN KINERET"" AND ETANERCEPT ARE USED
`IN COMBINATION COMPARED WITH WHEN KINERET"" IS
`
`PHYSICIANS' DESK REFERENCE®
`
`Table 1. Percent of Patients with ·ACR R115ponses in Studies 1 and 3
`
`Study 1 (Patients on MTXJ
`
`Study 3 (No DMARDs)
`
`Placebo
`
`(n=251)
`
`Kineretrn
`100mg/day
`(n=250)
`
`Placebo
`
`(n=ll9)
`
`KineretTM
`75 mg/day
`150mg/day
`(n=l15)
`(n=ll5)
`
`24%
`22%
`
`6%
`8%
`
`0%
`2%
`
`34%"
`38%'
`
`13%b
`17%b
`
`3%"
`6%"
`
`23%
`27%
`
`5%
`8%
`
`0%
`1%
`
`33%
`34%
`
`10%
`11%
`
`0%
`1%
`
`33%
`43%"
`
`8%
`19%"
`
`0%
`1%
`
`Response
`
`ACR20
`Month3
`Month6
`ACR50
`Month 3
`Month 6
`ACR70
`Month.3
`Month 6
`
`• p<0.05, Kineretn.t versus placebo
`b p<:0.01, Kineretn.t versus placebo
`'p<0.001, Kineret"' versus placebo
`
`Table 2. Effect of Kineret111 on Median ACR Component Scores in Study 1
`
`Placebo!MTX
`
`(N = 251)
`
`KineretTM/MTX
`100 mg/day
`(N = 250)
`
`Parameter (median)
`
`Baseline
`
`Month6
`
`Baseline
`
`MonthS
`
`Patient Reprirted Outcomes
`Disability index"
`Patient global assessment"
`Prunb
`Objective Measures
`ESR(mmlhr)
`CRP(mg/dL)
`Physician's Assessments.
`'Thnder/pninful joints<
`P)lys.idan globa! IISSC!Ssmentb
`Swollen )ointsd
`
`1.38
`51.0
`56.0
`
`35.0
`2.2
`
`20.0
`59.0
`18.0
`
`1.13
`41.0
`44.0
`
`32.0
`1.6
`
`11.0
`31.0
`10.5
`
`1.38
`51.0
`63.0
`
`36.0
`2.2
`
`23.0
`59.0
`17.0
`
`1.00
`29.0
`34.0
`
`19.0
`0.5
`
`9.0
`"26,0
`9.0
`
`• Health assessment questionnaire; 0 = best, 3 = worst; includes eight categories: dressing and grooming, arising, eating,
`walking, hygicn.c, reach, grip, and activities.
`b VISuai analog scale; 0 = best, 100 = worst
`'Scale0to68
`dScaleOto66
`
`USED ALONE. IN THIS COMBINATION STUDY NEUTROPE(cid:173)
`NIA (NEUTROPHIL COUNT s 100D/mm3) WAS OBSERVED
`IN 3% OF PATIENTS (2/58) . USE OF KINERET"' WITH TNF
`BLOCKING AGENTS SHOULD ONLY BE DONE WITH EX(cid:173)
`TREME CAUTION AND WHEN NO SATISFACTORY ALTER(cid:173)
`NATIVES EXIST.
`PRECAUTIONS
`General
`Hypersensitivity re<1ctions associated with Kineretrn ad(cid:173)
`ministration are rare. If a severe hypersensitivity reaction
`occurs, administration of 1{4l.eret"'' shoUld be discontinued
`and appropriate therapy initiated.
`Immunosuppression
`The impact of treatment with KineretT" on active and/or
`chronic infections and the development of malignancies is
`not known. (See WARNINGS, ADVERSE REACTIONS,
`Infections and Malignancies).
`Immunizations
`No data are available on the effects of vaccination in pa(cid:173)
`tients receiving Kineret"'. Live vaccines shoUld not be
`given concurrently with KineretTM. No data are available on
`the secondary transmission of infection by live vaccines in
`patients receiving Kineretrn (See Precautions, Immuno(cid:173)
`suppression). Since ;KineretTM interferes with normal im(cid:173)
`mune r.esponse mechanisms to new antigens such as vac(cid:173)
`cines, vaccination may not be effective in patients receiving
`Kineret"'.
`Information for Patients
`If a physician has determined that a patient can safely and
`effectively. receive Kineretn.< at home, patients and their
`caregivers shoUld be instructed on the proper dosage .and
`administration ofKineretn•. All patients shoUld be provided
`with the "Information for Patients and Caregivers" insert.
`While this "Information for Patients and Caregivers" insert
`provides information about the product and its use, it is not
`intended to take the place of regUlar discussions between
`the patient and healthcare provider.
`Patients shoUld be informed of the signs and symptoms of
`allergic and other adverse drug reactions and advised of ap(cid:173)
`propriate actions. Patients and their caregivers shoUld be
`thoroughly instructed in the importance of proper disposal
`and cautioned against the reus!! of needles, syringes, and
`drug product. A puncture-resistant container for the, dis(cid:173)
`posal of used syringes aboilld be available to the patient.
`The full container shoUld be disposed of according to the
`directions provided by the healthcare professional.
`Laboratory Tests
`:Patients receiving KineretTM may experience a decrease in
`neutrophil counts. ln the placeboccontrolled studies, 8% of
`patients receiving Kineretn< had de.creases. in neutrophil
`counts of at !east 1 World Health Organization (WHO) tox(cid:173)
`icity grade compared with 2% in the placebo control group.
`Six Kin_eret""·t>uted patienu (0;3%) experienced n~utrope­
`nia <ANC s 1. X !OSLLl- This is discussed in more detail in
`the Adverse Events-Hematologic Events section. Neutrophil
`
`counts shoUld be assessed prior to initiating Kineret TM
`treatment, and whlle receiving KineretTM, monthly for 3
`m!)nths, and thereafter quarterly for a period up to 1 year.
`Drug Interactions
`No drug-drug interaction studies in human subjects have
`been conducted. Thxicologic and toxicokinetic studies in rats
`did not demonstrate any alterations in the clearance or tox(cid:173)
`icologic profile of either methotrexate or Kineret"' when the
`two agents were administered together.
`Carcinogenesis, Mutagenesis, And Impairment Of Fertility
`Kineretn.< has not been evaluated for its carcinogenic poten(cid:173)
`tial in animals. Using a standard in vivo and in vitro bat(cid:173)
`tery of mutagenesis assays, KinereF>< did not induce gene
`mutations iD either bacteria or ,;,ammalian cells. In rats
`and rabbits, KineretTM at doses of up to 100-fold greater
`than the human dose had no adverse effects. on male or
`female fertility.
`,
`Pregnancy Category B
`Reproductive studies have been eonducted with Kineretrn
`on rats and rabbits at doses up to 100 times the human dose
`and have revealed no evidence of impaired fertility or harm
`to the fetus. There are, however, no adequate and well(cid:173)
`controlled studies in pregnant women. Because animal ·re(cid:173)
`production studies are not always predictive of human re(cid:173)
`sponse, Kineref"" shoUld be used during pregnancy oilly if
`clearly nseded.
`Nursing Mothers
`It is not known whether KirieretTM is secreted in human
`milk. Because many drugs "1'e secreted in human milk. cau(cid:173)
`tion shoUld be exercised if Kineret n• is administered to
`nu;sing women.
`Pediatric Use
`The safety and efficacy of Kineretrn in patients with juve(cid:173)
`nile rheumatoid arthritis 1JRAJ have not been established.
`Geriatric Use
`A total of 653 patients ;,: 65 years of age, including 135 pa(cid:173)
`tients ;,: 75 years of age, were studied in clinical trials. No
`differences in safety or effectiveness were observed between
`these patients and younger patients, but greater sensitivity
`of some older individuals cannot be ruled out. Because there
`is a hlgher incidence .of infections in the elderly popUlation
`in general, caution shoilld be used in treating the elderly.
`This drug is known to be substantially excreted by the kid(cid:173)
`ney, and the risk of toxic reactions to thls drug may be
`greater in patients with impaired renal function.
`
`ADVERSE REACTIONS
`The most serious adverse reactions were:
`• Serious Infections - see WARNINGS
`• Neutropenia, partiCularly when used i:O combination
`with TNF blocking agents - see WARNINGS
`The most common adverse reaction with Kineret.,... is injec(cid:173)
`tion site reactions. These reactions were the most common
`reason for withdrawing from studies.
`
`(nformatio.n will be superseded by supplements "!!d subsequent-editions
`
`

`

`PRODUCT INFORMATION
`
`Na.,...
`&eause elinieal Lrials are oonducted under widely varying
`Dia.rrhe-.
`and contru1led oonditiona, ad'o'C!r&e read:ic" ratas ~~
`Sinusitis
`in din~! tNJ.s of <1 Wv.g caru:tot be dired.ly QOmpared W
`lnfluenza.lJke
`rates in the clinical trials of another drog Md trn~.Y not pre(cid:173)
`did the rat.ea observed in a broader patient population in
`Symptoms
`Pain Abdominal
`clinical practice.
`The data de&rribed herein reflect exposure to Kineretn. in
`2606 patient.s, including 1812 exposed for at least 6 months
`and 070 exposed for at least one year. Studiea 1 and 4 used
`!.he recommended dose of 100 mg per day. The patients stud(cid:173)
`ied were reprHe.nt.ative of the geoeral population of
`patients with rheumatoid !il:rth.ritit..
`lniec-tion-5ito Reaction$
`'f'ho m6at. cornmoil ud consistently reported treat-ment,.
`related adverse event associated with Kineret.'"" is injection·
`site reaction (ISR). ~ m~rity of ISRs were repcrt.ed as
`mild. 'These typically lasted for 14 lO 28 days a11.d were char(cid:173)
`acterized by 1 or more of &be following: erythema, ~o­
`Ils, i.Ddammation, and pain. l.D Studies land 4, 71'itt of pa(cid:173)
`tients develo~ an ISR, whieb wu typically rcporU!d
`within the tii"Sl4 weeks of therapy. The develop