(cid:9) (cid:9)
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`EDITION
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`PDV
`55
`2001
`YS C ANS'
`
`RI- NC
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`

`

`(cid:9) (cid:9)
`
`174n'
`
`a
`
`UGC Itorutren". 11J0.1
`
`5
`
`aarleratand that TUALOMID® (thalid-
`omide) will be prescribed ONLY for nief.1
`Must NOT share it with ANYONE, even
`someone who has symptoms similar to
`mine. It must be kept out of the reach of
`children and should never be given to
`women who are able to have children.
`I have read the THALOMID® (thalido-
`mide) patient brochure and/or viewed the
`videotape, "Important Information for
`Men and Women Taking THALOMID®
`(thalidomide)". I understand the con-
`tents, including other possible health
`problems from THALOMID® (thalido-
`mide), so-called "side effects". I know that
`I cannot donate blood or semen while tak-
`ing THALOMID®(thalidemide).
`
`7. My doctor has answered any questions I
`have asked,
`I inidercianel that t moot participate fn ci
`wormy and liationt registry while I am an
`THALuammob thalidomide!, which will
`require soinpleting additional Forms.
`
`__--.
`Authorization:
`This information has been read aloud to me in the lan-
`guage of my choice. I understand that- if I do not follow
`all of my•doctor's instructions, I will not be able to re-
`cefire TeA-Lomux,P (thalidomide). I now autliarize my
`'death. to begin my treatment with THALOMID®
`(thalidomide).
`
`Patient Name (cid:9)
`(please print) (cid:9)
`
`Social Security No, (cid:9)
`(Only last six (cid:9)
`digits required)
`
`Date of Birth
`(mo./day/yr.)
`
`•
`Date
`Patient, Parent/ (cid:9)
`(mo./day/yr.)
`Guardian Signature (cid:9)
`1 Iowa fully explained to the patient the nature, pur-
`i ace. and risks of the Dosienont descrthed abase. ceps-
`1
`':113y the risk. to ...meen of ehildhearing poteatioi (cid:9)
`lays a_altad the psionl. If sborhe bee any guardians re-
`garding kwilia.14 Lh.mt111411it With TISALOMIDIE.ithalida.
`hadol and htnye anoWened Lbose menstiorio In Lk beat of
`aof niiihty..1 will enauro Linn lho iippropne be tempi.
`Hr: nit of the potash consent harm mu encaptetrat (in ad-
`ildim3, I wilt comply with all of nay obliotioria mid rt.
`if cinaibilitleS as a prescriber registered under the
`S Fe PR " restricted distribution program.
`
`I rtorizmit Name (cid:9)
`IPl.aia' print)
`
`Physician Signature (cid:9)
`
`DEA No.
`
`Date
`(mo /day/yr.)
`
`REFERENCES
`1, ;Inman JM. 1986. TeatrAtMicity. Cassarett and Doull's
`Tbilealogy, The Basic Siciegge of Poisons. Third Edition.
`Pages 195-220. New York: MacMillan Publishing Co.
`2 Smithels 11W and Newman CG. 1992. J. Med. Genet.
`29(10):716-723.
`3. Sampaio EP, Kaplan G, Miranda A, et a/. 1993 J. Infect.
`Dis, 168(2):496-414.
`4. Sarno EN, Crag GE, Vieira LM, et a/. 1991. Clip. Exp.
`Immunol. B4:10-108.
`5. Sampaio EP, Moreirit AL, Sarno EN, et al. 1992. J. Exp.
`Med. 175:1729-1.737.
`6. Nogueira AC, Neubert R, Helge H, et a/. 1994. Life Sci-
`.1tIon 5f42):7742.
`7. JOMILif.bri 311131, Greenspan IS, Surataler J, et at. 1997.
`Near If
`(cid:9) J. 14.841 3361215. 1481- 1493.
`8. Scltunurker IL, Smith Rt. acid Warms RT. 1965. Br. J.
`Phareisoil. 25:324-337.
`9 lyer CGS, laingudlon J, Rarnanujam K, et al_ 197L Bull
`WHO. 45:719-73
`10. Sheskin J and Convit J. 1969 Intl. J. Leprosy 37:135-
`146.
`II. Waters MFR- 1971 Lepr. Rev. 42:211--42
`alitehli shed dais. on file et rebonic
`ItALPI.00.1 11191 CO
`Shown in Product Identification Guide, page 310
`
`For EMERGENCY telephone numbers,
`consult the Manufacturers' index
`
`Centocor, Inc.
`200 GREAT VALLEY PARKWAY
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`Direct General Inquiries to:
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`For Medical Information/Adverse Experience Reporting
`Contiget
`Medical Information & Product Surveillance
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`Fax: (610) 651-6197
`
`REMICADE®
`INFLIXIMAB
`recombinant
`For IV Injection
`
`DESCRIPTION
`Rl7MICADElh linfftxsrnab1 as 9 thimatic 101_ monockined
`iintiloody with an app atomic molecular wraght of I 49,1 Oh
`clultisret. It it tote posed of human eanotant and entwine yeti-
`alik regions. I niikeimah koala epeorleally to human tumor
`nocroal factor alpha !INN I with nn aaaricintio.ti cunatani or
`101a Ml. Inflict mob m produced I.y a remonliiriont cell Imo
`cultured by continuous perfusion and is purified to a seises
`of steps ihnt includes lematitiPts to inactivate and rentrem
`viruses
`ill.:11.1/CADES it supplied an a sterile, oleic, lymph liked pees.
`tier for intrmuutem isquition Pohewlag meows/Z/31am' 'with
`10 ml.„ of Sterile Water far Injection, UST, the resulting 01
`to APPrbitl ritOtt4- 1,Z KttCh single-sae suck contain+ 100 mg
`milisiinah., 500 Pig .iAer1121C. 0.11 nig pollyntarbote VC 2.2 ling
`inonahnsic esdlunh plrmephntas and 6.1 mg dibasic. isudiurn
`phospliate Na pre a.rvatrere era present.
`CLINICAL PHARMACOLOGY
`General
`Infliminab neutralizes the biological mai city of TNE'33 by
`Laricling with Kiel affinity to the sobiblti and i-ranemem-
`',mine lama ofitilto and inhibits bindinn of l'Nh'w with ifs
`recupthru-14 latliviemb dicer not neutralize T111,0 (tymptio.
`toaln 0), a related al-bikini, that utilizes the same compiling
`A. TN rrr. Piolpimat selaeities ottribtakii 7141-,0,
`induction of pAelnlignunatury eyirdimmi with as (cid:9)
`rind
`11..-6. enhancement of truliseytrinigrotion by increasing en-
`dothelial layer ponneebility and 03qtrussiiin of atilleRil}11
`muitamlus by endothelial rolls and leukocytes, activation of
`rientruPlial and tositielfini hushl,iunal ANAttLy.
`r
`!MAK-MP. of
`gleam (.11.1.4 nisi-Uinta and other liner premiss, as well as
`tissue degrading enzymes produced by FyIlLiViticirted .1111.1165r
`dimwit trrylVA Cent expressing Liratikibmithrryit{, TNRI
`Icy Iry fliXiillab MI he !peed te. tope by complemaiir. or
`effector teas = 1nAuxrrwole Jeththut4 (cid:9)
`of
`TNE0 tit a wide-variety of in Mira bioasaoys unitising human
`fehroblasts. endothelial cells, urn nhlrltilcS Band T lymph*.
`true* and epithelial colds. Antl•THrn Antilxklittit reduce dia.
`el19e activity in the cotton-top tamarin colitis modal. and de-
`cream synavilaa and joint erosions in a marine model of col-
`lagen-induced arthritis Infliximab prevents disease in
`transgenic mice that develop polyarthritis as a result of con-
`stitutive ratarmaion of lie:Main (cid:9)
`and, when adminis-
`tered after dEneese onset, Ohms eroded prints to boil.
`Pharmacodynamics
`Elevated concentrations of TNFa have been found in the
`joints of rbAtiroatoid arthritis patiants' and the stools of
`Crohn's dimmea patients' and rnrralate with elevated dis-
`ease activity. In Crohn's disease, treatment with REMI--
`i'.:ADE rodured infiltration of hi tiammatary cells mid VIPo
`ill (cid:9)
`arow.,.4 the intesneo and reduced
`the proportion of iilmonticIVAT toils from 110 ilinlitial44.1-Lh
`ethic h3 oklooks TN.F.,, amd inlet-Woo p 0 In rheumatoid an
`thrill., treatment with RE.MICADS reduced indlteration of
`mtlatn rant nry. T.41.1711.11,70141111.Pri areas brii.p.”35,.ps-skpil aA
`expression dr mdidcdiv.R mediating cellutor Rahman iti
`sisinctut, inierrnhelnr adhesion maleene-1 tltlAN1-1 1 and
`rS11 (cid:9)
`.1.0.1M.1 11C.- 4Viflikkl- ILL theme...Utile
`▪
`lmn Initerleukin 8I IL-81 and iminottyth rhomirinatie protein
`tide`,!'-III KIWI !Mile itigirmidt.init
`UMW', I mid (cid:9)
`After treatment with fIXtvIKADX.,
`Monts wrih Cnthn's disease or ettemontoid arthritis exhrh•
`Sind detretiaed Ineela nl Sends' inteslouluii G (IL-ID and C.
`,eactirn pride ia WW1 l enipared Lo baseline. Peripheral
`Mood lyinpistitytes hum REM IC.ADK-trenind pniterila
`allowed sue ingnEficant dmerase in number Or Lh praibfft0t,lin
`trAilt.trtitTi to se cello fitikilpifiit ttrri.maybegt osiwn vampu,74E41,
`u. rvIls fturg eumemed pedients.
`Pharmacokinetics
`Single inirmemehis infusions of 1 to 20 mete showed a pre-
`dictable and Poem relationship between Iles dose adminis-
`tered and the maximum serum concentration and area un-
`der the concentration-time curve The volume of distribu-
`tion at steady state was independent of dose and indicated
`that in fliX1rnah was distributed primarily within the vascu-
`lar compartment. Median pharrnacokinetic results for the
`
`Cbttl•ttil.1.11-5/lUblb
`
`recommended doses of 3 mg/kg in rheumatoid arthritis and
`5 togflig (cid:9)
`Crchnh disease indicate flint the terminal hear•
`firm a< iniliainuth is KO to 9.5 don
`Lrellowieg a0 lnitlaI shoo of FLEHICADE, nspueltml infiniinres
`In 2 and 8 week* in fistittaing Crohnh disease mid rhu:uma-
`teid
`(cid:9) resulted in predioabtecancentrritilin,
`time Maim ifellecing each treatment. No systemic aces-
`EmbLian of iniliximah occurred Anon continued tviaffetod
`treatment with 3 nigtkg ar ]u ng01.2 at 4• or 6-week inter-
`vals in theurnatuid arthnlie pa bents or patient/ with mud-
`ernte ur IFtiVtDELCruhn;i dicerien mingled with 4 infusions of
`10 ingirdi REMIGADB et 8-week izit.ervels. No maim differ-
`ences in elearatellO or volume or distribution ware obacrved
`in pat-Coot subgroups defined by age or weight It is not
`known if there are differences in clennt ace or volume of dis-
`trkbutiun between gender subgroups or in patients with
`sacked impairment of hepatic or renal function,.
`CLINICAL STUDIES
`RheuMatoid Arthritis
`The safety and efficacy of RINK:AUK wherigivrat in con-
`junction with methotresnie fletTX1 were assemed in a mul-
`ticenter, randomised, doable-blind, pliteolsentiorrollial study
`dr 420 patients with netioe rheumatoid arthrilea (cid:9)
`Jan
`treatment MA kin Uth,5 Anti:INF Thal in Rltrumnioid A:-
`thrika with COrtnintitiltil Therapy lir grrnerr) Th,
`diba Age of patients erirtiliM was of years; with a maths',
`dnrneirm of abeam! of .8.4 pram and n median numbs!' of
`swollen and tender joints of 25 anti 31 respectively All pa-
`tients were to Inima received MTX fur 6 monasia sod be on
`it Math. dome > VIE mighurnk for 4 tletifikA Millais study. All
`NEMICADK nlnet placebo crimps continued their Jitable dose
`f MTX and folic acid.
`In addition to (cid:9)
`patient. received placebo, 3 meg; or II
`mg/kg of REMICADE by introveresna infusion at week.. 0, 2
`arid 0 Futlint.N1 (cid:9)
`infklaWaliE every four or meld
`weeks thereafter. Concurrent mount arshie dives of nrn) not.
`ticosteroids (10 mg/day) and/or nonstetoidal anti-inflamma-
`tory drugs was also lat-rmitted. The primary endpoint was
`the proportion of patients at week 30 who attained an im-
`provement. In .aigii% and symptoms es measured by the
`American College of 112.131kuhmtningy cnMrho, (ht K 297. An
`KR 243 niltponue is ditfma,i1 m.., at kens'. 5 20). ltriprovemant
`ii. boll" tender and awehen Joint immix Anil in 3 of the ful-
`hitting 5 Criteria iihynicioh global usossoinonl., patient
`global acenuenient...Ilinctmoolidisakility mostuint visual mu-
`11-102 pain stole nett erythrocyte serlinimitation rare (P;SR) or
`CRP
`At week 30, 41f1.16 (50%1 Dr patieitts Minded every 8 ,orelts
`with 3 mg/kg r.f TIEMICAUR plus hIr% idinmed an ACII 20
`ntivosinit with 1./1i41 120114 of pbtieszitst.hrtilitaitASSifilteebo
`plug iirrIfp<0 [3011. H.gIwr dose...ad/or more I-m.1cent ad-
`enlelltrattetill did had fetid( in higher rimponse rates. Re-
`sults are sh.urh In Pilger° 1.
`
`Weeks
`
`-0-- Placebo -0- 3 mgAg g 8 was -0- 10 mg/kg pit Wu
`3 nnykg q was --M- 10 rng/k8qi
`009584111 received concomitant rnethot‘exate
`
`Fi ure t. Percentage of Patients who Achieved an ACR 20
`
`Al weelt 30, Lite MICR '/5L response Wax 2741i for
`troaled with 3 mg/kg ItSMICADFC (cid:9)
`unary
`weeks plus MTX, compared in 5% fur 13041Dntm til.ani with
`placebo pica MTX C11,00011 The ACE 711 rospaiher wan 84:•
`For itilJtarl2i tinned with in morilig REMICADR every
`weeks Rini, AfrAl (cid:9)
`treated with 1141164.s
`phis MTX. l'atielt. remising 3 mew (cid:9)
`every 8
`weeks derocastrartail iniperior ainniostenreeri in all
`spouse componentsexcept HAIl compared to patients
`treated with platelie plus MTX noble 1). Data on use of
`REMICADE without concurrent MTX are limited (see PRE-
`CAUTIONS, linmuitogenicity)7 -8
`(See table 1 at top of next pagel
`Active Crohn's Disease
`The safety and efficacy of REMICADE were assessed in a
`randomized, double-blind, placettweattirelled dose macaw
`siody of 108 fordien is with modernittlAtartwere artireCrolsoh
`tinlwasel Plprter's Disease Activity hinters [CDh ll
`
`27g CNA All pniemila haul experienced an inadequate re-
`SpOialt lu print tonnrotinnui (cid:9)
`rikplet,
`1110'S nr palatal lot 5-aniinownlicylsot-if5-ASA' (60561
`a mike fl-mercaptopurineirvnthiotaine (cid:9)
`ki NAZI%) CM& k
`Oirltli11111111 nix of stable demr ntlipgierrie 4f cprIA-vallarytEht
`42A wan pOrrlitIA and 92% el palmist..
`0,11tiii and to motive n1 haw +PM' of 1111.,L. mwitratrnna
`The study was divided into three phases. In the first plinire,
`patients were randomized to receive a single intravenous
`
`Continued on next page
`
`Consult 2001 PDRa supplements and future editions for revisions
`
`(cid:9)
`

`

`1086/CENTOCOR
`
`PHYSICIANS' DESK REFERENCE®
`
`Remicade--Cont.
`
`Table 1
`
`MEDIAN VALUES AT-BASELINE & WEEK 30 FOR ACR COMPONENTS
`,
`S MAI j 13 arita
`REMICADE + MTX
`Baseline
`30 weeks
`32
`12
`19
`9
`3.8
`7.0
`6.1
`2.6
`6.6
`3.6
`1.8
`1.5
`3.1
`0.8
`40
`24
`
`Placebo + MTh
`Baseline
`30 weeks
`24
`16
`19
`13
`6.7
`5.9
`6.5
`5.0
`6.2
`5.5
`1.6
`1.5
`3.0
`2.3
`39
`35
`
`Parameter
`No. of Tender Joints
`No. of Swollen Joints
`Pain°
`Physician's Global Assessment'
`Patient's Global Assessment'
`Disability Index (HAQ)b
`CRP (mg/dL)
`ESR (mm/hr)
`
`II VI dose at pi sieetie, 5 10 et 30 o.gfog of RfalIC,ADE The
`primary. EL)1111A11111. WAR the proportion of patients who erne
`rinnosrl (cid:9)
`response, defined se a decrease fn CillAT by
`rs70 paints from baatelino at the 4-week evnluation and
`without are increase in Crishri's disease rardientiumi Or our.
`gory for Crohn's disease. Patienix who roNsanded at wnek-4
`were followed to week 12_ Secondary enclptaintli included the
`proportion of patients who were in clinical FOIII19131)011 at
`week 4 (CDAI .c1.66), and clinical respaisne over time.
`At week 4, four of twenty-fiVe (16%) of the placebo patients
`achieved a clinical responsevs. twenty-two of twenty-seven
`t92 ,t gr thin patients receiving 6 Inev'kg RENWAPH
`Ip c 0.051, oisessislkid, Fiukor's Enact teed. One of lwvaLy-
`five NV placebo Iuollanln and thiptaan sf twenty-Revco
`(4) patients reeeiving 5 regikg IIHM.ICA111-', believed a
`...15q et week 4. The MIESEILIUM respCnne to any doge
`C (cid:9)
`of REMICADE was observed within 2 to 4 weeks. The pro.
`portion of patients resptindisig etadualip thrainisbeti truer
`the 12 weeks of the evaluation period. There wins MS evi-
`dence of a dose response; doses higher than 5 mg/kg did not
`result in a greater proportion of responders. Results are
`shown in Figure 2
`
`• Weeks
`
`-0- Placebo Ins 25) (cid:9)
`-o- 5 mpAg (n e 27) (cid:9)
`
`rreirski In = 2a3
`20 my% (n e 26)
`
`Figure 2. Response WO paint decrease in COAT) tea Single
`IV REMICADE or Placebo OM.
`
`During the 12-week period following infuenna patients
`treated with REMICADE compared to plecuto demon-
`strated improvement in outcomes measured by the Inflarn-.
`contory lineirel Disease Queolionnaire.
`In tole sersitel please, 28 patients who did not respond to the
`Eli ALIO dose of fr, 10 or 20 mew of FiEllilICAIM &nitro& the
`AsteikeLl h single ID eseplui dose of
`upon label 'Anse (cid:9)
`Ton of twenty.
`TtEldlf:AllE 4 weeks atter 0.1n1 (cid:9)
`nine (34%) patients experienced a response 4 weeks after
`receiving the wound dose.
`Patients who remained in clinical response at week 8 during
`the first or second phase were eligible for the retreatment
`phase. Seventy-three patients were re-rondornixad et week
`REM-CADE
`12 to receive 4 infusions of placebo or 10 (cid:9)
`at 8-week intervals (weeks 12, 20, 28, 36) and were followed
`to week 48. In the limited data set available, no significant
`differences were observed between the REMICADE and pla-
`cebo re-treated groups.
`Fistulizing Crohn's Disease
`The safety and efficacy of REMICADE were assessed in a
`randomized, double-blind, placebo controlled study of 94 pa-
`tients with fistuliting Crebn'a &Pease with fistula(s) lbak
`were of at least 3 months duration.° Concurrent use of lia-
`ble doses of corticosteroids, 5-ASA, antibiotics, MTX, 6-MP
`and/or AZA was permitted, and 83% of patients continued to
`receive at least one of these medications Fifty-two (55%)
`had multiple cutaneously draining fistulas. 90% . of patients
`had fistula(s) in the per ional area and 1.0% bed abdominal
`fistula(s).
`Patients received 3 doses of placebo, 5 or 10 mg/kg REMI-
`CADE at weeks 0, 2 and 6 and were followed up to 26
`weeks The prime ry tunIpernt (cid:9)
`rrropoltilari
`who ralivnrnrr I a of !rural response, 111)111111.1 110 a-511)4 1.011194-
`600. from butioilec 111 the number of fi suila Col draining upon
`gentle compression, on at team. two rands-cutive *Wait. *die
`out an increase in medication or 6140010/ for .C.:ralialc dis-
`ease
`Eight of thin-p.-6m kzelo patients in the platefw erg
`achieved a clinical response vs. twenty-one of the thillY•cencr
`(116.9.1 patients in the 5 RIAU ftEMICADE. R1-1111) ly 0110),
`two.eided, Fisher's Exact Wall. Iiiglkeeen of LhirLy-two (66%)
`patients in the 10 mitrkg arm achieved a clinical 1)A1101.1667.
`The median time to onset of revalue in the REMICADIF.-
`treated group was 2 weeks The median duration of re-
`sponse was 12 weeks; OILS, 22 weeks there W11.6 no difference
`between either deer of izEmienng and placebo in this pro•
`portion of io.iltonts in nelfionse (Figure 3). New fintubifs) de-
`veloped in approximately( 15% of loth REMICAIW nut pla-
`cebo-treated patients.
`ISito figure 3 in next column]
`Stern of sixty (12%) evaluable REMICADE-treated pa-
`tients, cool purl to unc of thirty 011)0 3.50..1 placebo-treated
`patients, dovelapod an akottsii m Lhc area of Rawlins be-
`tween 6 rind 10 week. miter the Ind 0111101.00 of REmicAnr,
`Six of the REMICADE patients who developed an abscess
`had experienced a clinical response (see ADVERSE REAC-
`TIONS, infections).
`
`Visual Analog. Scale (.0.3liott, 10awor5H
`b Honfth Aegessment Quattionnoire, measurement of 8 categories: dressing and grooming, arising, eating, walking, hy-
`giene, reach, grip, and activities
`
`
`no
`
`75
`
`F
`if
`
`of (cid:9)
`week o 7 (cid:9)
`InkWon
`
`1 (cid:9)
`
`
`16 (cid:9)
`
`14
`
`Norio -4- wets (cid:9)
`Atwal•J
`Figure 3. Response Ifistula(s) donirel wilh Three Doses of REMICAOF
`Onniximabi or Placebo.
`
`Dose regimens other then closing at weeks 0, 2 /11111 6 have
`not been studied. Studio' have wet beep done to assess the
`effects of REMICADE on healing of the internal fistular ca-
`nal, on closure of non-cutaneously draining fistulas (e.g., en-
`tore-enters), or on cutaneously draining fistulas in locations
`other than perianal and periabdominal.
`INDICATIONS AND USAGE
`Rheumatoid Arthritis
`in manination with methotrexate, is indi-
`cated for the reduction in signs and symptoms of rheuma.
`told arthritis in patients who have had an inadequate re-
`sponse to methotrexate.
`•
`Crohn's Disease (cid:9)
`REMICAbirrs indicated for the reduction in signs and
`symptoms of Crohn's disease in patients with moderately to
`severely active Crohn's disease who have had an inadequate
`response to conventional therapy.
`The safety and efficacy of therapy continued beyond a sin-
`gle dose have not been established (see DOSAGE AND
`ADMINISTRATION).
`REMICADE is indicated for the reduction in the number of
`draining enterocutaneous fistulae in patients with fistulis-
`ing Crohn's disease.
`The safety and efficacy of therapy continued beyond three
`doses have not been studied (see DOSAGE AND ADMIN-
`ISTRATION).
`CONTRAINDICATIONS
`REMICADE should not be administered to patients with
`known hypersensitivity to any marine proteins or other,
` of the product.
`
`WARNINGS
`RISK OF INFECTIONS
`SERIOUS INFECTIONS, INCLUDING SEPSIS AND FATAL IN-
`FECTIONS, HAVE BEEN REPORTED IN PATIENTS RECEIVi
`ING TNF-BLOCKING AGENTS. MANY OF THE SERIOUS IN=
`FECTIONS IN PATIENTS TREATED WITH REMICADE HAVE
`OCCURRED IN PATIENTS ON CONCOMITANT IMMUNO-
`SUPPRESSIVE THERAPY THAT, IN ADDITION TO THEIR
`CROHN'S DISEASE OR RHEUMATOID ARTHRITIS, COULD
`PREDISPOSE THEM TO INFECTIONS. CAUTION SHOULD
`BE EXERCISED WHEN CONSIDERING THE USE OF REMI-
`CADE IN PATIENTS WITH A CHRONIC INFECTION OR A
`HISTORY OF RECURRENT INFECTION. REMICADE SHOULD
`NOT BE GIVEN TO PATIENTS WITH A CLINICALLY IMPOR-
`TANT, ACTIVE INFECTION. PATIENTS WHO DEVELOP A
`NEW INFECTION WHILE UNDERGOING TREATMENT WITH
`REMICADE SHOULD BE MONITORED CLOSELY. IF A PA-
`TIENT DEVELOPS A SERIOUS INFECTION OR SEPSIS,
`REMICADE THERAPY SHOULD BE DISCONTINUED Isee
`ADVERSE REACTIONS, Infections).
`Hypersensitivity
`REMICADE has been associated with hypersensitivity re-
`actions that vary in their time of onset. Most hypersensitiv-
`ity reactions, which include urticaria, dyspnea, and/or hy-
`potension, have occurred during or within 2 hours of inflix=
`imab infusion. However, in some cases, scrum sickness-like
`reactions have been observed in Crohn's disease patients 3
`to 12 days after REMICADE therapy was reinstituted fol-
`lowing an extended period without REMICADE treatment.
`Symptoms associated with these reactions include .fever,
`rash, headache, sore throat, myalgias, polyarthralgias,
`hand and facial edema and/or dysphagia. These reactions
`were associated with marked increase in antibodies to in-
`ffiximab, loss of detectable serum concentrations of REMI-
`CADE, and possible loss of drug efficacy. REMICADE
`
`should be discontinued for severe reactions. Medications for
`the treatment of hypersensitivity reactions (e.g., acetamino-
`
`phen,tions)_ antihistamines, corticosteroids and/or epinephrine)
`should be available for immediate use in the event of a re-
`action (see ADVERSE REACTIONS, Infusion-related Rear.
`
`PRECAUTIONS
`Autoimmunity
`Treatment with REMICADE may result in the formation of
`autoantibodies and, rarely, in the development of a lupus.
`like syndrome. If a patient develops symptoms suggestive of
`a lupus-like syndrome follqwing treatment with REMI-
`CADE, treatment should be discontinued (see ADVERSE
`REACTIONS, Autoantibodies / Lupus-like Syndrome).
`Malignancy
`Patients with long duration of Crohn's disease or rheuma-
`toid arthritis and chronic exposure to immanosuppressant
`therapies are more prone to develop lymphomas (see AD-
`VERSE REACTIONS, Malignancies/Lymphoproliferatiue
`Disease). The impact of treatment with REMICADE on
`these phenomena is unknown
`Immunogenicity
`Treatment with REMICADE can be associated with the de-
`velopment of ant.ilsodiss to inflisiniab (also re:torrid to as ho-.
`man noliclikostric Antibodies, L!ACA). One Ineadrid thirty-
`four of the 199 Crohn's disease patients treated with REMI-
`CADE were evaluated for the development of infliximab-
`ktieriliC antibodies; 18. (ps} were antiliody-pesitiva (the
`majority at iner titer, <1.261. Patients who war, antibody-
`positive were more likely to experience an infusion reaction
`(see ADVERSE REACTIONS, Infusion-related Reactions).
`Antibody development was lower among rheumatoid arthri-
`tis and Crohn's disease patients receiving immunosuppres-
`sant therapies such as 6-MP, AZA or MTX. With repeated
`daring of REMICADE, serum ultinintratices of infliximab
`Wee tlie1e7 in Thenntatoid arthettik patients who received
`concomitant MTX_ There are limited data available on the
`development of antibodies to infliximab in patients receiv-
`ing long-term treatment with REMICADE. Because immu-
`nogenicity analyses are product-specific, comparison of anti-
`body rates to those from other products is not appropriate.
`Vaccinations
`No data are available on the response to vaccination or on
`the secondary tranansiasion of infection by live vaccines in
`patients receiving Niiti-TNF therapy. It is recommended
`that live vaccines not be given concurrently.
`Drug Interactions
`Specific drug inter...Awn etodies, including inters-Aeons
`with Pittli, hove not been reminded. 'rho oviparity of pa-
`auntie in rhitamehoed aethritip Cr n1-101llililt1O6OAC 44nicA tri-
`als received one or more concomitant medications, In rheu-
`matoid arthritis, concomitant medications besides MTX
`were nonsteroidal anti-inflammatory agents, folic acid, cop
`ticosteroids and/or narcotics. Concomitant Crohn's disease
`medientione Were antibiotics, antiviralo, corheontisroids,
`6-P4PIA44 god aminosOlioylates. Patieate with f:rolni's dis-
`ease who received immunosuppressants tended to experi-
`ence fewer infusion reactions compared to patients on no
`immunissupprwtenets (see PRECAUTIONS, fiumariegtor,
`y rhi 4 ADVERSE REACTIONS, Itifusion. eridftd tune-
`1
`
`lions).
`Cseeinegiittesis, litulegeriesis era) Inuteirratinf of Fesillillt
`I eing".7101 111)4Les rn imsbutb: lame nil hash 16114)101014 to
`es. ))10,17. the ciiroinocenir peteni la I 141.1)4704.001/Alt or MAO
`genic effect, of inftieimah were observed in the urn atb
`;Ram,. is renuclets teat alt the Setirrioneau Egan-1.1{11..0"j'
`(Arn.m) (cid:9)
`renpa.ilveln, C111161111As:6111111 alle)1-1-11")0111. 4ta
`1101 111010rVisd 111 on annoy tscrfurinod icing 1-ALMAII iymrbe-
`-quiz. It t. nod kotro)h whether in IhSiniall CAll MOIL{ refl 11
`My In humans No unspriarmeni of fertility was observed 10 '
`fertility And general reproduction toxicity 'Rudy colder"'
`mire came an annlocans antibody that selectively
`its the functional activity of mouse TNFei.
`ProgitinCir Cowan,/ C
`S11110 tanixi11111.1n t100)1 user incur-easel WAIL THE. ilk r•Pr"lr''
`ether than humane owl rittinpitgisek tintritsil re1rudtte0
`titedIstA have owl bens ietikthictini with R DECADE fi.41,
`metal It Pt real known whether ItRMICADR rap cause fdJ
`harm when mbrikok*IRd lea PrOPOIll WOM011 rev Gill J11":„.
`reproduction rnpecity whir iniliaimali err present JO
`serum leant f,l.INfCAL il.rARNACYILOG Y,
`'tai liF,M/ChliEtliould tic 'men le a prelfhtuft womartradf
`if elrarly 11,41)61 Ne diettitiote of maternal Ion"e ty.
`tonicity or lerallogensity 111'.1A 1111671-14)11 an (cid:9)
`110W,1.41LM"
`
`Information will be superseded by supplements and subsequent editions
`
`(cid:9)
`

`

`wfulucitni in mice using an analogous anal':
`rued ely inhibits the functional activity of-
`miaow
`Leo reli.
`
`n (cid:9)bait 11'14
`au whether infliximab is excreted in human
`d sy.surniirally after ingestion. Because
`ofd.bidine are excreted in human
`nl (cid:9)
`'t
`Eraisse of the potential for adverse reactions-in
`lad fop, from REMICADE, a decision should be
`te discontinue nursing or hi discontinue the
`irw.• wow pn. account the importance of the drug tothe-
`
`• „ (cid:9)
`— (cid:9)
`
`
`
`
`i▪ • iw (cid:9)
`
`
`
`•FPC":1 andijir c„ay.reeys of REMICAD13 in poLidaui with kJ-
`
`_gem•
`Pedintcle petients with
`Frail, recur. hid arthritis end (cid:9)
`:
`
`,O dy (cid:9)
`coj.ths
`diffciimices were observed
`511101.y. (cid:9)
`Arnoi
`la the
`ce alder
`ril.xtivvnrrs++r a.' [sr yin rho, 7t vu (cid:9)
`y5ll ,,r1 p-11,enf., In Crulm's disease ritudies,
`n wrap+. r, v l 1114a1.210, 1.0,1165 or eltilir
`toku.muor whetlwr they reypuhel dale rolitly Irmo patients
`65. lbieo Lam them la es highest incidence of oiler.
`boos an rho elderly population in poor.), c.iitien obeidei he
`ycd in trd.gte. the elderly tare ADVERSE REACTIONS,
`10,44011.
`opoiltse RMOCIONS
`.k „al d171 p.ticrits were f-rcirted with RMICATIK in
`dmi,Lid Heti_ In both rheumatoid Mithri611. (cid:9)
`Crain). die-
`(cid:9) discentininal
`m, midi.. approeirnathly 5% of pa :a
`gmicAD% Feocu a efliderielne .11Sporixnerc The most COM.
`ypp mums fur diecontinuktiOh of L.Tool.-trufht were dyspnea,
`•Riceria and fiend...chi.
`opysicohieleted Heathens
`Amon ml sea etOeflOo,.
`Sn ,,deelon NieLiou was Illr!Tittl as Bay cutvenie meet GC-
`,rip2 donne the infusion or within 1 In 2 hours alter the
`Ley,. Seventeen perrent.of DIEMICADR•Stveied. patients
`k ell rhuieil trialu experienced an infusion rometimi nom-
`yrnd i6 77. of idricybo.trented patients. Among thir 3284
`EggEtr,AD8 inf.-miss. 4% more lifttImpittilikd by rloo.Porifie
`..0910 41 such ou'rover er chills, 1%. were accompanied by
`',pawns or art: aria. I% wore accompanied by cardiepolm.•
`aer7 reactiens fprinionlY chest pain. iineedension. hypor-
`terdiso !sr dyhimeul. 11116 0.1a wear dctoropiehied by Con •
`!herd wooduro, of proritiniforticazYn end cardiopulmonary
`reirtean. less than 20 of patienta discontinued liRlitl-
`CADR livea,did or La.ka (cid:9)
`all patiknU Rem'
`ered with treatment and/or discontinuation of infusion:
`REMICADE infusions beyond the initial infusion in rheu-
`matoid arthritis patients were not associated with a higher
`incidence of reactions.
`Patients with Crohn's disease who became positive for anti-
`bodies to infliximab were more likely to develop infusion re-
`actions than were those who were negative (36% vs. 11%
`respectively). Use of concomitant immunosuppressant
`agents appeared to reduce the frequency of antibodies to in-
`Ririe:lab and infusion reactions (see PRECAUTIONS, Ion-
`munogenicity and Drug Interactions)-
`Reactions following readministration
`In a clinical trial of forty patients with Crohn's disease re-
`treated with infliximab following a 2 to 4 year period with-
`out infliximab treatment, 10 patients experienced adverse
`events manifesting 3 to 12 days following'infusion of which
`6 were considered serious Signs and symptoms included
`myalgia and/or arthralgia with fever and/or rash, with some
`patients also experiencing pruritus, facial, hand or lip
`edema, dysphagia, urticaria, sore throat, and headache Pa-
`li:min experiencing these adverse events had not e