PDR®
`58
`2004
`
`EDITION
`
`PHYSCANS1
`DESK
`REFERENCE®
`
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`·
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`ISBN: 1-56363·471-6
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`

`

`PHYSICIANS' DESK REFERENCE®
`
`No ·gender-related pharmhcokin~tic differences were D?·
`served after correction for a patient's body weight. Healthy
`volunteers and patients with rheumatoid arthritis·dis-
`· r
`played similar adalimumab pharmacokinetics.
`No Pharmacok.inetic data are' availab~e in.patie~ts· with·he~
`patic or renal impairment
`HUMIRA has not been· studied in ·children.
`Drug Interactions
`MTX reduced adalimumab apparent clearance after ,single
`and multiple dosing by 29% andA4%:respectiVely:
`CLiNICAL STUDIES
`The efficacy and safety of :rr:uMIRA we:r:~.assess.~docin ·four
`randomized, ,double-blind studies ip.,p~tien,ts.;;,:::· age ,18 with
`~c;tive rheumatoid arthritis diagno_sed .. ?cgoi;~g t_o. AJ;n~r:i:(cid:173)
`can College ofRheumatology (AC,R) c_riteria. Pati~nts had .at
`least. 6 s\\_l"ollen. apd 9 tenderjoint$.-~IRA-w_as a!J.mlll;is~
`texed· .Subcutaneously .iJ;i ,combinati,on. with MTX-(12.5 _ to
`25 mg, S.tudies Land III) or as monotherapy (Study 11).or
`with other:_ diseas~-modifyiJ,lg anti-r4evmatic drugs
`,. ,;,,
`.
`,. ..
`(DMARDs) (E;tudy IV) .. -
`Study.r.eva_luated 2-71 patients who h~d fai.led th~rapy.w_~th
`at least• pne buJ no .more th~ four DMARP,s and ha/1 inad~
`equ_ate r~_~ponse to_ M:rx .. Do_ses of 20,·1¼:0,pr 80.mg of
`HUM-1,RA or plaGebo w-ere. giv;en every,.,other:.-week for ?4
`•,·, • _
`weeks.
`Study II evaluateµ 544-patients .w1Jo h~d failed 1ilierapy
`w_i~h. i;i.tJea.st onE: DMARD.-Doses of placebo, iQ,or .. 40 mg of
`F:D.JM,lfU\.w~re.given as monotherapy0 ev.:~.fY.,Qther v.;et;!;k or
`.
`.
`weekly fol' 2(> V>'.~~ks
`~tudy IU eyalua_fc'ld.619 patients w.ho·h~d ,in inadequate,re.(cid:173)
`sp9:i;i!5e- to. MTX, Ratient~, -r.ec;i?ived place.ho, _-49..;µi.g of
`Hl.Jlvlll~.t~.:ev~ry other.week.with. plaCeb9)p.jey.tions,_on a1ter(cid:173)
`nf!te_ ..ye?.k~;-.9.r. ~20·-mg_of HUMIJ{A WE;ekly for up_ to.]52 w~eks.
`Study III had an additional primary endpoint at 52,weeks of
`inhibition of disease progression (as detected l;>y. ,X:--_ray i::e-
`,.,·
`·.·
`.
`: .
`.
`,
`sults).
`Sttidy IV assessed safe~y_ :if!. 6.3!3 patients who, yv:~Te eitp.er
`D~D-qa..iye pr were pe:pni~~ed. to. rem3:in. on t~~fr. pre(cid:173)
`~:tjStu;ig rh~umatolo~c.therap:y: pr,_~vid~d th<;t~ the_r~PY .~as
`stable fo~ ,a _p;iini~u~ o_f_28;days. ~~ti~nts were randomi_.ted
`to· ~0.-ffi;g, of. "fWM.,:iEA, or· pl_a<::~1;,.ct~very ... 1?tl?~X ,w~e~Jor' 24
`..
`._,, _ _;
`, .. , ,
`. ,
`.,,.:.·:,_·,-.
`,·,..
`wee~i;;'.._.
`Tbe-percerit oflf(JMIRA tr~\(ted patient,;_achi~~g ACR 2.0,
`50. ~~ ;7~1'!~\SP,9µses in_. Studies II J¥ld I~I. ~r;e ~p.o"".,~}n Tal_:!~e
`fg;~ tible .I attop ofneitpage] .
`.,
`:
`,
`. . ••···
`_The re~,ult,;, pf.Study: I ,were_ shnilar .t9 $tudy )II; ;i.ati~nt~
`r~cei~g -~MIM.~q _ 1?g ~Y,~ry .o.~h~r:·Y-'-~e~ .~ -~t~dy I ~l~o
`achieved ACR 20, 50 and 70 response rates .of65%, 5,2%;iill.d
`Z4%, ~eS,l)f~ti~e.ly, ~9n;tpa_r~5J.,.to p~~c~.bo _r_E:l~pops~s! 9~ J.?%,
`.· ..
`7% and 3% respecti~cly, at 6,.I11ont!,s.(p<O.Ol).
`The_ .res':1).tey, qf the. Components_ O(the A~R re~ponse cz:it~ry~
`for S~µ~es 11 .~c;l. lJ_I are_ ,sh~~- i~-- ~able i,, J~p;rov.ell?-.e.11~
`..ya.~ se~n in alt,c9mpo~E:?t$ _an~ ?Vas Ig~-~~Il~ffJR W~eJf_.Q~.
`, ... ,
`. .. , .. ,,
`. .
`[See.tab,le 2 at top pf_next page] _ .. , .
`'.fhe time cnurse .oL>\CR 20,n,~pqi)~e for,St11dy,JII i~.sh.?'!'7!
`in, Figi;re 1. _In ~tµdy III, ·$Ii%, of patients witJ, '}GR 2Q .. r.e(cid:173)
`sp?Ilsesi ~£ w~e~.,f:4~:µiaiqt,ii~ed- th:e F~~p9r;ise .?-.~•.Pi, we~ks(cid:173)
`The_tinie course .pf ACR 20 response fo, Stu~y) and.Stuqy,11
`,
`"°'.ere, sii;o.il~r.
`Figure 1: Study III ACR 20 Resp_~nses_b'ver si'wfo,;'·
`
`---1111- 40 m·g· every other week - - o - -:Place~o
`
`I 60
`&_ 50 ~.
`~ 40
`t 30
`.,
`
`~ 20
`~
`~ 10
`
`In Study IV; 53% of pati~nts treated with HUMHlA 40 trig
`every other week plus standard·ofeare had an·ACRWte(cid:173)
`sponse· at·week 24 compared to· 35% on placebo plus stan(cid:173)
`dal'd Of.care (p<0:001).:No unique adverse·reactions related
`to ·the conibinatio'n :of HU.MIRA: and other DMARDs '.were
`observed.
`In all four studies, HUMIRA showed significantly greater
`improvement than ,placebo in. the·di'sability indeX,_Of Health
`Assessrrierit·Que"Stionnaire•{HAQ) from. baseline ·to'the end
`of study, and significantly greater improv.emeilt than .pla(cid:173)
`~ebo in the p.ea1th-outcomes ·as assessed ·by The Short Form
`Health Survey (SF 36). Improvement was seen in both· the
`Physical Component Summary (PCS) and the Mental Com(cid:173)
`ponent Summary (MCS):
`Radiographic Res()onse
`In Study III, structural-joint damage ,was··asses"Sed radi~(cid:173)
`graphically. and· expressed as change in· Total Sharp· Sco~e
`(TSS) and its components, the erosion score and Jolllt Space
`NarroWIDg (JSN) ·score; at ffionth 12 compared.to baseline:
`At baseline, the median TSS was approximately" 55 in the
`
`i.~t~~a!~fa:aoi;1~H~~i:t~~--~h:1l~::e~trh:1::~
`ei~~i-~f_.~dh~si_o~ J?Plfictif~~ teSp-'oJ?.s.ibl~ /or·1~~0cyte: ¥-gr_a(cid:173)
`tion (ELAM'.i, VCAMci; and ICAM.-1.with an IC50 of 1:C,2 X
`' .
`'
`. -;··
`. '
`.
`.
`.
`.·
`10-1"M'j.' ... ' '' .,
`~·~ar~ab9,c1_v,~_aJ?j~s .. _~
`·.~ ~h .. -'.
`-.
`,
`,
`'·
`.... ,,- ..
`·:'·_'r·,
`~e:z:- tr_e-?-~m~n(~~~.-~E:A,. a !ap~~ d~cr~ase_,jl_11eye1s of
`-~c~te' pli~~e,.f7.8.ctari~s .. <?.f)¥~ma.f\9Il'.'(q~r~ac£i~e p_rote_}n
`\CRP},.and. ~rythrq¢yt!' ~edim-enJ;,.tipn ri;te (ESR)) ;,.nd
`se;~ c:ytpl_<\~es (II,;c6) wiif ~ts•~~<\ c,:,mp~rtd,to. base!i_ne
`0- .P~tie_~t:S_ ~~t? :r;-h~urµat.o~~'~
`1 ep.iJ:?._ lev~ls _of ma-
`. !v.lP-3) \hat produce
`.
`trix ,mefa1lopi:qfeinasrs .(MMP-
`~~s:u::c~!f ~t!!!t~~~~~tf~J1tt!~:truction were
`P,har~~.po_ki,~~~ic,_ <:• ... ·.,, ___ ,
`.
`.,. _ _
`..
`.. ·.·
`,
`'fh.e-Ip~mu,~ 5:erum cp~~entra;~o~_(CuraJ and the ~:ime.to
`r~?-.ch the'._m~~_mp~ .JO:~_cen~a~A<?P., .. :(T.roax~. were_ 4.7
`:!:
`1_._G µg/mL,.an.<l:, ~3~ + ,-5?· J:?.cn~rs. resp~ctiy~~Y, follow_i~g a sin(cid:173)
`gle,AO rpg'_~µl?cu~aµeous_ admi~.is9"a~ion. of HUMig..A to
`h~l~P,y a9"y.lt subj~,ct,s. ,The av,erage,~qsoi.ut~ _J?ioavailability
`of;,.de1limum_ab ~stimated fromthr~e,st11diesfoll?wing a sin(cid:173)
`gle 40 mg subcutanf;oU.s do.s~ w~s f?_:49,b .. _Tlw p4armt3:!='.?k.iJ?.et(cid:173)
`~cs Of adali_mumab \Y_er~ linear ov~r: th_e d~se rallge Of 0.5 to
`io.o' mg/k_g,follqwin,g. 8..~}ngle intravenoµS:_'9:ose_.
`. _
`,
`'.!'he single·dose-ph~a~o~netics .µf,~dalimumab were 9~~
`te~I.H~d in s~yi::ra~ studi.es witp. intrav~nou~ _dmies ran~ng
`from,o.~5 t-9 ~0 n:ig/kg. ni~ distrib.qtion_vol~m,e (Vss) ranged
`fyon;i,.4.7 to 6.0 L. Tlw SY:S~rojc. cle~i3Jl~e-of ada).imumab is
`approximately 12 mL'hl: .. -The mean, terminal half-life was
`apprqxi[nately .2 ,i,yeek.s, ranging from.J-0 to 20 qays across
`studies. _1\da-l~u,m11b co;ncentratiqns in the synoyial ·fluid
`fr:om .five •rh~_u;rµ_a.!;oid • arthriti~ pa~ients r:anged from
`3,1-96%. of t~se. in, serum.
`Adalirp.umaQ: i;oe,an· stea_dy-state trough. !;:Oncentrati,on~_of
`approximately. 5 µg/mL-and·,B ·tq,.9 'Jlg/mL; were observed.
`without ·al).4;_w,ith,-methotre:x;_ate._(M'J;X) respe.ctive1y. TJ,1~
`se~ 3.Q.alimuilJab-•tro,ugh: levels._Jtt-. stea,dy ,increa5:ed ap(cid:173)
`proximately proportionally with. d.o.s~ follo"'.ing. 20, .40 and
`80 mg .eve_ry .Qther week and every we.ek suQcutaneous dos(cid:173)
`ing. Iri 101.1g--:-term stll.dies with dosing _more-than. tw.o,ye~rs,
`there Yv_as :no evidence of c_hange!;!, )n. cl~ar~~e.o.ver. time.
`Poptilation--pharmacok.inetic analyses 'revealed that there
`toward higher.-,apparent. · clearance pf
`Was .J~.; tren~
`ada1imumab in the presence of.anti .. adalimulliab antibod(cid:173)
`ies, and·lo:wer.,clearance with-. increasing.age ·in patients
`aged 4,_o·to>75 years. ·
`Minor. incre~ses ill' apparent cle~ance were,also·predicted
`in patients receiving doses lower· than ·the recommended
`dose and in ·patients. with high rheumatoid factor -or CRP
`cOncent'rations·.- These increases -are not likely to be clini(cid:173)
`cally.important.
`
`~h::~st:~~~dw~:q:;~y~!~i;~~;;[~~i1;~fµt~\~;~
`:cus~ion of the· ~fferen~. !3-Ssay. me~hod~ is 'co!lta,i_he~_: i~ 1-~-:
`~[!,lS P(. Cli~ic~l Bip_c_~ediisti-:/ 1~94:;3·r~4~0~4a~(t~fi -~'~Y.~
`e!.al_ ~sS~ys __ ~.nd .a~say ~-~trices:a~~- ~~a~I~?l_e_: p1~~~.,i¥'.:~
`;;i~i~~r c1?;~1i;~~!t~°:~1~~~~::lfyt11;·.M;: it~~f;
`
`Yi~~-~~ t?~._m?~-?:~
`
`t~fere1:c;e, ,b~t~he m?~~clona1
`
`lll~ii?~ril~liif ~
`
`4-70/ABBOTT
`
`Gengraf-Cont.
`
`Patients generally show some improvement in the clinical
`manifest3lions of psoriasis in 2 weeks:· satisfactory control
`and stabilization of the disease may .take 12-16 weeks to
`achieve. Results of a dose•titration clinical trial with
`Gengrat® indicate that an improvement of psoriasis by 75%
`or more (based on PASI) was achi-eved in 51 % of the -patients
`after 8 w:eeks and in 79% of the patients after 16 weeks.
`Treatment should be discontinued if satisfactory response
`cannot be achieved after 6 weeks at 4 mg/kg/day or the pa•
`tient's maximum tolerated dose. Once a patient is ade· .
`quately cori.troUed and appears stable the dose of Gengraf®
`should be lowered, and the patient treated with the lowest
`dose that maintains an adequate response (this should not
`necessaril)' be total clearing of the patient). In clinical tri(cid:173)
`als, cyclosporine doses at the lower en9, 9fthe recommended
`dosage range were effective in maintaip.ing a satisfactory re(cid:173)
`sponse in 60% of the patients. Doses below 2.5 mg/kg/day
`may also be equally effective_._
`Upon stopping treatment With cyclosppriD.e, relapse will oc(cid:173)
`cur in approximately six weeks (50?77-of the patients) to 16
`weeks (75% 9f the patients). In th~ majority of patients re(cid:173)
`bound does-not occur after cessation of treatment with
`cyclosporin~.- Thirteen cases of transformation of, chr(?p.ji:>
`plaque psoriasis to more severe forms of psoriasis have been ·
`reported. There were 9 cases of pustular and 4 cases
`of erythro'dermic psoriasis. Long··te·rm experience with
`Gengraf®.-in · psoriasis patients is limited and continuous
`treatmen't fol" extended periods greater than one year is not
`recommeJlOed. Alternation with othe·r forms of treatment
`should be considered in the long tepn management of pa-
`-
`tients with this life long disease.
`Blood Conc"entration Monitoring in· Transplant Patients:
`Tr8.Il.s})lant Centers h8ve found b~ood c6ncenh8.£i0n mo.riitOi(cid:173)
`ing of cyclosporine to be an essential component-pfpatiegt,
`~.ariag1::~e~t. Qfim~~rtancf~? blood ~o~ce_~tra~on~Il~l?(Si~(cid:173)
`are, the tYJ)e of as~·ay 1.1:s~d, t}_l.e tr~n;p1~~ted · 01:g;n~. a,n4
`otb~~ .i?1~.\_1noS_uppr_e,ss~ri} ._. 3:g€l_nt·s,_ ·-?~ing ~.d~i~is:t~ie9::.
`
`~~:;:~fix;;ci;t:::t~it!t:-t~:f~=~~, ~ifltf:;;
`
`~f-~~j~cti'?~: 1:1Pd ~-?~ci~y, __ dos~ ·a_djti~~I?:1.~~t~; 3:11d, ~?-e ·~~seS~;
`·_
`.:
`·.·.··-····.,_ ·~ .... _. ,
`. -.,
`;n;~nt'ofconiplf~~;: -'.'~.
`y~ou!5 -~ssay~ 4'.'1V·~ .?~E:n~~Se·d -~9. ~~3:su~e bloO<l: c~~5~n£~fi~
`~~ons o_f ciclos~dri.Ile .. <?~d~r ... s~~di~~ us~!l~. 8: )io~.-~P-~:Cifi.~ :_~s(cid:173)
`s~y oft€~_ cit~d co~celltr3:ti?n~ t~~f w~~e ro1;~??Y .~~e_th?~~
`?f ~~e sp~cific.,a_s~aY~- '.f];leref~i-'e, comp~.~o~ b~~€e:q:_ C?n~
`centrati?ns ~~ the _pub:I.i~hed'}i_~E:.r:_3.t~e -~~:--~rHifvi4u~
`patient con~~fit~ati~~- u~~ng.-~-u~en~ as~ayS -~·1~t-~b~.·~~~~
`with_ detailed kno;,,,ledge of.the ,assay metiiod~ -.mployed,.
`
`HUMIRA™
`(adalimumab}
`Rx only
`
`WARNING
`RISK OF INFECTIONS
`Cases of tuberculosis (frequently disseminated or ex(cid:173)
`tra.pulmonary at clinical presentation) have _been o~(cid:173)
`served in patients receiving HUMIRA. ·
`PatientS· should be evaluated for latent tuberculosis in(cid:173)
`fection with a tuberculin skin test. Treatffient of ·13tent
`tuberculosis infection should be initiated prior to ther-
`.
`•
`apy with HUMIRA.
`
`DESCRJPTION
`HUMIRA_ (adalimumab) is a recombinant human' 'igGl
`monoclonal antibody specific for .human tumqr necrosis Jae(cid:173)
`tor (TNF). lfUM:IRA was created using phage display tech(cid:173)
`nology resulting in an antibody with_ human de0-v~d heavy
`and light chain variable regions and _h,uman lgG_l:K con(cid:173)
`stant regions. HUMIRA is produced _by: r_ec9mb~ant -DNA
`technology in a mammalian cell expression sys_tem_ ,_?--UQ. )?
`purifieQ .by~;process that includes specific viral inactivation
`and removal steps. It consists of 1330 amin~_.aciqs and.has a
`m9l_e<;ula,. .. ~~ight of approximately 148 kilodaltons.
`HU.MIR~)s_ s-µpplied in single-use, 1 mL pre-filled glass sy(cid:173)
`ringes as a sterile, preservative-free solution foq~ubc,u.tane(cid:173)
`ous administration. The solution of_ ffU~IBA is.,clear, and
`color.~e~~~-.:v,,:~th a pH of about 5.2. Ea"ch sYTinie delivers
`0.8 ml, (:40 n:,g) of drug product. Each 0.8 mL HUMIRA con(cid:173)
`tain.ii,49,:~g-,i:dalimumab, 4.93 mg sodium chloride, 0.69 mg
`IDOI?,_<?b~i~- s-9dium phosphate dihydrate, 1.22 mg dibasic
`sodium. phQ;:;phate dihydrate, 0.24 mg sodium citrate,
`1.04 mg citric acid monohydrate, 9.6 :rq.g mannitol, 0.8 µig
`polysorbate_80 and.Water.for Injection, USP. Sodium hy-
`' '·
`droxide added as:ne·Cessary·to·adjust pH:
`CLlNtbALP~COLOGY
`. . . , . .
`-~,~~~~~r _-
`A4a1,;;;iiliiab !firi'dii speclfically to TNf•alpha and, blocks its
`i~te~ct~~n "?~1i th_e _p?.5;~d.p75 Ce~ ~ut1ace .T~F. n~~eptors.
`A_~~ii#u'~ah~I~O)y~~~~S~ae:~_!NE,~~r~·~sing C:ell~ ~n v'it1;0
`m·~~.i 'Pte~e1:1_ce .: Pf,~oPll}le_in;enL Ad.9.l~ID~~t> ~.oe_~ tiot bi~d
`6r inactivate Jyri,photo:cin '(TNF-beta): TNF i,s a naturally
`.oC~u~n~. Cyto~~ ,!h~(i~ i1?:Volved i~ il_~hh~l infla~D;latory
`~1 _i_ID.11:1{0e ~~?P~~~e~:-'El?V!J.~d._~eV~~;.o(~~ .~e"f~upd_i.n
`the synov4tl.fluid ofrheumatoid artbntis piltierits-·and play
`animp~rtap.t r~le m, both the patholojiic inflamma~ion ru1d
`the joiµt dj,s:t"'ction that.ax~ hallinai!tl<, of rheumatoi_d _ar-
`
`!
`
`-~?riitoririg i~ po~-~ repl_?-~efu~D.t for rell~ f~ct~OJ.?. ~o~.it~.r~
`·
`'·
`: ' .. '"'"'
`'
`ing or ~tissue biof)sies. ' , ·
`HOW SUPPLIED
`Gengra~ Capsules (cyclosporin·e capsules, USP [ivlODI(cid:173)
`FIEDI)
`25mg·
`Oval,white imprinted in blue, the corporate logo a,' 2fr mg,
`and the Abbo-Code OR
`Packages of3(cid:144) urnt,dose blisters. (NDC-0074-6463-32).
`'
`· ·
`100 mg
`·
`Oval; white; 'with two blue stripes, imprinted· iii blue; tlie
`corporate logo a, 100 mg; and Abbo-Code OT.
`Packages of 30 unit-dose blisters. -(NOC 0074-6479-32).
`Ill the original unit-dose container at
`Store and Di"spense:
`controlled rc>om temperature i5°-30°C ·(59°-·86°F). (See
`USP) . . .
`
`*Sandirnilitl.ne® is a:registered traderilark 6fNovartiS Phar(cid:173)
`·corpOratiOn.
`mac€Ut~cals
`©Abbott
`~~llfa'.ctj.red by: Abbott Labor_ato'ries North Ch~ca:fto, IL
`.
`.
`60064, U.S.A.
`Distributed b_y: Sru1gStat Me.dical Corporation Fremont, CA
`,
`.
`94555, U.SA
`03-5242-R4
`Revis.i,d:-January, 2003
`ABBOTT .LABORATORIES
`NOilTH CHICAGO, IL 60064, U.S.A.
`SANGSTAT
`The Transplant Company"
`Fremont, CA 94555, U.S.A.
`Shown in Producf Identification Guide, page 303
`
`h'lformation· Will be' superseded by supplements·:and subsequent editions
`
`

`

`ry 9ther week groups. The results are
`:~O mg ~1[RA/MTX treated patients _demon(cid:173)
`a~!~i~gTaphic progression than p~tients receiv~
`
`ab~veJ
`NS·AND USAGE
`_.
`.
`. dicated for,.red~ci~g signs and s~ptoms and
`
`. mo~erate~y to se".'erely acti:~. r~eu_m~~<?~d -~ (cid:173)
`
`ilf · iogression of s~~ctur-:1 _da11:age m ~du_It I?~(cid:173)
`ta~e h8d ~tl inadequ_ate ~~s~ons~ ~ _ o~_e o~. m?re
`
`-~ , If(tMIRA 'can be used alone or m co~bm~tion
`s. or other DMARDs.
`!CATIONS
`MIRA should not be administ_en:,d to ·pabents with
`wn hypersensitivity to HUMI.RA or,.~-~~,~[ ~ts -~~~po-
`tsl'' "''
`.
`wARNJNGS
`::.· OUS INFECTIONS AND SEPSIS, INCLUDING FATAL!'
`--~~E~·.-,HAVE BEEN REPORTED WITH THE USE OF TNF
`BLOCKING AGENTS INCLUDING HUMIRA. MANY, OF THE
`SERIOUS INFECTIONS HAVE-OCCURRED IN_·PATIENT.S.ON
`CONC!)MITANT IMMUNOSUPPRESSIVE THERAPY THAT,
`IN AQ,DITION TO THEIR RHEUMATOID ARTHRITIS,· COULD
`!!REDISPOSE THEM,TO INFECTIONS. TUBERCULOSIS AND
`INVASIVE OPPORTUNISTIC FUNGAL JNFECTIONS: HAVE
`BEEN oBsERVED 1N P;ATIENTs. _ rnl'(\TER. wm:t .:r.111F
`BLOCKING AGE:NTS INCL,','[!ING HUMIRA.
`'TREATMENT WITH HU MIRA SHOULD NOT BE INITIATED IN
`PI\TIENTS WITH ,.:,ACTIVE: · INFECTIONS · INCLUDIN_G
`CFIRONIC OR LOCAUZED' INFE_CTIONS: PATIEN_TS Wl:lO
`DEVELOP A NEW INFE,CTl()N WHl_t~· UNDERGOINGTREI\T~
`MElliT WITH H_UMIRA SHOULD '~F MONITORED ClOSEtY.
`ACiMINiSTRATIQN OF f:!UMIRA SHOUlD~BE DISCONTIN(cid:173)
`UED IF A. PATIENT DEVEVLbPS A SERIOUS INFECTION.
`PHYSICIANS SHOULD EXERCfSE CAUTfON' WHEN· CpN(cid:173)
`SIDERING THE USE OF HUMIRA IN PATIENTS WITfi ,1,.:111s:
`TORY ()f RECURRENT INFECTION OR U)\lbERLYING CON'
`DITIONS WHICH MAY PREDISPOSE THEM;ro iNFECTIONS,
`oo··PATIENTS WHO HAVE 'RESIDED IN REGIONS-WHERE
`TUBERCULOSIS'• AND HISTOPLASMOSIS. ARE ENDEMIC
`
`~c':i:it::;t~~~:o~;t':Jt:}~~:F~~~ ~~i:~tli
`
`HUIV!IRA TREATMENT SHOULD BE-CAREFULLY COiilSID'.
`ERED BE~QRE'INITIATION OF HUMIRA THERAPY.
`N0lirOldgic Events
`Usfof'TNF blocking agents, includinf HUMIRA, has been
`~ssodate4 wi~~ rare cas~s·of·eXacer~·atiOn d(c_Iinical ~YIDP:
`
`!~:~ t:i~b:t!1;ro~r;~::r:~:-:::t~l~~oe~~~:!::g ~~;
`
`use ofHUMIR.A in patients with preexisting or recent•ons~
`central nervo:u:s sySteri:I demyeliilating disorders.
`Maligiiancies·
`. · '·.
`.,,,i,
`.
`.
`'
`Lyciphomas have ~een obse1:-ed in~ l?a~ients treated w,~th
`TNF blocking agents including HUMIRA. In clinical trials,
`patients treated with HlJMIRA had a higher incidence of
`lymphoma than the. exp~c~d ·r~t_e in._ th.~ fi'erl~al populatioi:
`(see ADVERSJs llEA~TIONS'Malignancfl,s). While pa(cid:173)
`tients with- rheu'matoid· ·arthritfa, p'3.rticUlaTly those ·with
`highly ictive\diS~_~se~1lll~Y ?,eat a hiiher ~S-~ (up to ?.everfil
`fold) for the development' of 1ymphoma, the role· of TNF
`~Io·ckers•in' the dev;~loprnenf;o(ffialignarlc)' is not known.4•5
`PRECAUTIONS
`General
`Allergic reactions have been observed __ in:a1?:pZ:oX3::rp~te{y)%
`of patient~ 1."~ceiv~ng HpMI:84.)t ar.l:· 4naphylacti,C reactio71
`i;:ir other s_erious alle:i:-gic reaCtioY1_ occllrs, administration of
`HUMIRA. should be: discontinued immediately and appcq-
`priat\:!_. tq.~ral)y initiated'. -
`-
`lnforrriation to Patients
`The first injection should be performed up.ger th,e sµperyj(cid:173)
`sion of a qualified health care professioii.al. 'If a· p3.tierit :or
`caregiver iS'.to administer HUMIRA, he/she·sholl1d be Ill(cid:173)
`structed -in. injection techniques and their ability. to inject
`subcutaneously should. be -3.sses.sed to ensuie ·the ·proper .ad(cid:173)
`ministration ofHUM!RA (see HUMIRA, PATIENT INFORMA(cid:173)
`TION LEAFLET). A puncture-resistant:·container for •disposal
`of.needles and syringes should be used. Patients oi caregiv(cid:173)
`ers. should be instructed in the ·.technique· as well as· proper
`syringe·and:needle•,disposal, and be cautioned against reuse
`of these i terriS:
`Tuberculosis
`As observed with other TNF blockin·g .agents; tubel',eulosis
`associated with the:administration• of HUMIRA in clinical
`trials has·been.repOrted ·(see •WARNINGS). While cases
`were· observed af all .dos'es; the incidence of tuberculosis,re(cid:173)
`activations was parttcularly increased•.cat doses of HUMIRA
`that were higher: than th8:'·I'ecominended·O.ose:JAJJ 0 patients
`recovered after standard antimicrobial therapy. No :deaths
`due. to tul;>ercul~tsi~ occ.µrred during th_e c~cal .trials.
`B~for~. ip}ti_ation ;OJ ~herapy y,rith HUMI~, patients should
`be evaluated foi; active or .latent tuberculosis infection with
`a ·tuberculin- skin te.St. if latent infection- ·~s diagnose~, ap(cid:173)
`propriate- prop!lyl!lxis)n accord!3.pc;e with the Centers ~for
`I;>iseaeyf Control and Prevention guidelipes6 sQ.(?uld be insti(cid:173)
`tuted. Patients should be instructed to seek medical advice
`if siglls/sYI11ptoms (e.g_., p~rsi~'t~nt cough, wasting/weight
`loss, low: grade fever) suggestive of a tuberculosis infection
`
`lmmunosuppression .
`, , .
`The possibility exists .for. TNF:.blocki_ng agents, including
`HUMIRA, to affect hos,t Qefenses against infectiOn~.and ma(cid:173)
`lignancies since TNF mediates inflammation and modulates
`
`Table 1; ACR Respons_~s.Jt:1 .. f:'l_acebo-Controlled Trials {Percent of Patients)
`
`··st~dyll
`!Ylo'noth_eraRV
`,(21,.lll(eeksl.
`
`Study 111.
`,
`Meth<:1tr.e.~a~e C(?,f1lbination
`(24.and 52.weeksl
`
`ABB0TT/471
`
`~espouse
`
`PlacebO
`
`P,lacebo/MTX
`
`HUMIRAIMTX
`40 ~g
`ev~ry, Other week
`
`· N=207
`
`Month'6
`
`Month 12
`
`ACRSO
`
`Month 6
`
`Mon'tlil2
`
`ACR70 r,
`
`Month 6
`
`Parameter (median)
`
`Study I(
`
`Placebo
`N:110
`
`Number oftender,joints. (0-68J.
`Number of swollen joints (0-66)
`Physician global assessmentb
`Patient global assessmentb
`Painb
`Disability index (HAQ)'
`CRP (mg/dL)
`
`Basel~rye .. Wk.26 BaseliJle'
`
`Wk24·
`
`35'_ .
`19
`... 7.0
`7,5 ,·
`7.3
`2.0
`3.9·
`
`26
`16
`6.1
`6.3
`6.1
`1.9
`,, 4.3
`
`31
`18
`6'6
`7,5
`7,3
`1.9
`·4,6
`
`16*
`10*
`3.7*
`4.5*
`4.1*
`1.5*',
`1.8*'
`
`26'
`17·
`6.3
`5.4
`6.0
`.'l,5
`LO
`
`. 15
`11
`. 3:5
`'3,9
`3.s:r
`... l.3
`0.9°'
`
`·c24
`ls' ,,
`6.5
`5.2
`·5'.8
`·1.5
`1.0
`
`C) 8*.
`5*
`··2.0•
`2.0*
`··; ·2:i*
`0:8*
`0.4*
`
`'40 mg HUMIRA administered every other we~k ...
`,•
`•
`.-.
`bVisualanaloguescale;Q::::;-best,lO=wors(
`':
`·.: . . . . . .. ['
`.
`. .
`,
`.
`.
`.
`.
`; 0 = best·, 3 = worst, measure& th~ patient's ability,to perfo.rm the
`c Disability Index of the Health Assessment Qti.~sti0nn~e2
`following: dress/groom, arise, eat, walk, :i;each,:gtj:p,.Dlaintain hygiene, and_maintain·daily.·.activity
`*p<0.001, HUMIRA vs. placebo, based on·_~_!:!a;ii:_~hangE!Jrom' baseline•<
`
`Placebo/MTX' ···
`
`:HUMIRA/MTX
`40 mg every
`other week.
`
`Total Sharp score
`
`Erosion score
`
`2.7
`
`1.6
`
`0.1
`
`0.0
`
`Placebo/MTX·
`HUMIRA/MTX
`.(~5% Confiden'ce
`, Interval*)'
`
`2.6 (L4,'~s) -·
`
`'l:6'(0'.9,'2,2)
`
`,JSN score
`
`1.0
`
`0.1
`0.9 (0.3, ·l.4)
`*95% confidence mtervals for the differences m change scores between:.MTX and HUMIRA.:
`**Based on rank analysis
`cellular immune responses. In a study of 64 patients with
`rheumatoid arthritis treated with HUMIRA, there was·.-no
`evidence of depression of delayed-type hypei-se:rlsitivitY, de(cid:173)
`pression of immunoglobuli1\ levels, or change. in' eintiriiera(cid:173)
`tion of effector T- and B-cells and NK-cells,-monOCyte/tnac(cid:173)
`rophages, and neutrophils. The impact of treatment wit~
`~~~ on ~p~ ~ev~_lo:pment and cou~s~ ~f m~l_i~ancies,
`as'well as active· and/or chrohic infectio~s is 11:ot fullY,un~er(cid:173)
`stood (see_ WARNINGS,.ADVERSE REACTIONS; lnlec(cid:173)
`tionS a'r'ld MaHgrtancieS). The safety _and effic~cY of
`HUMIRA in patients with immunosuppT"ession have not
`been evaluated.
`lr:nn:n,tnization.s .
`.
`-
`. ,
`_ ,
`.
`,.
`, • .
`No ·data are. available on the eff~cts _of. v~ccina,ti_on in p_a-.
`tients receiving HUMIRA. Live vaccines should not be given
`concurrently wit}l HUMiftA_, No data,·are.;:i.yailable-on tl;ie
`secondary tran$missio71 pf infection by live vaccines iri na-
`tients receiving HUMIRA.
`·
`Autoimmunity
`··
`.. _.
`--.
`,
`Treatment with HUMI.RA ni.ay r~sult in tP,e formation of au(cid:173)
`toa,ntibodie_s and, rarely, in .tf).e d~ye_lopment of a lupus:Jike
`s~droµ1e. If a patient develops syrqp,to~s--~\lggestiye• 9f a
`lupus-like -syndI"ome.following treatment w!th HUMIRP,..,
`treatment should be discontinued (see A))VERSE RMC~
`TIONS, Autoantibo~ii~s).
`.
`Drug Interactions
`HUMIRA has been studied in rheumat9id ar:thcitis patient~
`taking concomitant MTX (see_ CLINICAL-PHARMACOL,
`OGY:_ Drug Interactions) •. The data do not suggest-the ne_ed
`for dose adjustment of either HUMIRA or MTX.
`.
`.
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`Long-term animal studies of HUMIRA have not been con(cid:173)
`ducted to ev~luate the carcinogenic potential or its effect on
`
`,'
`
`<0.001
`
`<0.001
`
`0.002
`
`!~;~iJb~~~~1~rtilf:f~cufJ~ 1!!~~!e!tr~!tcc\::f t!lf~!~
`
`Stilnioirella-Escherichia coli (Ames) ·assa'y, respe_CtivelY.
`Pregnancy
`Pregnancy Category B-An embryo-fetal perinatal "d€Vefop(cid:173)
`ment toxicity-study has been performed in cjnomolgus inon:
`keys at. dosages uir to 100 mg/kg. (266· times human AUC
`when given 40,mg.subcutaneous with MTX,every week or
`373 times human AUC when 'given 40 mg ,subcutaneous
`without MTX) a.Jld has revealed no evidence of harm to the
`fetuses .due.to 8dalimumab. There are, however, no ade(cid:173)
`quate and well-controlled studies iri pregnant women.· Be(cid:173)
`cause animal: ·reproduction and developmental studies are
`not always predictive of .human response, HUMIRA
`(adalimumab) should be used during pregnancy only if
`clearly needed.
`NL.\rsing Mothers
`.
`. . ,
`It is not kpown whether adaiim,um~b is .excreted in hµman
`milk or al;>Sorbed systemically aft.er ingestion. f?ecause
`many 9"rugs -and immunoglo_bulins are excreted in h~an
`milk,, a~d because of the potenti3il for serious adverse reac(cid:173)
`tions in nu,r:sing infants from ffi!MI~, a tje_cision should bE!
`maPe.wheth_er to discontinue nursing or·to discontinue the
`drug, taking into account the importance 9f the drug to the
`mother.
`Pediatric Use
`Safety a~d effectiveness of HUMIRA in p~diatric patient~
`have not been established.
`Geriatric Use
`A total of 519 patients 65 _ye_ars of age az:id older, including
`107 pa~ients 75 years and older, received HUMIRA in clio-
`
`Continued on next page
`
`Cons~lt ~ O O 4 PDR® supple'!1e~ts and-future editions for revisions
`
`

`

`472/ABBOTT
`
`Humira-Cont.
`
`ical studies. No overall difference in effectiveness was ob(cid:173)
`served between these subjects and younger subjects. The
`frequency or serious infection and maligrulllcy among
`HUMIRA treated ~ubjects over age 65 was higher than for
`those Wldl!r age 65. Because there is a lugber incidence of
`infections and malignancies in the elderly population in
`general, caution should be used when treating the elderly.
`ADVERSE REACTIONS
`General
`The most serious adverse reactions were (see WARNINGS):
`• ·serious Infections
`• Neurologic Events
`• Malignancies
`The most common adverse reaction with HUMIRA was in(cid:173)
`jection site reactions. In placebo-oontrolled mals; 20% of pa(cid:173)
`tients treated witl, a!J?-j!RA developed iDjec~on site. reac(cid:173)
`tions {erythema and/or itclling, hemorrhage, pain or
`swalliQg), co.mpared to 14'if; of patients rt'Ceiving placebo.
`Most injectioa site reactions were desaribed as mild and
`generally did not necessitate drug discontinuation.
`The proportion of patie11ts who discontinued treatment due
`to adverse events during the double-blind, placebo-con(cid:173)
`trolled portion of Studies I, 11, ID and IV was 7% for pa(cid:173)
`tients takmg B:UMIRA-and-4~ fo1'-placebo-treated patients_
`The mQllt common advetSe evtmts leading I.a discontinua(cid:173)
`tion of HUMIRA were clinical flare reaction (0.7%), -rash
`.
`(0.3%) and pneumonia (0.3%).
`Because clinical trials are conducted under widely varying
`and controlled conditions, adverse rellction rates observed
`in clinical trials of a drug cannot be directly compared to
`rates in the clinical trials of another drug and inay not pre(cid:173)
`dict the rates observed in a broader patient population in
`clinical practice.
`Infections
`In placebo-c!>ntrolred trials, the mte of infection we.s 1 per
`patien year. in the Hll;MIRA treated {'Stients and ().9 per
`patient yew: in the. placebooi:reated..palients. The infectiODs
`consisted primarily or upper respimtory tract infections,
`bronchitis and. urirulJj' tract iofections. Most patients con(cid:173)
`tinued on HUMIRA after tbe infection resolved. The inci(cid:173)
`dence of serious infections was 0.04 per patient year in
`HUMIRl1. trea.ted patients aod 0.02 per patient year ill
`placebo-treated patie.ots- Serious infections observed in(cid:173)
`cluded pneumonia, septic arthritis, prosthetic and post(cid:173)
`surgical infed:ions, erysipelas, cellulitis, diverticulitis, and
`pyelonephritis (see WARNINGS).
`Thirteen cases of tuberculosis, including miliary, lymphatic,
`pcrir.oneal, and pulmonary were reported in clinical trials.
`Most of the cases of tuberculosis oteurred within the first
`eight months after initiation of therapy and may reflect re-
`1:TUdescence of latent disease. Six cwres ofiilvasive opportu(cid:173)
`nistic infections· caused by histoplasma, aspergillus, and no(cid:173)
`cardia were also
`reported
`in clinical
`trials
`(see
`WARNINGS).
`Malignancies
`Among 2468 rheumatoid arthrl~s patients treated in clini(cid:173)
`cal trials with RUMIRA for a median. of"24 .mont.hs, 48 ma(cid:173)
`lignancies of vario.us types Wetl! observed, including 10 pa(cid:173)
`tients with lymphoma. The St:andard:ized Incidence Ratio
`(SIR) (ratio of observed .rate. to age-adjusted expected fre(cid:173)
`quency in the general population) for malignancies was 1.0
`(95'ilo CI, 0.7, 1.3) and forJymphomU was 5.4.(96% Cl, 2.6,
`10.0). An increase of up to several fold in the rate of lym(cid:173)
`phomas bas been reportoo in the rheumatoid arthritis pa,_
`tient population•, and may be further increased in pa