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`
`2007
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`PHYSCANS'
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`

`

`914/BRISTOL"MYERS SQUIBB
`
`Erbitux-Cont.
`
`Squamous Cell Carcinoma of the Head and Neck
`The recommended dose of ERBITUX (Cetuximab). in com(cid:173)
`bination with radiation therapy is 400 mg/m2 as an initial
`loading dose (first infusion) administered as a 120-minute
`IV infusion (maximum infusion rate 5 mUmin) one week
`p~or to initiation of a ??urse of radiation therapy. The rec(cid:173)
`ommended weekly maintenance dose (all other infusions)
`is 250 mg/m2 infused over 60 minutes (maximum infusion
`rate 5 rnL!min) weekly for the duration of radiation therapy
`(6-7 weeks). In clinical studies, Cetuximab was adminis(cid:173)
`tered 1 hour prior to radiation therapy.
`The
`recommended dosing regimen for single-agent
`ERBITUX in the treatment of recurrent or metastatic
`squamous cell carcinoma of the head and neck is a
`400-mg/m2 initial dose followed by 250 mg/m2 weekly until
`disease progression or unacceptable toxicity.
`Colorectal Cancer
`The recommended dose of ERBITUX, in combination with
`irinotecap., or as monotherapy, is 400 mg/m2 as an initial
`loading dose (first infusion) administered as a 120-minute
`IV infusion (maximum infusion rate 5 rnUmin). The rec(cid:173)
`ommended weekly maintenance dose (all other infusions)
`is 250 mg/m2 infused over 60 minutes (maximum illfu.sion
`rate 5 miJmin).
`Dose Modifications
`Infusion Reactions
`If the patient experiences a mild or moderate (Grade 1 or 2)
`infusion reaction, the infusion rate should be permanently
`reduced by 50%.
`ERBITUX should be immediately and permanently discon(cid:173)
`tinued in patients who experience severe (Grade 3 or 4)
`infusion reactions. (See WARNINGS and ADVERSE RE(cid:173)
`ACTIONS.)
`Dermatologic Toxicity and Related Disorders
`Dosage modifications for dermatologic toxicity are recom(cid:173)
`mended for severe acneform rash (NCI CTC Grades 3 or 4),
`as specified in Table 6. ERBITUX dosage modification is
`not recommended for severe raruation dermatitis. (See
`WARNINGS and ADVERSE REACTIONS.)
`[See table 6 at top of previous page]
`Preparation for Administration
`DO NOT ADMINISTER ERBITUX AS AN IV PUSH OR
`BOLUS.
`ERBITUX must be administeredwnh the use of a low protein
`binding 0.22-micrometer in-line filter.
`ERBITUX is supplied as a· 50-mL, si~gle-use vial
`containing 100 mg of Cetuximab at a concentration of
`2 mg/mL in phosphate buffered saline. The solution should
`be clear and colorless and may contain a small amount of
`easiLy visible, white, amorphous, Cetuximab particulates.
`DO NOT SHAKE OR DILUTE.
`PREPARE INFUSION USING APPROPRIATE ASEPTIC
`TECHNIQUE. ERBITUX SHOULD BE ADMINISTERED
`VIA INFUSION PUMP OR SYRINGE PUMP.
`Infusion Pump:
`• Draw up the volume of a vial using a sterile syringe at(cid:173)
`tached to an appropriate needle (a vented needle or pin
`may be used).
`• Fill ERBITUX (Cetuximab) into a sterile evac~ated con(cid:173)
`tainer or bag such as glass containers, polyolefin bags
`(eg, Baxter Intravia), ethylene vinyl acetate bags (eg,
`Baxter Clintec), DEHP plasticized PVC bags (eg, Abbott
`Lifecare), or PVC bags.
`• Repeat procedure until the calculated volume has been
`put into the container. Use a new needle for each vial.
`• Administer through a low protein binding 0.22-micrometer
`in-line filter (placed as proximal· to the patient as
`practical).
`• Affix the infusion line and prime it with ERBITUX be(cid:173)
`fore starting the infusion.
`·
`• Maximum infusion rate should not exceed 5 mUmin.
`• Use 0.9% ~aline solution to flush line at the end of
`infusion.
`.
`Syringe Pump:
`• Draw up the volume of a vial using a sterile syringe at(cid:173)
`tached 1? an appropriate needle (a vented needle or pin
`may be used).
`• Place the syringe into the syringe driver of a syringe
`pump and set the rate,
`• Administer through a low protein binding 0.22-micrometer
`in-line filter rated for syringe pump use (placed as prox-
`imal to the patient as practical).
`_
`• Connect up the infusion line and start the infusion after
`priming the line with ERBITUX (Cetuximab)
`• Repeat procedure until the calculated volume has been
`infused.
`• Use a new needle and filter for each vial.
`• Maximum infusion rate should not exceed 5 mL/min.
`• Use 0_9% saline solution to flush line at the end of
`infusion.
`ERBITUX should be piggybacked to the patient's infusion
`line.
`Following the ERBITUX infusion, a 1-hour observation pe(cid:173)
`riod is recommended. Longer observation periods may be
`required in those who experience infusion reactions.
`HOW SUPPLIED
`ERBITIJX® (Cetuximab)is supplied as a single-use, 50-mL
`vial containing 100 mg of Cetuximab as a sterile,
`preservative-free, injectable liqnid. Each carton contains
`one ERBITUX vial (NDC 66733-94S-23).
`
`Stability and Storage
`Store vials under refrigeration at zoe to soc (36oF to 46°F).
`DO NOT FREEZE. Increased particulate formation may oc(cid:173)
`cur at temperatures at or below 0°C. This product contains
`no preservatives. Preparations of ERBITUX (Cetuximab)
`in infusion containers are chemically and physically stable
`for up to 12 hours at 2°C to soc (36°F to 46°F) and up to S
`hours at controlled room temperature (20°C to 25°C; 6S°F
`to 77°F) Discard any remaining solution in the infusion
`container after S hours at controlled room temperature or
`after 12 hours at 2° to 8°C, Discard any unused portion of
`the vial.
`ERBITUX'"' is a registered trademark of ImClone Systems
`Incorporated.
`Manufactured by 1m Clone Systems Incorporated, Branch(cid:173)
`burg, NJ 08S76
`Distributed and Marketed by Bristol-Myers Squibb Com(cid:173)
`pany, Princeton, NJ 08543
`lmCione Systems Incorporated
`Bristol-Myers Squibb Company
`©2006 by ImClone Systems Incorporated and Bristol(cid:173)
`Myers Squibb Company.
`All rights reserved.
`ER-B0001-03-06
`Based on 51-022606-04, 1169848A4
`Shown in Product Identification Guide, page 309
`
`Revised March 2006
`
`ORENCIA®
`[oh-REN-see-ah]
`(abataceptl
`Rx only
`
`DESCRIPTION
`ORENCIA" (abatacept) is a soluble fusion protein that
`consists of the. extracellular domain of human cytotoxic T(cid:173)
`lymphocyte-associated antigen 4 (CTLA-4) linked to the
`modified Fe (hinge, CH2, and CH3 domains) portion of
`human immunoglobulin G 1 (IgG 1). Abatacept is produced
`by recombinant DNA technology in a manimalian cell ex(cid:173)
`pression system. The apparent molecular weight of abata(cid:173)
`cept is 92 kilodaltons.
`OREN CIA is supplied as a sterile, white, preservative-free,
`lyophilized powder for parenteral administration. Follow(cid:173)
`ing reconstitution \vith 10 mL of Sterile Water for Injection,
`USP, the solution of OREN CIA is clear, colorless to. pale
`yellow, with a pH range of 7.0 to S.O. Each single, use vial of
`ORENCIA provides 250 mg abatacept, 500 mg maltose,
`17.2 mg monobasic sodium phosphate. and 14.6 mg soqium
`chloride for admini~tration.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Ahatacept, a selective costimulation modulator, inhibits T
`cell (T lymphocyte! activation by binding to CD80 and
`CD86, thereby blocking interaction with CD2S. This inter(cid:173)
`action provides a costimulatory signal necessary for full ac(cid:173)
`tivation ofT lynipnocytes; implicated iri the pathogenesis
`of rheumatoid arthritis (RA). Activated T lymphocytes are
`found in the synovium of patients with RA.
`In uitro, abat.acept decreases T cell pi'olifcrotlon nnd inhib(cid:173)
`its the production or the cytokines Lumor necrosjs factor
`alpha (TNFOl), interferon-y. and interleukin-2, In a rat
`collagen-induced arthritis model, abatacept suppresses in(cid:173)
`flo.mmabon, d~ases ant.i-collngen nntibod.y production,
`and reduces aiitij;en specific production ofjnterfcron-y. The
`'(Clnt:ionship or lhese biological response marken; lo the
`Table 2: ACR Responses in Placebo-Controlled Trials
`
`PHYSICIANS' DESK REFERENCE ®
`
`mechanisms by. which OREN CIA exerts its effects m RA is
`unknown.
`Pharmacodynamics
`In clinical trials with ORENCIA (abatacept) at doses ap(cid:173)
`proximatin·g 10 mglkg, decreases were observed in serum
`levels
`of
`soluble
`interleukin-2
`receptor
`(siL-2r),
`interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive
`protein (CRP), matrix metalloproteinase-3 (MMP3), and
`tumor necrosis f!ICtor alpha CTNFe>). The relationship of
`these biological response markers to the mechanisms by
`which OREN CIA exerts its effects in RA is unknown.
`Pharmacokinetics
`The pharmacokinetics of abatacept were studied in healthy
`adult subjects after a single 10 mglkg intravenous infusion
`and in RA patients after multiple 10 mg/kg intravenous in(cid:173)
`fusions (see Table 1).
`
`Table 1: Pharmacokinetic Parameters (Mean, Range) in
`Healthy Subjects and RA Patients After 10 mg/kg
`Intravenous lnfusion{s)
`
`Healthy Subjects
`(After 10 mg/kg
`Single Dose)
`n=13
`
`RA Patients
`(After 10 mg/kg
`Multiple Doses")
`n=14
`
`292 (175-427)
`
`295 ( 171-398)
`
`16.7 (12-23)
`
`13.1 (8-25)
`
`0.23 (0.16-0.30)
`
`0.22 (0.13,0.47)
`
`0.09 (0.06-0.13)
`
`0.07 (0.02-0.13)
`
`PK Parameter
`
`Peak
`Concentration
`(Cmnxl [mcg/mL]
`
`Terminal half-life
`(t 112)[days]
`
`Systemic
`clearance (CL)
`[miJhlkg]
`
`Volume of
`distribution (Vss)
`[Likg]
`
`• Multiple intravenous infusions were administered at days
`1, 15, 30, and monthly thereafter.
`·
`
`The pharmacokinetics of abatacept in RA patients and
`healthy subjects appeared .to be comparable. In ·.RA pa(cid:173)
`tients, after multiple intravenous infusions, the pharma(cid:173)
`cokinetics of abatacept showed proportional increases of
`Cmax and AUC over the dose range of 2 mg/kg to 10 mglkg.
`At 10 mglkg, serum concentration appeared to reach a
`steady-state ,by day 60 with a mean (range) trough concen(cid:173)
`Lrnt(on or24 (lr66)·l!1cig/mL. No sys(emic Acc;umulotlon of
`abat.nccpl occurred upon continued repeated l.:reatmcnt
`with 10 mglkg at monthly intervals in RA patients.
`Population phnrmocokinetic onal}'llCS in RA Jl(lt.ientt; re(cid:173)
`v~alcd that ther wli\S a k"Ontl 19wnrd highflr clearance of
`n~ot.!lcepl W!th inc~eusiog body wwghL . Age iind gender
`(wh~n corrected for body wcight) did not affecl. cleantnce.
`Concomitant methotrexate (MTX), nonsteroidal anti(cid:173)
`inffam.matory drugs (NSAIDs), corticosteroids, and TNF
`blocking·oge:nts dld not itillueoce abatocept clearo.nCO-
`The pbnrmncokinc.tics 'of abalocepl have not been stu rued
`m children nd adole5eents. No formal studtl!li were coo·
`ducted to examine the effects of eith~r renal or hepatic im(cid:173)
`pairment on the pharmacokinetics of abatacept
`CLINICAL STUDIES
`The efficacy and safety nfORENCIA (abatacept) were as(cid:173)
`sessed in five randomized, double-blind; placebo-controlled
`studies in patients "" age 18 with active RA diagnosed ac(cid:173)
`cording to American College of Rheumatojogy (ACR) crite-
`
`Percent of Patients
`
`Inadequate Response
`toDMARDs
`
`Inadequate Response
`toMTX
`
`Inadequate Response
`to TNF Blocking Ag'ent
`
`Study I
`
`Study Ill
`
`Study IV
`
`ORENCIA"
`( abatacept)
`n = 32
`
`Placebo
`n=32
`
`ORENCIA•
`+MTX
`n=424
`
`Placebo
`+MTX
`n=214
`
`ORENCIAb
`+DMARDs
`n=256
`
`Placebo '
`+DMARDs
`n=133
`
`53%
`NA
`NA
`
`16%
`NA
`NA
`
`6%
`NA
`NA
`
`NA
`
`3lo/c
`NA
`NA
`
`6%
`NA
`NA
`
`0
`NA
`NA
`
`NA ·
`
`62%•*•
`68%***
`73%**'
`
`32%***
`40%'**
`4S%* ..
`
`13%***
`20%* **
`29%***
`
`14%***
`
`37%
`40%
`40%
`
`8%
`17%
`1S%
`
`3%
`7%
`6%
`
`2%
`
`46%***
`50%***
`NA
`
`lS%*•
`20%***
`NA
`
`6%*
`10%**
`NA
`
`NA
`
`18%
`20%
`NA
`
`6%
`4%
`NA
`
`1%
`2%
`NA
`
`NA
`
`Re~ponse Rate
`
`ACR20
`Month3
`Month6
`Month12
`
`ACR50
`Month3
`Month6
`Month 12
`
`ACR70
`Month3
`Month6
`Month12
`
`Major Clinical
`Responsee
`
`* p<0.05, ORENCIA vs placebo.
`* * p<0.01, OREN CIA vs placebo.
`• * * p<O.OOl, ORENCIA vs placebo.
`"10mglkg.
`b Dosing based on weight range (see DOSAGE AND ADMINISTRATION).
`'Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period.
`
`Information wiiiiJe superseded by supplements and 5ubSequent editions
`
`

`

`PRODUCT INFORMATION
`
`BRISTOL~MYERS SQUIBB/915
`
`Table 3: Components of ACR Response at 6 Months
`
`Inadequate Response
`toMTX
`Study Ill
`
`Inadequate Response to
`TNF Blo.cking Agent
`Study IV·
`
`OREN CIA
`+MTX
`n=424
`
`Placebo
`,+MTX
`n=214
`
`OREN CIA
`+DMARDs
`n=256
`
`Placebo
`+DMARDs
`n.;, 133
`
`Component (median)
`
`Baseline Month 6
`
`Baseline Month 6
`
`Baseline Month 6
`
`Baseline Month6
`
`28
`
`19
`
`67
`66
`
`7***
`
`29 .
`
`27
`
`31
`
`20
`
`70
`64
`
`14
`
`11
`
`50
`48
`
`30
`
`13***
`
`21
`
`10***
`
`73
`71
`
`43**
`44***
`
`1,75
`
`1.13***
`
`1.76
`
`1.38
`
`1.88
`
`1.38***
`
`31
`
`20
`
`74
`73
`
`2.00
`
`69
`
`24
`
`H
`
`64
`63
`
`L75
`
`54
`
`69
`
`21***
`
`68
`
`0.9***
`
`40
`
`1.8
`
`71'
`
`32***
`
`3.4
`
`1.3*•*
`
`'2.8
`
`2.3
`
`ria. Studies I, II, III, 8Ild IV required patients to have at
`least 12 tender and: 10 swollen joints at randomization.
`Study V did not require any specific number of tender or
`swollen joints. OREN CIA or placebo treatment was given
`intravenously at weekS 0, 2, and 4 and then every 4 weeks
`thereafter.
`Study I evaluated ORENCIA (abatacept) as monotherapy
`in 122 patients with active ·RA who had titiled at least one
`non-biologic, disease-modiJYing, anti-rheumatic drug
`(DMARD) or etanercept. In Study II and Study III, the ef(cid:173)
`ficacy and safety of ORENCIA were assessed in patients
`with an-inadequate response to MTX and who were contin(cid:173)
`ued on their stable dose of MTX. In Study IV, the efficacy
`and safety of OREN CIA were a.sSessed in patients with an
`inadequate response to a TNF blocking agent, with the
`TNF· blocking agent discontinued prior to randomization;
`other DMARDs were permitted. Study V primarily as(cid:173)
`sessed safety in patients with active RA requiring addi(cid:173)
`tional intervention in spite of current therapy with
`DMARDs; all DMARDs used at enrollment were continued:
`Patients in Study V were not excluded for comorbid medical
`conditions.
`Study I patients were nndomized to receive one of three
`doses ofORENCIA (0.5, 2, or 10 mg/kg) or placebo ending
`at week 8. Study li patients were randomized to :receive
`ORENCIA 2 or 10 mg!kg or placebo for 12 months. Study
`III, IV; and V patients were randomized to receive a dose of
`ORENOIA based on weight range or placebo for 12 months
`(Studies III and V) or 6 months (Study IV). The dose of
`ORENCIA was 500 mg for patients weighing less than
`60 kg, 750 mg for patients weighing 60 to 100 kg, and
`1 gram for patients weighing greater than 100 kg.
`Clinical Response
`The percent of ORENCIA (abatacept)-treated patients
`achieving ACR 20; 50, and 70 responses and major clinical
`response in Studies I, III, and IV are shown in Table 2.
`ORENCIA-treated patients had higher ACR 20, 50, and 70
`response rates at 6 months compared to placebo-treated
`patients. Month 6 ACR response rates in Study II for the
`10 mg/kg. group were similar to the ORENCIA group in
`Study III.
`In Studies III and IV; improvement in the ACR 20 response
`rate versuS placebo was observed within 15 days in some
`patients. In Studies II and lii, ACR response rates were
`maintained to 12 months in ORENCIA-treated patients.
`ACR responses were maintained up to three years in the
`open-label extension of Study II.
`
`~ [See table 2 at bottom of previous page] •
`
`The results of the components o{the ACR response criteria
`for Studies III and IV are shown m Table 3. In OREN CIA(cid:173)
`treated patients, greater improvement was seen in all ACR
`response criteria components through 6 and 12 months
`than in placebo-treated patients.
`[See table 2 at bottom of previous page]
`The time course of ACR 50 response for Study III is shown
`in Figure 1. The time course for Study IV was similar.
`
`Figure 1
`
`Time Course of ACR 50 Response ,
`Inadequate Response to MTX (Study Ill)
`
`--- ORENCIAIMTX -{]- Placebo/MTX
`
`80
`70
`"' c: 80
`'6 c: 50
`~ ., 40
`a:
`-c .,
`~ .,
`
`30
`20
`10
`
`Q.
`
`0
`
`2
`
`4
`
`8
`
`10
`
`12
`
`Months
`
`ORENCIA-treated patients experienced greater improve(cid:173)
`ment than placebo-treated patients in morning stifrness.
`Radiographic Response
`Structural joint damage was assessed radiographically and
`expressed as change in Genant-modified Total Sharp
`Score2 (TSS) and its components, the erosion score and
`Joint Space Narrowing (JSN) score, at inoilth 12 compared
`to baseline. In Study III the baseline median TSS was 31.7
`in ORENCIA-treil.ted patients and 33Acin placeb0rtreated
`patients. The results are shown in Table 4. ORENCIAIMTX
`slowed the progression of structural damage compared to
`placebo/MTX alone.
`[See table 4 above]
`Physical Function Response and Health-Related Out(cid:173)
`comes
`Improvement in :physical function was measured by \he
`Health Assessment Questionnaire Disability Index fHAQ(cid:173)
`3 In Studies IT-V, OREN CIA (abatacept)demonstrated
`DIJ. 1
`•
`greater -improvement from baseline than placebo in .the
`HAQ-DI. The results from Studies II and ·III are shown in
`Table 5. Siii:I.ilar resu,lts were 'observed in Study V. During
`the openClabel period of Study' II, the improvement in
`physical function has been maintained for up to 3 years.
`
`Number of
`~en~er joints
`(0,68)
`Number of
`swollen joints
`(Q-66)
`Pain lei
`Patient global
`asses$ment a.
`D~bility
`index b
`Physician
`global
`assessment o
`CRP(mg/dLl
`
`2.2
`
`2.1
`
`• p<_9.01, ORENCIA vs placebo, based on '}lean percentchan(.<efrom baseline.
`• ~ p<O.OOl. l:lREN,CJA v~ placebo, based. on mean percent chonge rTOm baseline.
`• Visual analog seal ;. 0 ,3 best, 100 = \von;t.
`··
`· ·
`·
`b Health Aosessmonl Que~tionnaire ' : 0 .. besl, 3 ~ worst; 20 questions; 8 categories: dressing and grooming, arising,
`eating, walking, hygi,ene, reach, grip, and activities.
`' .
`.
`
`Table 4: Mean Radiographic Changes Over 12 Months in Study Ill
`
`Parameter
`
`l'otal Sharp score
`Erosion score
`JSN score
`
`ORENCIA/MTX
`n=391
`
`Placebo/MTX
`n=195
`
`1.21
`0.63
`0.58
`
`2.32
`1.14
`1.18
`
`' Based on non-parametric analysis.
`
`Placebo/MTX-
`ORENCIA/MTX
`(95% Confidence Interval)
`
`1.11 (0.35, 1.88)
`0.51 (0,08~0 . 94)
`0.60 (0.21, 0.99)
`
`P-value8
`
`0.012
`0.029
`0.00!1
`
`Table 5: Mean Improvement from Baseline in Health Assessment Questionnaire Disability lndex·(HAQ-DII
`
`HAQ Disability Index
`
`Baselilie (Mean)
`
`Mean Improvement Year 1
`
`lna~equate Response to Methotrexa~e
`
`Study II
`
`Study Ill
`
`OREN CIA"
`·. +MTX
`(n= 115)
`
`0.98c
`
`0.40c·***
`
`Pla:i:ebo
`+MTX
`(n= 119)
`
`0.97"
`
`0.15c
`
`ORENCIAb
`+MTX
`(n=422)
`
`1.69d
`
`0.66.·***
`
`Placebo
`;tMTx
`<n=212l
`
`1.69.<'
`
`0.37d
`
`••• p<0.001, ORENCIA vs placebo.
`'lOmg/kg.
`b Dosing based on wuigh~rllnge (see DOSAGE AND ADMINISTRATION).
`.
`c Modlfi~.d H,!'allh i\sses$-menL Qu.eslionnairo.' ' 0 ~ best, 3 = w~;~dit.; 8 queitions; 8 Clltegorie~~: dressing anil groommg,
`ari$lng1 eating, walking, hygjene, reach, grip, and activities.
`• Health Assessment Questionnaire 1
`: 0 = best, 3 = worst; 20 questions; 8 categories: dressing nnd grooming, arising,
`eating, walking, hygiene, reach, grip, and activities.
`•
`
`[See table 5 above]
`Health-related quality of life was assessed by the SF-36
`questionnaire4 at 6 months in Studies II, III, and IV and at
`12 months in Studies II and III. In these studies, improve(cid:173)
`ment was observed in the ORENCIA (abatacept) group as
`compared with the placebo group in all 8 domains of the
`SF -36 as .vyell as the Physical Component Summary (PCS)
`and the Mental Compi)Ilent Summary (MCS).
`
`iNDICATIONS AND USAGE
`ORE!~~ CIA 1s indicated for -reducing signs nnd symploms,
`inducing major clinical response. slo"~ng th pro~on of
`slructural damage, and iinp~oving physical function m
`adult patients with moderately to severely active rheuma(cid:173)
`toid_ arthritis who hnve bod ll.n inndeq_uat.c r sponse to one
`or more DMARDs, s uch nil mcthoLrexal" or TNF
`lllll.(tg(lnists. QRENCJA n1ay oo used us monplhernpy or
`con.comitorltly with Dli1.Alllis olher Lhan TNF nntllgonis~a.
`O{tENCIA aboi.a.cept) should not oo 1dministl:redconcom,
`itunlly wilh TNF antogonisls. ORENCIA is not recom(cid:173)
`mended for use concomitantly with ana.kinra.
`
`CONTRAINDICATIONS
`ORENCIA should not be administered to patients with
`k.riown hypersensitivity to OREN CIA or any of its compo-
`·
`nents.
`
`W~GS
`Concomitant Use with TNF Antagonists
`In controlled clinical trials, patients receivingconcomitant
`OREN CIA and TNF antagonist therapy experienced more
`infections (63%) and serious infections (4.4%) compared to
`patients treated with only TNF antagonists (43% and0:8%;
`respectively) (see ADVERSE REACTIONS: Infections).
`These trials failed to demonstrate an important enhance-
`
`ment of efficacy with concomitant admi.rnstration of
`ORENCIA (abataceptl with TNF antagonist; therefore,
`concurrent therapy with ORENCIA and a TNF antagonist
`is not recommended. While transitioning from TNF antag(cid:173)
`onist therapy to ORENCIA therapy, patients should be
`monitored for ~igns of inf!'Ction.
`PRECAUTIONS
`Hypersensitivity
`Of 2688 patients treated with OREN CIA 'in clinical trials,
`there were two cases of anaphylaxis or anaphylactoid re(cid:173)
`actions. Other events potentially associated with drug hy(cid:173)
`persensitivity, such as hypotens-ion, urticaria, and dyspnea,
`each occurred in less t.lmn 0.9'7- of ORENCIA-lrenrod pa(cid:173)
`tients. Appropriate medical support measures for the treat(cid:173)
`ment of hypersensitivity reactions should be available for
`immediate use in the event of a reaction (se~ ADVERSE
`REACTIONS: Infusion-Related Reactions and Hypersensic
`tivity Reactions).
`.
`.
`.
`lnfe<:tlon~
`Phy,t~icians should exercise caution. w.hen cqnsidering tl)e
`use of O:RENCIA m patients 'vith a hisuny of recurrent on(cid:173)
`fectians, und!!rlying conditions wlikb may predlspes<t them
`to infections, or chronic. latanl, or localized infections. Pa(cid:173)
`tients who de,•!!lop a nc' infection while undcrgoongtreal-
`~:r:\i~,;~fo~:;g;~~:tdb~ed~~!~';;'~~~~~s~~ ~=t
`dt!Velops a serious infection (see ADVERSE REACTIONS:
`Infections). A higher rate of serious infections has been ob-
`rved
`in patients LreoLecf wilh
`conCUJTC.nL TJ).'P
`anmgonists und ORENCIA (lree WARNINGS: Concomitant
`Usa with TNF Antagonists).
`Prior to initiating immunomodulatory therapies, including
`ORENCIA, patients should be screened for latent tubercu-
`
`Continued: on next page
`
`Consult.2007.PDR& supplement;s and future editions for revisions
`
`

`

`916/BRISTOL-MYERS SQUIBB
`
`Orencia-Cont.
`
`losis iofection with a tuberculin skin test. ORENCIA
`(abatacept) has not been studied in patients with a positive
`tuberculosis screen, and the safety ofORENCIA in individ(cid:173)
`uals with latent tuberculosis infection is unknown. Pa(cid:173)
`tients testing positive in tuberculosis screening should be
`treated by standard medical practice prior to therapy with
`OREN CIA.
`Immunizations
`Live vaccines should not be given concurrently with
`ORENCIA or within 3 months of its discontinuation. No
`data are available on the secondary transmission of iofec(cid:173)
`tion from persons receiving live vaccines to patients receiv(cid:173)
`ing OREN CIA. The efficacy of vaccination in patients re(cid:173)
`ceiving OREN CIA is not known. Based on its mechanism of
`action, OREN CIA may blunt the effectiveness of some im(cid:173)
`munizations.
`Use in Patients with Chronic Obstructive Pulmonary
`Disease (COPDl
`COPD patients treated with ORENCIA developed adverse
`events more frequently than those treated with placebo, in(cid:173)
`cluding COPD exacerbations, cough, rhonchi, and dyspnea.
`Use of ORENCIA in patients with rheumatoid arthritis
`and COPD should be undertaken with caution and such pa(cid:173)
`tients should be mon.itored for worsening of their respira(cid:173)
`tory status (see ADVERSE REACTIONS: Adverse Reac·
`tions in Patients with COPD).
`Information for Patients
`Patients should be provided the ORENCIA Patient Infor(cid:173)
`mation leaflet and provided an opportunity to read it prior
`to each treatment session. Because caution should be exer(cid:173)
`cised in admin.istering ORENCIA to patients with active
`infections, it is important that the patient's overall health
`be assessed at each visit and any questions resulting from
`the patient's reading of the Patient Information be dis(cid:173)
`cussed.
`Drug Interactions
`Formal drug interaction studies have not been conducted
`with ORENCIA.
`Population pharmacokinetic analyses revealed that MTX,
`NSAIDs, corticosteroids, and TNF blocking agents did not
`influence abatacept clearance (see CLINICAL PHARMA(cid:173)
`COLOGY: Pharmacokinetics), The majority of patients in
`RA clinical studies received one or more of the following
`concomitant medications with ORENCIA: MTX, NSAIDs,
`corticosteroids, TNF blocking agents, azathioprine,
`chloroquine,
`gold,
`hydroxychloroquine,
`lefiunomide,
`sulfasalazine, and anakinra.
`Concurrent admin.istration of a TNF antagoriist with
`ORENCIA has been associated with an increased risk of
`serious iofections and no sign.ilicant additional efficacy
`over use of the TNF antagon.ists alone. Concurrent therapy
`with OREN CIA and TNF antagon.ists is not reco=ended
`(see WARNINGS: Concomitant Use with TNF Antagonists).
`There is insufficient experience to assess the safety and ef(cid:173)
`ficacy of OREN CIA (abata'cept) admin.istered concurrently
`with anakinra, and therefore such use is not recommended.
`Immunosuppression
`The possibility exists for ~rugs inhibiting T cell activation,
`including OREN CIA, to affect host defenses against iofec(cid:173)
`tions and malignancies since T cells mediate cellular
`immune
`responses. The
`iinpact of treatment with
`OREN CIA on the development and course of malignancies
`is not fully understood (see ADVERSE REACTIONS: Ma·
`lignancies). In clinical trials, a higher rate of infections was
`seen in ORENCIA-treated patients compared to placebo
`(see ADVERSE REACTIONS: Infections).
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`In a mouse carcinogenicity study, weekly subcutaneous in(cid:173)
`jections of 20, 65, or 200 mglkg of abatacept administered
`each week for up to 84 weeks in males and 88 weeks in fe(cid:173)
`males were associated with increases in the incidence of
`malignant lymphomas (all doses) and mammary gland tu(cid:173)
`mors (intermediate- and high-dose in females). The mice
`from this study were infected with murine leukemia virus
`and mouse mammary tumor virus. These viruses are
`associated with an increased incidence of lymphomas and
`mammary gland tumors, respectively, in immunosuppres(cid:173)
`sed mice, The doses used in these studies were 0.8-, 2.0-
`and 3.0-fold, the human exposure at 10 mglkg, respectively,
`based on AUC. The relevance of these findings to the clin.i(cid:173)
`cal use of OREN CIA is unknown.
`In a one-year toxicity study in cynomolgus monkeys,
`abatacept was admin.istered intravenously once weekly at
`doses up to 50 mglkg (9-fold the human exposure at
`10 mglkg dose based on AUC). Abatacept was not
`associated with any sign.ilicant drug-related toxicity. Re(cid:173)
`versible pharmacological effects consisted of minimal tran(cid:173)
`·sient decreases in serum lgG and minimal to severe lym(cid:173)
`phoid depletion of germinal centers in the spleen and/or
`lymph nodes. No vidcno:e ot lymphomas or pteneoplasl:ic
`morpho\ogicChangu was observed, despite the presence or
`n virus Uym!!b.OQyptoviru.~) known to en use these Ja.ons
`in immunosuppressed monkeys within the time frame of
`this study. '!'he -cclevance of these findings to the clin.ical
`use 11fORENC!Ais unknown.
`No mutagenic potential of abatacept was observed in the in
`uitro reverse Am or Ghine~ hamster ovary/hypo>UUI(cid:173)
`dline .guaDine pliosphoribosy\-~nafe~ (CliO!HGPRT)
`forwal'd paint muta.tion (with urwnhont motabo1ic ncti.,a(cid:173)
`tioD) ~. and na chli)mcl80mlll ahenatio.ns "" re ob(cid:173)
`eened in hUIIUin lymphocyt.U (with or \l.;thou~melabo!ic
`a~uoo) &teated 1rith llba~pt. ln ~. abataoept had
`
`no adverse effects on male or female fertility at doses up to
`200 mglkg every three days (11-fold a human dose based on
`AUC).
`Pregnancy Category C
`Abatacept was found not to be teratogenic in mice at doses
`up to 300 mglkg and in rats and rabbits at doses up to
`200 mg/kg daily (29-fold a human 10 mg/kg dose based on
`AUC in rats and rabbits). Rats treated with abatacept
`every three days during early gestation throughout the lac(cid:173)
`tation period showed no adverse effects in the offspring at
`dose" up to 45 mg/kg (3-fold a human 10 mglkg dose based
`on AUC). At a dose of200 mglkg(ll-fold a human 10 mglkg
`do"e based on AUC), alterations of immune function con(cid:173)
`sisted of a 9-fold increase in the T-cell dependent antibody
`response in female pups and inflammation of the thyi:oid in
`one female pup out of 10 males and 10 females evaluated.
`Whether these findings indicate a risk for development of
`autoimmune disease