(cid:9) (cid:9)
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`New Business Development: Mukesh Mehta, RPh
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`
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`EDITION
`
`PDV
`55
`2001
`YS C ANS
`DTSK
`RI- NC
`
`MEDICAL ECONOMICS Copyright 2001 and published by Medical Economics Company, Inc. at Montvale, NJ 07645-1742. All rights reserved. None of
`the content of this publication may be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or
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`THOMSON HEALTHCARE
`PHYSICIANS' DESK REFERENCE, PDfr, Pocket PDR', The POW Family Guide to Prescription Drugs', The PDR' Family
`GuitIS to Women's Haeilli and Prescription Drugs', /Intl Tna POW Family. Guide to Ntitrillen and Hea1111' aro registered trademarks used herein under license. PDFt for
`Ophthalmic Marileinosfm. FOR for Nonpresoription Drugs and Dietary suppramentarm, Port Companion Guide". PDR PharrnacopoeiaTM Pucka! Edition, FOR° for Herbal
`Maolcines'm, FOR for Nuiritionel Supplements'TM, MDR' Medical Dictionarymf, POW Nurse's Drug Handbooks'. PDFr .Nurse's Drctionary'm, The FOR' Family Guide
`EficYcloPsdla of MediCal Care'"', The PDR` Family Guide to Natural fvlethcines and Healing Thorapiesm, Ina POR' Family Guide to Common Fkilmsritem, The PM' Family
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`lode. 1,,esirrent, New Ateclia; . Suzanne BeDell; Vice Pi (•,:i,(.1,1, Corporate Haman
`0.1liceis of Mealcul fir:enemies Company:Prof4deni and allef Executive Officer: Curtis B. (cid:9)
`1,,111101.1 M Rn.sir, Chief Finarroi/r/ Officar: Christopher Carldi; Vica Pres/dent and Coniroll.'r; B; any Gray, Or:i, Pro,snitalt, Finance: Donna (cid:9)
`wee pregittent,
`Senior Vice President, Operations: John N. Ware
`hriViCO3 (cid:9)
`
`Ex. 1007 - Page 1
`
`

`

`.CENT.00ORPI085
`
`recommended doses of 3 mg/kg in rheumatoid arthritis and
`5 mg/kg in Crolink disease indicate that the terminal half-
`life of infliximeh is 8.0 to 9.5 days.
`Following an initial dose of REMICADE, repeated in regent;
`at 2 arid 6 weeks in fistulizing CrOhn's disease and rhourtia.
`tuid arthritis patients remitted in predictable concentratien-
`time profiles following each treatment. No systemic accu-
`mulation of inffiximrsh octurred upon continutal repeated
`treatment with '3 mg/kg or 10 mg/kg at 4- or 8-reek inter-
`vals in rheumatoid arthntia patients or patients with mod-
`erate or severe Crohn's disease retreated with 4 infusions of
`10 tng/kg REMICADE at 8-week intervals. No major differ-
`ences in clearance or volume of distribution were observed
`in patient subgroups defined by age or weighL It is not
`known if there are differences in clearance or volume of dis-
`tribution between gender subgroups. or in patients with
`marked impairment of hepatic or renal functien.
`CLINICAL STUDIES
`Rheumatoid Arthritis
`The safety and efficacy of REMICADE when given in con-
`junction with methotrexitte (MIX) were asseseed in a mul-
`ticenter, randomised, double-blind, placebo-controlled study
`of 429 patients with active rheumatoid arthritis despite
`treatment with M'I'X (the A nti-TNE (cid:9)
`i n'Elimintatoid At-
`thnto with Concomitant Therapy or ATTRACT). The me-
`dian age of patients unrolled was 54 years, with a median
`duration of disease of 8.4 years sad a median number of
`swollen and tender joints of 20 and 31 respectively All pa-
`tients were to have received MIX for 6 menthe and be on
`atablo dose -1". 12.5 ing/week for 4 weeks prior to study. All
`REMICADIe and placebo grimes continued their xtable dose
`of MIX and folic and.
`In addition to MTX, patients received placebo, 3 mg/kg ur 10
`mg/kg of REMICADE by intravenous infusion at weeks 0, 2
`and 6 followed by additional infusions every four or eight
`weeks thereafter Concurrent use of arable doses of arnica-tr.
`ticosteroids (10 mg/day) and/or nonsteioidal anti-inflamma-
`tory drugs was also permitted. The primary endpoint was
`the proportion of patients at week 30 who attained an im-
`provement in signs end symptoms as mongered by the
`American College of Ilheunintnlogy criteria, (ACR 20). An
`ACR 20 response is defined as at lanai. la 20% improvement
`in both lender end swollen joint iminte and in 3 of the fol-
`lowing 5 criteria. physician global assessment, pntlent
`global aseessinent, fenctional/dittahility measure, visual an-
`alog pain orate and erythrocyte sedimentation rate (ESE) or
`CRP
`At week 30, 43/88 (50%) or patients treated every &weeks
`with 3 mg/leg of REMICADE plus MTX attained an ACE 20
`compared with 18/3'48120961 of pntients treated with placebo
`plus MIX (p<0.0011. Higher doses nnil/or mere frequent ad-
`ministrntiona did not result in higher response rates. Re-
`sults are shown in Figure 1.
`
`% Patients Responding
`
`Weeks
`
`-0-- rawe.e. -0-- 3 inks o e wks -171- 10 meere Ake
`-A- 3 rnotlig q a wka --M- 10 rnsea2 q 4 wk.
`
`AS Weeps received concomitant melhotresale
`
`ire 1, Percentage of Patients who Achieved an ACR 20,
`
`At week 30; the ACE 50 response was 27% for patients
`treated with 3 mg/kg REMICADE (infliximab) 'every 8
`weeks plus MTX, compared to 5% for patients treated with
`placebo plus MTX (p•,.0 001). Tho ACE 70 response woe 8%
`for patients treated with 3 ing/ke REMICADE every
`weeks plan MIX and 0% for patients treated with placebo
`0115 MTX, Patients receiving :1 nig/kg REMICADE every 8
`weeks doinonstratiul superior improvement in all ACE re-
`sponse components except HAQ compared to patients
`treated with placebo plus MIX (Table 1). Data on use of
`REMICADE without concurrent MTX are limited (see PRE-
`CAUTIONS, Intmurrogenicity)P
`(See table 1 at top of next page]
`Active Crohn's Disease
`The safety and efficacy of REMICADE were assessed in a
`randomized, double-blind, placebo-controlled dose ranging
`study of 108.patients with moderate to severe active Crohn's
`dleelleee (Cretin's Disease Activity Index (CDAl)
`:a.2204001. All patients had experienced an inadequate re-
`sponge to prior cenviiiitional therripies, including certain.
`teraids (60% of patients), 5-amlnenancylates (5-ASA) (60%)
`andlor 6.increnptopunne/arathioprine I6-MP/AZ/0 (37%1.
`Cuncurrent use of stable dose regimens. of corticosteroids,
`5.ASA, 6-M1' nnii/or AZA was permi tted and yr, orpattents
`continued to receive at least unit of thmirriediratinus
`The study was divided into three phases. In the first pliase,
`patients were randomized to receive a single intravenous
`
`Continued on next page
`
`Consult 20 01 PIM supplements and future editions for revisions
`
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`Contact:
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`
`REMICADE®
`INFLIXIMAB
`recombinant
`For IV Injection
`
`DESCRIPTION
`REM1CADE8! (inffinraati) IS a chimeric IgGI, ninnuelonal
`antibody with an appruximate molecular weight of 149,100
`&ikons. It is composed of human constant and murine vari-
`able regions. Inlliximab binds epticifically to human tumor
`necrosis factor alpha (TN Fo) with an association constant of
`1010 (cid:9)
`Infliximeb is produced by a recombinant cell lure
`cultured by continuous perfusion and is purified by a aeries
`of steps that includes measures to inectivate arid 'remove
`viruses.
`REMICADE is supplied as a sterile, white, lyophilized pow-
`der for intravenous infusion. ',gnawing reeonstitution with
`10 mf. of Sterile Water fur Injection, OSP the resulting pH
`is approximately 7.2. Each eingleuse vial contains 100 mg
`inffiximeb, 500 rag sucrose, 0.5 mg polysnrbate 80, 2,2 mg
`monobasic sodium phosphate and 6.1 mg dibasic sodium
`phosphate. No preservatives are present.
`
`CLINICAL PHARMACOLOGY
`General
`InIfiximab neutralizes the biological activity of TNFo by,
`binding with high affinity to the soluble and transmem-
`brane forms of TNFo and inhibits binding nr 'MA/ with its
`ronapters." Infliximab does not neutralize INNIS (lymptio.
`toxin a), a related cytokine that Utilizes the same receptor/I
`us 1'We. Biological. activities nttributed to TNFili include:
`induction of pro.inllanunatory cytokines such aa IL-I, and
`IL-6, enhancement of- leukocyte mtgration by increasing en•
`dothelial layer permeability and expression of ndliepion
`molecules by endothelial cello and leukocytes, activation of
`noutruphil and easinophil functional activity, induction of
`acute phase reactants and other liver proteins, as well as
`tissue degrading enzymes produced by aynovietyteri and/or
`chondroeytes Cells expressing traneinembrane TNFo
`bound by ifilliximah can be lysed in stem by complement or
`effector cells.' Infliximab inhibits the functional activity of
`INF. rn a wide variety of in vitro bioaseuye uti lining human
`fibroblasts, endothelial cells, neutrophila;3 B and T lynipho.
`cytes and epithelial cells. Anti-TNFo antibodies reduce dis-
`ease activity in the cotton-top tamarin colitis model. and de.
`cream syneyitie and joint erosions in a marine niedel of col-
`lagen-induced arthritis Infliximab prevents disease in
`transgenic mice that develop polyarthritis as a result of con-
`stitutive exproosion of human TNFo, and, when adminis-
`tered after disease onset, allows eroded Joints to heal..
`Pharmacodynamics
`Elevated concentrations of TNFo have been found in the
`joints of rheumatoid arthritis •patientss and the stools of
`Crohn's diseute patients' and correlate with elevated dis-
`ease activity. In Crohn's disease, treatment with REM!,
`CADE reduced infiltration of inflammatery mils. and TNEn
`production in inflamed ;trees of the intestine, and reduced
`the proportion of mo Min uclear cella from the lamina propria
`nide to express. 174Fa and interferon .1. 4 In rheumatoid ar-
`thritis, treatment with REMICADE reduced infiltration of
`Inflammatory cells into inflamed areas of the joint as well as
`eX131'ASSAltl.ef moleculee mediating cellular Adhesion I E.
`selector, intercellular adhesion molecule-1 (ICAM-1) and
`vascular cell adhesion molecule-1 (VC:AM-DI, chemoattraa
`lion linterlookin 8 (11.-81 and monoeyte chemetactic protem
`(MCP-Ill mid tiaouo degrarIntion luintris midalloproteinase
`(MMP) 1 and 31.1 After treatment with REMICADE, pa-
`tients with Crohn'a disease or rheumatoid arthritic extol).
`Red decreased levels of serum inlerleulun 6 (ILef)) and C•
`rometivir protein (CRP) imnipared to baseline. Peripheral
`Mood lymphocytes from REMICADE-treated patients
`showed no significant decrease in number or in proliferative
`responses to to ogre mitogenic stmailation when compared
`to cella front untreated patients.
`Pharmacokinetics
`Single intravenous infusions of 1 to 20 niginig showed a pre-
`dictable and linear relationship between the 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 infliximab was distributed primarily within the vascu•
`lar compartment. Median pharmacokinetic results for the
`
`:(Ni-Uttivimi 'Lily . (cid:9)
`
`t IV;
`
`gai
`
`7.
`
`INFil
`
`8
`
`I understand that Ttinom[ua (thalid-
`
`omide) will be prescribed'ONLY for me in
`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®.(thalidomide). ,
`My doctor has answered any questions I
`have asked,
`I tinderstand that I moat participate in a
`roomy and patient registry while I am on
`'THALOMID® (thalidomide), which will
`require completing additional forms.
`
`Authorization:
`This information has been read aloud to me in the lan-
`guage of my choice. I -understand thatlf I do not follow
`all of my doctor's instructions, I will not be able to re-
`Mille TliALOMID® (thalidomide) I now authorize my
`- deafer 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)
`(ma/day/yr.)
`Guardian Signature (cid:9)
`I hoes fully explained to the patient the nature, pur-
`re, and risks of the treatment described above, espe-
`cially the risks to women of childbearing potential. I
`have asked the patient if olw/be has arty questions re-
`garding lier/hie treatment with THALOMID® (thalido.
``iiiide) and have answered those questions to the beat of
`My ability. I will ensure that tile appropriate amigo.
`etifitsef the patient consent form are completed. In ad-
`dition, I will comply with all of my obligations and re-
`sponsibilities as a prescriber registered under the
`S.T.E.PS ". restricted distribution program.
`
`•
`',Physician Name (cid:9)
`• (please print)
`
`Physician Signature (cid:9)
`
`DEA No.
`
`Date
`(mo /day/yr.)
`
`REFERENCES
`L Manson JM. 1986. Teratogenicity. Cassarett and Doull's
`Tbsicology: The Basic Science of Poisons. Third Edition,
`Pages 195-220. New York: MacMillan Publishing Co.
`2. Smithels RW and Newman CG. 1992. J. Med. Genet.
`29(10):716-723.
`3. Sampaio EP Kaplan G, Miranda A, et al. 1993. J. Infect.
`Dis. 168(21:408-414.
`4. Sarno EN, Gran GE, Vieira LM, et al. 1991, Clin. Exp.
`Immunol: 84,108-108.
`5. Sampaio EP, Moreire AL, Sarno EN, et al. 1992. J. Exp.
`Med. 175:1729-1737.
`6 Nogueira AC, Neubert It, Helge H, et a/. 1994. Life Sci-
`ences 551.2k77-92.
`7. Jacobson .1M, Greenspan .15, Spritzler J, et at. 1997.
`Now Eng..1. Med 336(21)44M-1493.
`8. 8thiminker 1-1, Smith EL, and Williams RT. 1965. Br. J.
`Miami/not 26;324-337.
`9 lyer CGS, leartgniilon J, Ramanujam K, et al. 1971. Bull.
`WHO. 45:719-732.
`10. Sheskin J and Convit J. 1969 Intl. J. Leprosy. 37:135-
`146.
`11. Waters MFR. 1971. Lepr. Rev. 42:26-42,
`12. Unpublished data, on file at Celgeite.
`TEALII.003 11/99 CO
`Sharon in Product Identification Guide, page 310
`
`For EMERGENCY telephone numbers,
`consult the Manufacturers' Index
`
`Ex. 1007 - Page 2
`
`

`

`1086/CENTOCOR
`
`PHYSICIANS' DESK REFERENCE®
`
`Remicade--Cont.
`
`Table 1
`
`MEDIAN VALUES AT EASELINE & WEEK 30 FOR ACR COMPONENTS
`3 tneekg q 8 wks
`REMICADE + MTX
`Baseline
`30 weeks
`32
`12
`19
`9
`7.0
`3.8
`6.1
`2.6
`6.6
`3.6
`1.8
`1.5
`0.8
`3.1
`40
`24
`
`Placebo + MTX
`Baseline
`30 weeks
`24
`16
`, 19
`13
`6,7
`5.9
`6.5
`5.0
`6.2
`5.5
`1.8.
`1.5
`2.3
`35
`
`39
`
`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
`
`Visual Analog. Scale (0=beat, 10aworst)
`Health Assessment Questionnaire, measurement of 8 categories: dressing and grooming, arising, eating, walking, by.
`giene, reach, grip, and activities
`
`(IV) dose of placebo. 5, 10 or 20 nig/kg of REMICADE. The
`prinuiryandpoint was the proportion of patients who expe-
`rionced &clinical response, defined as a decrease in CDAI by
`a-70 points from baseline at the 4-week evaluation and
`without an increase in Crohn's disease medications ur sur-
`gery for Crohn's disease, Patients who responded at week 4
`warn followed to week 12. Secondary endpoints included the
`proportion of patients who ware in clinical remission at
`week 4 (CDAI <150), and clinical response over time.
`At week 4, four of twenty-6,-1e (16%) of the placebo patients
`achieved a clinical response vs. twenty-two of twenty-seven
`(82%) of the patients receiving 5 mg/kg REMICADE
`(p < 0.001, two-sided. Fisher's Exact teat). One of twenty.
`five (4%) placebo patients and thirteen of twenty-seven
`(48%) patients receiving 5 ing/kg REMICADE achieved a
`CDAI <150 at week 4. The maximum response to any dom
`of REMICADE was observed within 2 to 4 weeks. The pro-
`portion of patients responding gradually diminished over
`the 12 weeks of the evaluation period. There was no 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
`
`is
`
`100
`
`75
`
`se'
`
`26
`
`0
`Weak 0
`labolon
`
`-0- Placebo (n e 25) (cid:9)
`5 mg/kg In 27) (cid:9)
`-
`
`-a- 10 mgem (n.20)
`- 20 mew (n 25)
`
`Figure 2. Response (z70 point decrease in CIA)) to a Single
`IV REMICADE or Placebo Dose.
`
`During the 12-week period following infusion, patients
`treated with REMICADE compared to placebo demon-
`strated improvement in outcomes measured by the Inflam-
`matory flaws! Disease Questionnaire.
`In the second phase, 29 patients who did not respond to the
`single dose of 0. 10 or 20 mg/kg of REMICADE entered the
`open label phase and received a single 10 mg/kg dose of
`REMICADE 4 weeks after the initial dose. 'fbn of twenty-
`nine (34%) patients experienced a response 4 weeks after
`receiving the second 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-randomized at week
`12 to receive 4 infusions of placebo or 10 mg/kg REMICADE
`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 fistglising Crohn'n disease with fistula(s) that
`were of at least 3 months duration.10 Concurrent use °rata-
`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 perianal area and 10% had 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 primary endpoint was the proportion of patinae
`who experienced a clinical response, defined as a-50% reduc-
`tion from baseline in the number of fistula(s) draining upon
`gentle compression. on at least two consecutive visits, with-
`out an increase in medication or surgery for Crohn's dis-
`ease.
`Eight of thirty-one (26%) patients in the placeltu non
`achieved a clinical response vs. twenty-one of the thirty-one
`(68%) patients in the 5 metig REMICADE arm (II = 0.002,
`two-sided, Fisher's Exact test). Eighteen of thirty-two (56%)
`patients in the II mg/kg arm achieved a clinical response.
`The median time to onset of response in the REMICADE-
`treated group was 2 weeks The median duration of re-
`sponse was 12 weeks; niter 22.weeks there was no difference
`between either dose of REMICADE and placebo in the pro-
`portion of patients in response (Figure 3). New fistula(s) de-
`veloped in approximately 15% of both REMICADE and pla-
`cebo-treated patients.
`ISae figure 3 in next column]
`Seven of sixty (12%) evaluable REMICADE-treated pa-
`tients, compared to one of thirty-one (3.5%) placebo-treated
`patients, developed an abscess in the area of listulas be-
`tween 6 and 16 weeks after the last infusion of REMICADE.
`Six of the REMICADE patients who developed an abscess
`had experienced a clinical response (see ADVERSE REAC-
`TIONS, Infections).
`
`-0- Raabe (cid:9)
`
`5 apeto --•- marine
`
`Figure 3. Response thrtilla(s) dowel wilh Three Doses of REMICAOF
`or Placebo.
`
`•
`
`Dose regimens other than dosing at weeks 0, 2 and 6 have
`not been studied. Studies have not been 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-
`tero-entero), or on cutaneously draining fistulas in locations
`other than perianal and periabdominal.
`
`INDICATIONS AND USAGE
`Rheumatoid Arthritis
`IfERICADE, in combination with methotrexate, is indi-
`cated for the reduction in signs and symptoms of [banns,
`toid arthritis in patients who have had an inadequate re-
`sponse to methotrexate.
`•
`Crohn's Disease (cid:9)
`REMICADE is 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' fistuliz-
`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 murine proteins or other;
`component of the product.
`
`WARNINGS
`RISK OF INFECTIONS
`SERIOUS INFECTIONS, INCLUDING SEPSIS AND FATAL IN-
`FECTIONS, HAVE BEEN REPORTED IN PATIENTS RECEIV:
`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 (see
`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, serum 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-
`fliximab, loss of detectable serum concentrations of REMI-
`CADE, and possible loss of drug efficacy. REMICADE
`
`Information will be superseded by supplements and subsequent editions
`
`should be discontinued for severe reactions. Medications for
`the treatment of hypersensitivity reactions (e.g., acetamino.
`phen, antihistamines, corticosteroids and/or epinephrine)
`should be available for immediate use in the event of a re-
`action (see ADVERSE REACTIONS, Infusion-related Reac-
`tions)
`
`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 immunosuppressant
`therapies are more prone to develop lymphomas (see AD-
`VERSE REACTIONS, Malignancies/ Lymphoproliferative
`Disease). The impact of treatment with REMICADE on
`these phenomena is unknown
`Immunogenicity
`Treatment with REMICADE can be associated with the de-
`velopment ufantibod los to infliximab (also referred to as hu-.
`man antichimeric antibodies, IIACA). One hundred thirty-
`four of the 199 Crohn's disease patients treated with REMI-
`CADE were evaluated for the development of infliximab-
`specific antibodies; 18 03%) were antibody-positive (the
`majority at low titer, <1:20).. Patients who were 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
`dosing of REMICADE, serum concentrations of infliximab
`were higher in rheumatoid arthritis 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 transmission of infection by live vaccines in
`patients receiving anti-TM' therapy. It is recommended
`that live vaccines not be given concurrently.
`Drug Interactions
`Specific drug interaction Studios, including interactions
`with MTX, have nut been conducted. The majority of pa-
`tients in rheumatoid arthritis or Crohn's disease clinical tri-
`als received one or more concomitant medications. In rheu-
`matoid arthritis, concomitant medications besides mirx
`were nonsteroidal anti-inflammatory agents, folic acid, co,
`ticosteroids and/or narcotics. Concomitant Crohn's disease
`medications were antibiotics, antiviral*, corticosteroids,
`6-54P/A4A and aminnaaricylates. Patients with Crohn's dis-
`ease who received immunosuppressants tended to experi-
`ence fewer infusion reactions compared to patients on no
`immunosuppressants (see PRECAUTIONS, Immanoilen'
`ity and ADVERSE REACTIONS, Infusion.edatert Reac-
`tions)
`Carcisiogenosis, Mutagerresis and Impairment of FertilnY
`lang•term studies in animals have not been performed 14
`evaluate the carcinogenic potential. No clastogenic or mum-
`genic effects of infliximah were observed in the in sum.
`mouse micronucleus test or the Salmonella Eechenthio roll
`(/trues) assay, respectively. Chromosarruil aberrations we0
`not observed in an assay poi-finned using human lymph'
`cytes, It is not known whether inffixiniab can impair Nail •
`ity in humans. No impairment of fertility was observed in s
`fertility rind general reproduction toxicity study conduct!-4
`in mice using an analogous antibody that selectively Web'
`its the functional activity of mouse TNFa.
`Pregnancy Category C
`Since infliximab does not arms-react with TM,. in specks
`other than humans and chimpanzees, animal reproffiirlsn'
`studies have net been conducted with REMICADE
`insub), It ix not known whether HEMICADE can cause fetal
`harm when administered to a pregnant woman or can sal"
`reproduction capacity while Whin-nal' is present irt Ups
`serum (ere CLINICAL. PHARMACOLOGY, Pharmacolnail'
`REMICADE should be given to a pregnant woman 011
`crubrl,°:,
`if clearly need-al No evidence of maternal (cid:9)
`toxicity or teralagenicily was observed in a ilcvsloproce.'
`
`Ex. 1007 - Page 3
`
`

`

`soul eer,rrieruips.are
`
`CENTOCOR/1087
`
`,,.,. Andy conducted in mice using an analogous anti..
`isedirely inhibits the functional activity of.
`lioft'w • (cid:9)
`too, that.
`ci.
`Plum°:1 s.."(1,11.1rrobern whether infliximab is excreted in human:
`"'"...166,nresd systemically after ingestion. Because
`It
`rook or
`1111d inimunoglobulins are excreted in human
`Miulsert'' ' becil use of the potential for adverse reactions in
`ta from REMICADE, a decision should be
`oulling,--4„,ag to discontinue nursing or in discontinue the
`
`riltu:taWki"6;.-g te'r La account the importance of the drug to the
`
`wr
`sod off .divenees of REMICADE in patients with ju-
`P (cid:9)
`Serlilt:rhelmi'doid 'arthritis' and in pediatric patients with
`ev-r.h.,6 ntnartae have not been established
`
`elltACT study, no overall differences were ubserved
`G.111.6461rTIse
`
`in effective obis or safety in the 72 pe. (lents aged 65 or older
`(cid:9) studies,
`m„nnind In younger patients. In Croluia
`were insufficient numbers of patients aged 65 or older
`there
`todetennine whether they respond differently from patients
`46d 18 to 0. Because there is a higher incidence of infec-
`nos in the elderly population in general, caution should be
`in treating the elderly Owe ADVERSE REACTIONS,
`Infections).
`ApviarsE REACTIONS
`A total of 771 patients ware treated with REMICADE in
`&me' al triale.le both Thal mataid arthri ti a and Croke.'"
`rase trials, approximately 5%, of petients discontinued
`REMICADE because of adverse experiences. The most com-
`mon reasons fur discontinuation of treatment were dyspnea,
`enjoins and headache-
`Infusion-related Reactions
`mote infusion reactinne
`An initiation reaction wan defined as any adverse event ac-
`euering during the infusion or within 1 tai 2 hears after the
`infueioa. Seventeen percent of REMICADE- treated patients
`in all clinical male experienced an infusion reaction com-
`pared to 7% of placebo-treated patients. Among the 3284
`RESIICADR infusions. 4% were accompanied by nonspecific
`symptoms such atilever or chills, 1% were accompanied by
`pruritus or urticaria, I% were accompanied by cardiopulmo-
`nary reactions (primarily chest pain, hypotension, hyper-
`tension or dysprical, and (LP& were accompanied by cam
`limed symptoms of pro ritudurticiarin and cardiopulmenary.
`imetiens. Luse than 2% of patients discontinued ItEP41-
`CADE because of infusion reactions, and all patients recov-
`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%
`rispectively). Use of concomitant immunosuppressant
`agents appeared to reduce the frequency of antibodies to in-
`'hairnet) and infusion reactions (see PRECAUTIONS, Im-
`munogenicity and Drug Interactions).
`Reactions following readrninistration
`In a clinical trial of forty patients with Cretin'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-
`tients experiencing these adverse events bad not experf-
`cared infusion-related adverse events associated with their,
`initial innocanab therapy. Of the 40 patients enrolled, these
`adverse events occurred in 9 of 23 (39%) who had received
`ilqUkd formulation which is no