REMICADE®
`(infliximab)
`
`for IV Injection
`
`DESCRIPTION:
`
`REMICADE® (infliximab) is a chimeric IgGlk monoclonal antibody with an approximate
`molecular weight of 149,100 daltons. It is composed of human constant and murine variable
`regions. Infliximab binds specifically to human tumor necrosis factor alpha (TNFa) with an
`Infliximab is produced by a recombinant cell line cultured by
`association constant of 1010 (cid:9)
`continuous perfusion and is purified by a series of steps that includes measures to inactivate and
`remove viruses.
`
`REMICADE is supplied as a sterile, white, lyophilized powder for intravenous infusion.
`Following reconstitution with 10 mL of Sterile Water for Injection, USP, the resulting pH is
`approximately 7.2. Each single-use vial contains 100 mg infliximab, 500 mg sucrose, 0.5 mg
`polysorbate 80, 2.2 mg monobasic sodium phosphate, monohydrate, and 6.1 mg dibasic sodium
`phosphate, dihydrate. No preservatives are present.
`
`CLINICAL PHARMACOLOGY:
`
`General
`
`Infliximab neutralizes the biological activity of TNFa by binding with high affinity to the soluble
`and transmembrane forms of TNFa and inhibits binding of TNFa with its receptors." Infliximab
`does not neutralize TN F[3 (lymphotoxin a), a related cytokine that utilizes the same receptors as
`TNFa. Biological activities attributed to TNFa include: induction of pro-inflammatory cytokines
`such as interleukins (IL) 1 and 6, enhancement of leukocyte migration by increasing endothelial
`layer permeability and expression of adhesion molecules by endothelial cells and leukocytes,
`activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and
`other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or
`chondrocytes. Cells expressing transmembrane TNFa bound by infliximab can be lysed in vitro by
`complement or effector cells.2 Infliximab inhibits the functional activity of TNTa in a wide variety
`of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils,3 B and T
`lymphocytes and epithelial cells. Anti-TNFa antibodies reduce disease activity in the cotton-top
`tamarin colitis model, and decrease synovitis and joint erosions in a murine model of collagen-
`induced arthritis. Infliximab prevents disease in transgenic mice that develop polyarthritis as a
`result of constitutive expression of human TNFa, and, when administered after disease onset,
`allows eroded joints to heal.
`
`Pharmacodynamics
`
`Elevated concentrations of TNFa have been found in the joints of rheumatoid arthritis patients5
`and the stools of Crohn's disease patients° and correlate with elevated disease activity. In
`rheumatoid arthritis, treatment with REMICADE reduced infiltration of inflammatory cells into
`inflamed areas of the joint as well as expression of molecules mediating cellular adhesion [E-
`selectin, intercellular adhesion molecule-1 (ICAN1-1) and vascular cell adhesion molecule-I
`(VCAM-1)], chemoattraction [IL-8 and monocyte chemotactic protein (MCP-1)] and tissue
`degradation [matrix metalloproteinase (MMP) 1 and 3].4 In Crohn's disease, treatment with
`REMICADE reduced infiltration of inflammatory cells and TNFa production in inflamed areas of
`the intestine, and reduced the proportion of mononuclear cells from the lamina propria able to
`express TNFa and interferon.] After treatment with REMICADE, patients with rheumatoid
`arthritis or Crohn's disease exhibited decreased levels of serum IL-6 and C-reactive protein (CRP)
`compared to baseline. Peripheral blood lymphocytes from REMICADE-treated patients showed
`
`14
`
`

`

`no significant decrease in number or in proliferative responses to in vitro mitogenic stimulation
`when compared to cells from untreated patients.
`
`Pharmacokinetics
`
`Single intravenous infusions of 3 mg/kg to 20 mg/kg showed a predictable and linear relationship
`between the dose administered and the maximum serum concentration and area under the
`concentration-time curve. The volume of distribution at steady state was independent of dose and
`indicated that infliximab was distributed primarily within the vascular compartment. Median
`pharmacokinetic results for doses of 3 mg/kg to 10 mg/kg in rheumatoid arthritis and 5 mg/kg in
`Crohn's disease indicate that the terminal half-life of infliximab is 8.0 to 9.5 days.
`
`Following an initial dose of REMICADE, repeated infusions at 2 and 6 weeks in fistulizing
`Crohn's disease and rheumatoid arthritis patients resulted in predictable concentration-time
`profiles following each treatment. No systemic accumulation of infliximab occurred upon
`continued repeated treatment with 3 mg/kg or 10 mg/kg at 4- or 8-week intervals in rheumatoid
`arthritis patients or patients with moderate or severe Crohn's disease retreated with 4 infusions of
`10 mg/kg REMICADE at 8-week intervals. The proportion of patients with rheumatoid arthritis
`who had undetectable infliximab concentrations at 8 weeks following an infusion was
`approximately 25% for those receiving 3 mg/kg every 8 weeks, 15% for patients administered 3
`mg/kg every 4 weeks, and 0% for patients receiving 10 mg/kg every 4 or 8 weeks. No major
`differences in clearance or volume of distribution were observed in patient subgroups defined by
`age or weight. It is not known if there are differences in clearance or volume of distribution
`between gender subgroups or in patients with marked impairment of hepatic or renal function.
`
`CLINICAL STUDIES:
`
`Rheumatoid Arthritis
`
`The safety and efficacy of REMICADE when given in conjunction with methotrexate (MTX)
`were assessed in a multicenter, randomized, double-blind, placebo-controlled study of 428 patients
`with active rheumatoid arthritis despite treatment with MTX (the Anti-TNF Trial in Rheumatoid
`Arthritis with Concomitant Therapy or ATTRACT). Patients enrolled had a median age of 54
`years, median disease duration of 8.4 years, median swollen and tender joint count of 20 and 31
`respectively, and were on a median dose of 15 mg/wk of MTX. Patients received either placebo +
`MTX or one of 4 doses/schedules of REMICADE + MTX: 3 mg/kg or 10 mg/kg of REMICADE
`by intravenous infusion (IV) at weeks 0, 2 and 6 followed by additional infusions every 4 or 8
`weeks in combination with MTX. Concurrent use of stable doses of folic acid, oral corticosteroids
`(5.10 mg/day) and/or nonsteroidal anti-inflammatory drugs was also permitted.
`
`CLINICAL RESPONSE
`
`All doses/schedules of REMICADE + MTX resulted in improvement in signs and symptoms as
`measured by the American College of Rheumatology response criteria (ACR 20)7 through 54
`weeks (Figure 1).
`
`15
`
`

`

`I
`I (cid:9)
`I (cid:9)
`I (cid:9)
`I (cid:9)
`1 (cid:9)
`I (cid:9)
`I (cid:9)
`I (cid:9)
`1 (cid:9)
`I (cid:9)
`6 10 14 18 22 26 30 34 38 42 46 50 54
`
`100 j,
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`% Patients Responding
`
`Week
`
`0 2 (cid:9)
`
`—0— Placebo (cid:9)
`
`--0— 3 mg/kg q 8 wks —0— 10 mg/kg q 8 wks
`3 mg/kg q 4 wks (cid:9)
`10 mg/kg q 4 wks
`
`All groups received concomitant MTX.
`
`Figure 1 (cid:9)
`
`Percentage of Patients who Achieved an ACR 20
`
`Compared to placebo + MTX, all doses/schedules of REMICADE + MTX consistently resulted in
`greater effects on each component of the ACR 20, except for the HAQ, where only the 3 higher
`doses/schedules showed improvements in HAQ. Results from patients receiving 3 mg/kg q 8
`weeks are shown in Table 1. Responses to the higher doses or more frequent administrations were
`similarly distributed.
`
`16
`
`

`

`Table 1
`
`COMPONENTS OF ACR 20
`
`Placebo + MTX
`
`3 mg/kg q 8 wks
`REMICADE + MTX
`
`Base-line
`
`Week 54
`
`Base-line
`
`Week 54
`
`24
`
`19
`
`6.7
`6.5
`
`6.2
`
`1.8
`
`3.0
`
`16
`
`13
`
`6.1
`5.2
`
`6.2
`
`1.5
`
`2.3
`
`32
`
`19
`
`7.0
`6.1
`
`6.6
`
`1.8
`
`3.1
`
`10
`
`9
`
`4.8
`2.6
`
`4.5
`
`1.5
`
`0.8
`
`Parameter
`(medians)
`
`No. of Tender
`Joints
`No. of Swollen
`Joints
`Pain'
`Physician's
`Global
`Assessment a
`Patient's Global
`Assessment'
`Disability Index
`(HAQ)
`CRP (mg/dL)
`
`' Visual Analog Scale (0=best, 10=worst)
`Health Assessment Questionnaire, measurement of 8 categories: dressing
`and grooming, arising, eating, walking, hygiene, reach, grip, and
`activities(0=best, 3=worst)8
`
`All doses/schedules of REMICADE + MTX resulted in a higher number of patients experiencing
`ACR 50 and ACR 70 compared to placebo + MTX (Table 2).
`
`17
`
`

`

`TABLE 2
`PERCENTAGE OF PATIENTS WHO ACHIEVED AN ACR RESPONSE
`AT WEEKS 30 AND 54
`
`REMICADE + MTX
`
`Response
`
`ACR 50
`Week 30
`
`Week 54
`
`ACR 70
`Week 30
`
`Week 54
`
`Placebo
`+ MTX
`
`(n=88)
`
`3 mg/kg *
`q 8 wks
`
`3 mg/kg*
`q 4 wks
`
`10 mg/kg*
`q 8 wks
`
`(n=86)
`
`(n=86)
`
`(n=87)
`
`10 mg/kg*
`q 4 wks
`
`(n=81)
`
`5%
`
`9%
`
`0%
`
`2%
`
`27%
`
`21%
`
`8%
`
`11%
`
`29%
`
`34%
`
`11%
`
`18%
`
`31%
`
`40%
`
`18%
`
`26%
`
`26%
`
`38%
`
`11%
`
`19%
`
`* p < 0.05 for each outcome compared to placebo
`
`Health outcome measures were assessed by the SF-36 questionnaire. The eight subscales of the
`SF-36 were combined into two summary scales, the physical component summary (PCS) and the
`mental component summary (MCS).9 At week 54, patients treated with 3 mg/kg or 10 mg/kg of
`REMICADE every 8 or 4 weeks showed significantly more improvement in the PCS compared to
`the placebo group, and no change in the NICS.
`
`Radiographic Response
`
`Structural damage in both hands and feet was assessed radiographically at week 54 by the change
`from baseline in the van der Heijde-modified Sharp score, a composite score of structural damage
`that measures the number and size of joint erosions and the degree of joint space narrowing in
`hands/wrists and feet.1° Approximately 80% of patients had paired x-ray data. Results are shown
`in Table 3.
`
`18
`
`

`

`TABLE 3
`RADIOGRAPHIC CHANGE FROM BASELINE TO WEEK 54
`
`Median
`(10,90 (cid:9)
`percentiles) (cid:9)
`
`Placebo +
`MTX
`
`REMICADE + MTX
`
`3mg/kg
`q8wks
`
`3mg/kg
`q4 wks
`
`10mg/kg
`q8 wks
`
`10mg/kg
`q4 wks
`
`p-value*
`
`(N=64)
`
`(N=71)
`
`(N=71)
`
`(N=77)
`
`(N=66)
`
`55 (14, 188)
`
`57 (15, 187)
`
`45 (8, 162)
`
`56 (6, 143)
`
`43 (7, 178)
`
`4.0 (-1.0, 19.0) 0.5 (-3.0, 5.5)
`
`0.1 (-5.2, 9.0)
`
`0.5 (-4.8, 5.0)
`
`-0.5 (-5.7, 4.0)
`
`p<0.001
`
`25 (8, 110)
`
`29 (9, 100)
`
`22 (3, 91)
`
`22 (3, 80)
`
`26 (4, 104)
`
`2.0 (-1.0, 9.7)
`
`0.0 (-3.0, 4.3)
`
`-0.3 (-3.1, 2.5)
`
`0.5 (-3.0, 2.5)
`
`-0.5 (-2.7, 2.5)
`
`p<0.001
`
`26 (3, 88)
`
`29 (4, 80)
`
`20 (3, 83)
`
`24 (1, 79)
`
`25 (3, 77)
`
`1.5 (-0.8, 8.0)
`
`0.0 (-2.5, 4.5)
`
`0.0 (-3.4, 5.0)
`
`0.0 (-3.0, 2.5)
`
`0.0 (-3.0, 3.5)
`
`p<0.001
`
`Week 54
`
`Total Score
`Baseline
`Change
`from
`baseline
`
`Erosion Score
`Baseline
`Change
`from
`baseline
`
`JSN Score
`Baseline
`Change
`from
`baseline
`
`* For comparisons of each dose against placebo
`
`Data on use of REMICADE without concurrent MTX are limited (see Precautions,
`Immunogenicity). 11.12
`
`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 disease13
`[Crohn's Disease Activity Index (CDAI) ?_220 and s400]. All patients had experienced an
`inadequate response to prior conventional therapies, including corticosteroids (60% of patients), 5-
`arninosalicylates (5-ASA) (60%) and/or 6-mercaptopurine/azathioprine (6-MP/AZA) (37%).
`Concurrent use of stable dose regimens of corticosteroids, 5-ASA, 6-MP and/or AZA was
`permitted and 92% of patients continued to receive at least one of these medications.
`
`19
`
`(cid:9)
`

`

`The study was divided into three phases. In the first phase, patients were randomized to receive a
`single IV dose of placebo, 5. 10 or 20 mg/kg of REMICADE. The primary endpoint was the
`proportion of patients who experienced a clinical response. defined as a decrease in CDAI by >70
`points from baseline at the 4-week evaluation and without an increase in Crohn's disease
`medications or surgery for Crohn's disease. Patients who responded at week 4 were followed to
`week 12. Secondary endpoints included the proportion of patients who were in clinical remission
`at week 4 (CDAI <150), and clinical response over time.
`
`At week four. 4 of 25 (16%) of the placebo patients achieved a clinical response vs. 22 of 27
`(82%) of the patients receiving 5 mg/kg REMICADE (p < 0.001, two-sided, Fisher's Exact test).
`One of 25 (4%) placebo patients and 13 of 27 (48%) patients receiving 5 mg/kg REMICADE
`achieved a CDAI <150 at week 4. The maximum response to any dose of RENIICADE was
`observed within 2 to 4 weeks. The proportion of patients responding gradually diminished over the
`12 weeks of the evaluation period. There was no evidence of a dose response; doses higher than 5
`mg/kg did not result in a greater proportion of responders. Results are shown in Figure 3.
`
`100
`
`% Responding
`
`0
`
`Week
`
`Infus(on
`
`—0— Placebo (n = 25)
`
`—e-- 10 mg,kg (n = 28)
`
`5 mgikg (n = 27)
`
`—a,— 20 mg/kg (n = 291
`
`Figure 3 (cid:9)
`
`Response (z70 point decrease in CDAI) to a Single IV REMICADE or Placebo
`Dose
`
`During the 12-week period following infusion, patients treated with REMICADE compared to
`placebo demonstrated improvement in outcomes measured by the Inflammatory Bowel Disease
`Questionnaire.
`
`In the second phase, 29 patients who did not respond to the single dose of 5, 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. Ten of 29(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/1:g 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 placebo re-treated groups.
`
`20
`
`

`

`Fistulizing Crohn's Disease
`
`The safety and efficacy of REMICADE were assessed in a randomized, double-blind, placebo-
`controlled study of 94 patients with fistulizing Crohn's disease with fistula(s) that were of at least
`3 months duration.`4 Concurrent use of stable 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 REMICADE at weeks 0, 2 and 6 and were
`followed up to 26 weeks. The primary endpoint was the proportion of patients who experienced a
`clinical response. defined as .5090 reduction from baseline in the number of fisrula(s) draining
`upon gentle compression, on at least two consecutive visits, without an increase in medication or
`surgery for Crohn's disease.
`
`Eight of 31 (26%) patients in the placebo arm achieved a clinical response vs. 21 of the 31 (68%)
`patients in the 5 mg/kg REMICADE arm (p = 0.002, two-sided, Fisher's Exact test). Eighteen of
`32 (56%) patients in the 10 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 response was 12 weeks; after 22 weeks there was no difference between either dose of
`REMICADE and placebo in the proportion of patients in response (Figure 4). New fistula(s)
`developed in approximately 15% of both REMICADE- and placebo-treated patients.
`
`2
`
`6
`
`10
`
`14
`
`18
`
`22
`
`—0— P!acebo —•!-- 5 mg/kg AI-- 10 mg/kg
`
`100
`
`75-
`
`50 —
`
`25 —
`
`% Responding
`
`0
`Week 0
`
`Infusion t
`
`Figure 4 (cid:9)
`
`Response [fistula(s) closure] with Three Doses of REMICADE or Placebo
`
`Seven of 60 (12%) evaluable REMICADE-treated patients, compared to 1 of 31 (3.5%) placebo-
`treated patients, developed an abscess in the area of fistulas between 8 and 16 weeks after the last
`infusion of REN1ICADE. Six of the REMICADE patients who developed an abscess had
`experienced a clinical response (see ADVERSE REACTIONS, Infections).
`
`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 canal, on closure of
`non-cutaneously draining fistulas (e.g., entero-entero), or on cutaneously draining fistulas in
`locations other than perianal and periabdominal.
`
`21
`
`

`

`INDICATIONS AND USAGE:
`
`Rheumatoid Arthritis
`
`REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms and
`inhibiting the progression of structural damage in patients with moderately to severely active
`rheumatoid arthritis who have had an inadequate response to methotrexate.
`
`Crohn's Disease
`
`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 single dose have not been established
`(see DOSAGE AND ADMINISTRATION).
`
`REMICADE is indicated for the reduction in the number of draining enterocutaneous fistulas in
`patients with fistulizing Crohn's disease.
`The safety and efficacy of therapy continued beyond three doses have not been established
`(see DOSAGE AND ADMINSTRATION).
`
`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 DISSEMINATED TUBERCULOSIS,
`HAVE BEEN REPORTED IN PATIENTS RECEIVING TNF-BLOCKING AGENTS,
`INCLUDING RENIICADE. SOME OF THESE INFECTIONS HAVE BEEN FATAL.
`MANY OF THE SERIOUS INFECTIONS IN PATIENTS TREATED WITH REMICADE
`HAVE OCCURRED IN PATIENTS ON CONCOMITANT IMMUNOSUPPRESSIVE
`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
`REMICADE IN PATIENTS WITH A CHRONIC INFECTION OR A HISTORY OF
`RECURRENT INFECTION. REMICADE SHOULD NOT BE GIVEN TO PATIENTS
`WITH A CLINICALLY IMPORTANT, ACTIVE INFECTION. PATIENTS SHOULD BE
`MONITORED FOR SIGNS AND SYMPTOMS OF INFECTION WHILE ON OR AFTER
`TREATMENT WITH REMICADE. NEW INFECTIONS SHOULD BE CLOSELY
`MONITORED. IF A PATIENT DEVELOPS A SERIOUS INFECTION INCLUDING
`SEPSIS, REMICADE THERAPY SHOULD BE DISCONTINUED (see ADVERSE
`REACTIONS, Infections). PATIENTS SHOULD BE EVALUATED FOR THE RISK OF
`TUBERCULOSIS, INCLUDING LATENT TUBERCULOSIS.'s TREATMENT FOR
`TUBERCULOSIS SHOULD BE INITIATED PRIOR TO TREATMENT WITH
`REMICADE.
`
`77
`
`

`

`Hypersensitivity
`
`REMICADE has been associated with hypersensitivity reactions that vary in their time of onset.
`Most hypersensitivity reactions, which include urticaria, dyspnea, and/or hypotension, have
`occurred during or within 2 hours of infliximab 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 following 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 infliximab, loss of detectable serum concentrations of
`REMICADE, and possible loss of drug efficacy. REMICADE should be discontinued for severe
`reactions. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen,
`antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the
`event of a reaction (see ADVERSE REACTIONS, Infusion-related Reactions).
`
`Neurologic Events
`
`Infliximab and other agents that inhibit TNF have been associated in rare cases with exacerbation
`of clinical symptoms and/or radiographic evidence of de-myelinating disease. Prescribers should
`exercise caution in considering the use of REMICADE in patients with pre-existing or recent
`onset of central nervous system de-myelinating disorders.
`
`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 following treatment with REMICADE, treatment should be discontinued (see
`ADVERSE REACTIONS, Auroantibodies/Lupus-like Syndrome).
`
`Malignancy
`
`Patients with long duration of Crohn's disease or rheumatoid arthritis and chronic exposure to
`immunosuppressant therapies are more prone to develop lymphomas (see ADVERSE
`REACTIONS, Malignancies/Lymphoproltferative Disease). (cid:9)
`The impact of treatment with
`REMICADE on these phenomena is unknown.
`
`Immunogenicity
`
`Treatment with REMICADE can be associated with the development of antibodies to infliximab.
`One hundred thirty-four of the 199 Crohn's disease patients treated with REMICADE were
`evaluated for the development of infliximab-specific antibodies; 18 (13%) 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 arthritis and Crohn's disease patients
`receiving immunosuppressant 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 receiving long-term treatment with RENIICADE. Because immunogenicity
`analyses are product-specific, comparison of antibody rates to those from other products is not
`appropriate.
`
`23
`
`

`

`Vaccinations
`
`No data are available on the response to vaccination or on the secondary transmission of infection
`by live vaccines in patients receiving anti-TNF therapy. It is recommended that live vaccines not
`be given concurrently.
`
`Drug Interactions
`
`Specific drug interaction studies, including interactions with NITX, have not been conducted. The
`majority of patients in rheumatoid arthritis or Crohn's disease clinical studies received one or
`more concomitant medications. In rheumatoid arthritis, concomitant medications besides MTX
`were nonsteroidal anti-inflammatory agents, folic acid, corticosteroids and/or narcotics.
`Concomitant Crohn's disease medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA
`and aminosalicylates. Patients with Crohn's disease who received immunosuppressants tended to
`experience fewer infusion reactions compared to patients on no immunosuppressants (see
`PRECAUTIONS, Immunogenicity and ADVERSE REACTIONS, Infusion-related Reactions).
`
`Carcinogenesis, Mutagenesis and Impairment of Fertility
`
`Long-term studies in animals have not been performed to evaluate the carcinogenic potential. No
`clastogenic or mutagenic effects of infliximab were observed in the in vivo mouse micronucleus
`test or the Salmonella-Escherichia coli (Ames) assay, respectively. Chromosomal aberrations were
`not observed in an assay performed using human lymphocytes. Tumorigenicity studies in mice
`deficient in TNFcc demonstrated no increase in tumors when challenged with known tumor
`initiators and/or promoters. It is not known whether infliximab can impair fertility in humans. No
`impairment of fertility was observed in a fertility and general reproduction toxicity study
`conducted in mice using an analogous antibody that selectively inhibits the functional activity of
`mouse TNFa.
`
`Pregnancy Category B
`
`Since infliximab does not cross-react with TNFa in species other than humans and chimpanzees,
`animal reproduction studies have not been conducted with REMICADE. No evidence of maternal
`toxicity, embryotoxicity or teratogenicity was observed in a developmental toxicity study
`conducted in mice using an analogous antibody that selectively inhibits the functional activity of
`mouse TNFa. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF
`analogous antibody produced maximal pharmacologic effectiveness. Doses up to 40 mg/kg were
`shown to produce no adverse effects in animal reproduction studies. It is not known whether
`REMICADE can cause fetal harm when administered to a pregnant woman or can affect
`reproduction capacity. REMICADE should be given to a pregnant woman only if clearly needed.
`
`Nursing Mothers
`
`It is not known whether infliximab is excreted in human milk or absorbed systemically after
`ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of
`the potential for adverse reactions in nursing infants from REMICADE, a decision should be made
`whether to discontinue nursing or to discontinue the drug, taking into account the importance of
`the drug to the mother.
`
`24
`
`

`

`Pediatric Use
`
`Safety and effectiveness of REMICADE in patients with juvenile rheumatoid arthritis and in
`pediatric patients with Crohn's disease have not been established.
`
`Geriatric Use
`
`In the ATTRACT study, no overall differences were observed in effectiveness or safety in 72
`patients aged 65 or older compared to younger patients. In Crohn's disease studies. there were
`insufficient numbers of patients aged 65 and over to determine whether they respond differently
`from patients aged 18 to 65. Because there is a higher incidence of infections in the elderly
`population in general, caution should be used in treating the elderly (see ADVERSE REACTIONS,
`Infections).
`
`ADVERSE REACTIONS:
`
`A total of 771 patients were treated with REMICADE in clinical studies. In both rheumatoid
`arthritis and Crohn's disease studies, approximately 6% of patients discontinued REMICADE
`because of adverse experiences. The most common reasons for discontinuation of treatment were
`dyspnea, urticaria and headache. Adverse events have been reported in a higher proportion of
`patients receiving the 10 mg/kg dose than the 3 mg/kg dose.
`
`Infusion-related Reactions
`
`Acute infusion reactions
`
`An infusion reaction was defined as any adverse event occurring during the infusion or within 1 to
`2 hours after the infusion. Nineteen percent of REMICADE-treated patients in all clinical studies
`experienced an infusion reaction compared to 8% of placebo-treated patients. Among the 4797
`REMICADE infusions, 3% were accompanied by nonspecific symptoms such as fever or chills,
`I% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension,
`hypertension or dyspnea), <1% were accompanied by pruritus, urticaria, or the combined
`symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions
`including anaphylaxis were infrequent. Less than 2% of patients discontinued REMICADE
`because of infusion reactions, and all patients recovered with treatment and/or discontinuation of
`infusion. REMICADE infusions beyond the initial infusion in rheumatoid arthritis patients were
`not associated with a higher incidence of reactions.
`
`Patients with Crohn's disease who became positive for antibodies to infliximab were more likely
`to develop infusion reactions than were those who were negative (36% vs. 11% respectively). Use
`of concomitant immunosuppressant agents appeared to reduce the frequency of antibodies to
`infliximab and infusion reactions (see PRECAUTIONS, Immunogenicity and Drug Interactions).
`
`Reactions following readministration
`
`In a clinical study of forty patients with Crohn's disease retreated with infliximab following a 2 to
`4 year period without 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. Patients experiencing
`these adverse events had not experienced infusion-related adverse events associated with their
`initial infliximab therapy. Of the 40 patients enrolled, these adverse events occurred in 9 of 23
`(39%) who had received liquid formulation which is no longer in use and 1 of 17 (6%) who
`received lyophilized formulation. The clinical data are not adequate to determine if occurrence of
`these reactions is due to differences in formulation. Patients' signs and symptoms improved
`substantially or resolved with treatment in all cases. There are insufficient data on the incidence of
`these events after drug-free intervals of less than 2 years. However, these events have been
`
`75
`
`

`

`observed infrequently in clinical studies and post-marketing surveillance at intervals of less than 1
`year.
`
`Infections
`
`In REMICADE clinical studies, treated infections were reported in 32% of REMICADE-treated
`patients (average of 37 weeks of follow-up) and in 22% of placebo-treated patients (average of 29
`weeks of follow-up). The infections most frequently reported were upper respiratory tract
`infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. No
`increased risk of serious infections or sepsis were observed with REMICADE compared to
`placebo in the ATTRACT study. Among REMICADE-treated patients, these serious infections
`included pneumonia, cellulitis and sepsis. In the ATTRACT study, one patient died with miliary
`tuberculosis and one died with disseminated coccidioidomycosis. Other cases of tuberculosis,
`including disseminated tuberculosis, also have been reported post-marketing. Although the
`relationship to REMICADE is unknown, most of the cases of tuberculosis occurred within the first
`two months after initiation of therapy with infliximab and may reflect recrudesence of latent
`disease (see WARNINGS, RISK OF INFECTIONS). Twelve percent of patients with fistulizing
`Crohn's disease developed a new abscess 8 to 16 weeks after the last infusion of REMICADE (see
`CLINICAL STUDIES, Fistulizing Crohn's Disease).
`
`Autoantibodies/Lupus-like Syndrome
`
`In the ATTRACT rheumatoid arthritis study through week 54, 49% of REMICADE-treated
`patients developed antinuclear antibodies (ANA) between screening and last evaluation, compared
`to 21% of placebo-treated patients. Anti-dsDNA antibodies developed in approximately 10% of
`REMICADE-treated patients, compared to none of the placebo-treated patients. No association
`was seen between REMICADE dose/schedule and development of ANA or anti-dsDNA.
`
`Of Crohn's disease patients treated with REMICADE who were evaluated for antinuclear
`antibodies (ANA), 34% developed ANA between screening and last evaluation. Anti-dsDNA
`antibodies developed in approximately 9% of Crohn's disease patients treated with REMICADE.
`The development of anti-dsDNA antibodies was not related to either the dose or duration of
`REMICADE treatment. However, baseline therapy with an immunosuppressant in Crohn's disease
`patients was associated with reduced development of anti-dsDNA antibodies (3% compared to
`21% in patients not receiving any immunosuppressant). Crohn's disease patients were
`approximately 2 times more likely to develop anti-dsDNA antibodies if they were ANA-positive
`at study entry.
`
`In clinical studies, three patients developed clinical symptoms consistent with a lupus-like
`syndrome, two with rheumatoid arthritis and one with Crohn's disease. All three patients
`improved following discontinuation of therapy and appropriate medical treatment. No cases of
`lupus-like reactions have been observed in up to three years of long-term follow-up (see
`PRECAUTIONS, Autoirrimuntry)
`
`NIalignanciesfLymphoproliferative Disease
`
`In completed clinical studies of REMICADE for up to 54 weeks, 7 of 771 patients developed 8
`new or recurrent malignancies. These were non-Hodgkin's B-cell lymphoma, breast cancer,
`melanoma, squamous, rectal adenocarcinoma and basal cell carcinoma. There are insufficient data
`to determine whether REMICADE contributed to the development of these malignancies. The
`observed rates and incidences were similar to those expected for the populations studied 16 ' 17 (see
`PRECAUTIONS, Malignancy).
`
`Other Adverse Reactions
`
`Adverse events occurring at a frequency of at least 5% in all patients treated with REMICADE are
`shown in Table 4. Patients with Crohn's disease who were treated with REMICADE were more
`
`26
`
`

`

`likely than patients with rheumatoid arthritis to experience adverse events associated with
`gastrointestinal symptoms.
`
`