REMICADETM
`REMICADETm
`INFLIXIMAB
`INFLIXIMAB
`for IV Injection
`for IV Injection
`
`DESCRIPTION:
`DESCRIPTION:
`
`Remicade (Infliximab) is a chimeric IgGlic 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 association constant of 10m
`Infliximab is produced by a recombinant cell line cultured by continuous perfusion and is purified
`by a series of steps that includes measures to inactivate and remove viruses.
`
`Remicade (Infliximab) is a chimeric 1gGl~ 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 aipha (TNFaj with an association constant of i 0’” Mm’. Infliximab is produced by a recombinant cell line cultured by 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 and 6.1 mg dibasic sodium phosphate. No preservatives are present.
`
`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 and 6.1 mg dibasic sodium phosphate. No preservatives are present.
`
`CLINICAL PHARMACOLOGY:
`CLINICAL PHARMACOLOGY:
`
`General
`General
`
`transmembrane forms of TNFa and inhibits binding of TNFa with its receptors. l-s Infliximab does not neutralize TNFP (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 IL- 1 and IL-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, and induction of acute phase and other liver proteins.4 Cells expressing transmembrane TNFa bound by Infliximab can be lysed
`
`“a..+,-ol;,c,,
`th, h;,l,,;,,l
`on+;.,;,.,
`nf TNC,v
`h., h;nrl;mm
`.rr;+h h;mh nff;e.;e,,
`cr\ th,
`.-.,l..hl,
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`Tnfl;v;moh
`Infliximab neutralizes the biological activity' of TNFa by binding ‘with high affinity' to the, soluble and
`lllllllzllllLI”
`IICIUCILIIIL.LJ
`L11b “l”l”~;lLcll
`aLC‘“lLy
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`auu
`transmembrane forms of TNFa and inhibits binding of TNFa with its receptors. 1-3 Infliximab does not
`neutralize TNFI3 (lymphotoxin a),1 a related cytokine that utilizes the same receptors as TNFa.
`Biological activities attributed to TNFa include: induction of pro-inflammatory cytokines such as IL-1
`and IL-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, and induction of acute phase and other liver proteins.4 Cells expressing
`in vitro
`transmembrane TNFa bound by Infliximab can be lysed in vitro by complement or effector cells .2
`Anti-TNFa antibodies reduce disease activity in a cotton-top tamarin colitis model.5 Infliximab
`in vitro
`inhibits the functional activity of TNFa in a wide variety of in vitro bioassays utilizing human
`bioassays utilizing human fibroblasts, endothelial cells, neutrophils,” B and T lymphocytes6,7 and epithelial cells.’
`fibroblasts, endothelial cells, neutrophils,3 B and T lymphocytes6'7 and epithelial cells.8
`
`by complement or effector cells.2 Anti-TNFa antibodies reduce disease activity in a cotton-top tamarin colitis model.5 Infliximab inhibits the functional activity of TNFa in a wide variety of
`
`Pharmacodynamics
`Pharmacodynamics
`
`Elevated concentrations of TNFa have been found in the stools of Crohn's disease patients and
`correlate with elevated disease activity.9 Treatment with Infliximab reduced infiltration of
`inflammatory cells and TNFa production in inflamed areas of the intestine,8 and reduced the proportion
`of mononuclear cells from the lamina propria able to express TNFa and interferon y.1° After treatment
`with Infliximab, patients with Crohn's disease have decreased levels of serum IL-6 and C-reactive
`protein compared to baseline.8 Peripheral blood lymphocytes from Infliximab-treated patients,
`in vitro
`however, showed no decrease in proliferative responses to in vitro mitogenic stimulation when
`
`Elevated concentrations of TNFa have been found in the stools of Crohn’s disease patients and correlate with elevated disease activity.’ Treatment with Infliximab reduced infiltration of inflammatory cells and TNFa production in inflamed areas of the intestine,8 and reduced the proportion of mononuclear cells from the lamina propria able to express TNFa and interferon y.” After treatment with Infliximab, patients with Crohn’s disease have decreased levels of serum IL-6 and C-reactive protein compared to baseline.8 Peripheral blood lymphocytes from Infliximab-treated patients, however, showed no decrease in proliferative responses to
`
`mitogenic stimulation when 12a August
`
`1998
`12a August 1998 (cid:9)
`
`1 of
`Page 1 of
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`Page
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`compared to cells from untreated patients.8
`
`Pharmacokinetics
`Pharmacokinetics
`
`Data from a study of single intravenous infusions of 1, 5, 10 or 20 mg/kg showed a direct and linear
`relationship between the dose administered and the maximum serum concentration (Cmax) and area
`under the concentration-time curve. The volume of distribution at steady state (Vd), clearance and
`mean residence time were independent of the administered dose. Infliximab has a prolonged terminal
`half-life and is predominantly distributed within the vascular compartment. A single infusion of the
`recommended dose of 5 mg/kg resulted in a median C. of 118 vig/mL, a median Vd equal to 3.0
`liters and a terminal half-life of 9.5 days. During the clinical studies, no pharmacokinetic differences
`were observed in patient subgroups defined by gender, age, weight or hepatic or renal function.
`Corticosteroid use significantly increased the Vd of Infliximab from 2.8 to 3.3 liters (a 17% increase,
`possibly secondary to corticosteroid-mediated changes in electrolyte balance and fluid retention). No
`evidence of accumulation was observed after repeated dosing in patients with fistulizing disease given
`5 mg/kg Infliximab at weeks 0, 2 and 6, or in patients with moderate or severe Crohn's disease
`retreated with 4 infusions of 10 mg/kg Infliximab at 8-week intervals.
`
`Data from a study of single intravenous infusions of 1, 5, 10 or 20 mg/kg showed a direct and linear relationship between the dose administered and the maximum serum concentration (C,,,) and area under the concentration-time curve. The volume of distribution at steady state (V,), clearance and mean residence time were independent of the administered dose. Infliximab has a prolonged terminal half-life and is predominantly distributed within the vascular compartment. A single infusion of the recommended dose of 5 mg/kg resulted in a median C,, of 118 ug/rnL, a median V, equal to 3.0 liters and a terminal half-life of 9.5 days. During the clinical studies, no pharmacokinetic differences were observed in patient subgroups defined by gender, age, weight or hepatic or renal function. Corticosteroid use significantly increased the V, of Infliximab from 2.8 to 3.3 liters (a 17% increase, possibly secondary to corticosteroid-mediated changes in electrolyte balance and fluid retention). No evidence of accumulation was observed after repeated dosing in patients with fistulizing disease given 5 mg/kg Infliximab at weeks 0,2 and 6, or in patients with moderate or severe Crohn’s disease retreated with 4 infusions of 10 mg/kg Infliximab at 8-week intervals.
`
`CLINICAL
`STUDIES:
`CLINICAL STUDIES:
`
`Active Crohn’s Disease
`Active Crohn's Disease
`
`The safety and efficacy of Infliximab were assessed in a randomized, double-blind, placebo-controlled
`dose ranging study of 108 patients with moderate to severe active Crohn's diseases [Crohn's Disease
`Activity Index (CDAI) 2220<_400].12 All patients had experienced an inadequate response to prior
`conventional therapies, including corticosteroids (60% of patients), 5-aminosalicylates (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.
`
`The study was divided into three phases. In the first phase, patients were randomized to receive a
`single intravenous (IV) dose of either placebo, 5, 10 or 20 mg/kg of Infliximab. 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.
`
`The safety and efficacy of Infliximab were assessed in a randomized, double-blind, placebo-controlled dose ranging study of 108 patients with moderate to severe active Crohn’s disease” [Crohn’s Disease Activity Index (CDAI) >220<400] .I2 All patients had experienced an inadequate response to prior conventional therapies, including corticosteroids (60% of patients), 5-aminosalicylates (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. The study was divided into three phases. In the first phase, patients were randomized to receive a single intravenous (IV) dose of either placebo, 5, 10 or 20 mg/kg of Infliximab. The primary endpoint was the proportion of patients who experienced a clinical response, defined as a decrease in CDAI by 2 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 4, four of twenty-five (16%) of the placebo patients achieved a clinical response vs. twenty- two of twenty-seven (82%) of the patients at 5 mg/kg Infliximab (p < 0.001, two-sided, Fisher’s Exact test). One of twenty-five (4%) placebo patients and thirteen of twenty-seven (48%) patients receiving 5 mg/kg Infliximab achieved a CDAI ~150 at week 4. The maximum response to any dose of Infliximab was observed within 2 to 4 weeks. The proportion of patients in response 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 1. 12a August 1998 Page 2 of
`
`At week 4, four of twenty-five (16%) of the placebo patients achieved a clinical response vs. twenty-
`two of twenty-seven (82%) of the patients at 5 mg/kg Infliximab (p < 0.001, two-sided, Fisher's Exact
`test). One of twenty-five (4%) placebo patients and thirteen of twenty-seven (48%) patients receiving
`5 mg/kg Infliximab achieved a CDAI <150 at week 4. The maximum response to any dose of
`Infliximab was observed within 2 to 4 weeks. The proportion of patients in response 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 1.
`
`12a August 1998 (cid:9)
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`Page 2 of
`
`compared to cells from untreated patients.’
`

`

`100
`
`75
`
`50
`
`25
`
`0
`
`% Responding
`
`0
`
`2
`
`4
`
`Weeks
`
`8
`
`12
`
`—0— Placebo (n = 25) (cid:9)
`-- 5 mg/kg (n = 27) (cid:9)
`
`—a— 10 mg/kg (n = 28)
`
`—A— 20 mg/kg (n = 28)
`
`Figure 1. Response (70 point decrease in CDAI) to a Single IV Infliximab or Placebo Dose
`
`During the 12-week period following infusion, patients treated with Infliximab compared to placebo
`demonstrated improvement in quality of life as measured by the Inflammatory Bowel Disease
`Questionaire.13
`
`In the second phase, 29 patients who did not respond to the single dose of 5, 10 or 20 mg/kg of
`Infliximab entered the open label phase and received a single 10 mg/kg dose of Infliximab 4 weeks
`after the initial dose. Ten 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 Infliximab 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 Infliximab
`and placebo-treated groups..
`
`Fistulizing Crohn’s Disease
`Fistulizing Crohn's Disease
`
`0 2 4 a Weeks -0- Placebo (n = 25) --w- lOmg/kg(n=28) -o- 5mg/kg(n=27) -A- 20 mg/kg (n = 28) Figure 1. Response (2 70 point decrease in CDAI) to a Single IV Infliximab or Placebo Dose During the 12-week period following infusion, patients treated with Infliximab compared to placebo demonstrated improvement in quality of life as measured by the Inflammatory Bowel Disease Questionaire. 13 In the second phase, 29 patients who did not respond to the single dose of 5, 10 or 20 mg/kg of Infliximab entered the open label phase and received a single 10 mg/kg dose of Infliximab 4 weeks after the initial dose. Ten 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 Infliximab at g-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 Infliximab and placebo-treated groups..
`The safety and efficacy of Infliximab 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. Concurrent use of stable doses of corticosteroids, 5-ASA, antibiotics, methotrexate, 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 either placebo, 5 or 10 mg/kg Infliximab 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 2 50% reduction from baseline in the number of fistula(s) draining upon gentle compression, on at least two consecutive visits, without an increase in medication for Crohn’s disease, or surgery for Crohn’s disease. Eight of thirty-one (26%) patients in the placebo arm achieved a clinical response vs. twenty-one of the thirty-one (68%) patients in the 5 mg/kg Infliximab arm (p = 0.002, two-sided, Fisher’s Exact test). 12a August 1998 Page 3 of
`
`The safety and efficacy of Infliximab 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. Concurrent use of stable doses of corticosteroids, 5-ASA, antibiotics, methotrexate, 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 either placebo, 5 or 10 mg/kg Infliximab 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 z 50% reduction from baseline in the number of fistula(s) draining upon
`gentle compression, on at least two consecutive visits, without an increase in medication for Crohn's
`disease, or surgery for Crohn's disease.
`
`Eight of thirty-one (26%) patients in the placebo arm achieved a clinical response vs. twenty-one of the
`thirty-one (68%) patients in the 5 mg/kg Infliximab arm (p = 0.002, two-sided, Fisher's Exact test).
`
`12a August 1998 (cid:9)
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`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
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`

`Eighteen of thirty-two (56%) patients in the 10 mg/kg arm achieved a clinical response.
`
`The median time to onset of response in the Infliximab-treated group was 2 weeks. The median
`duration of response was 12 weeks; after 22 weeks there was no difference between either dose of
`Infliximab and placebo in the proportion of patients in response (Figure 2). New fistula(s) developed
`in approximately 15% of both Infliximab and placebo-treated patients.
`
`100
`
`75
`
`25
`
`2
`2 (cid:9)
`
`6
`6 (cid:9)
`
`14
`14
`
`16
`18
`
`:
`22
`
`10
`10
`Weeks
`Weeks
`-o-
`5 mglkg
`+
`lOmg/kg
`Placebo
`-0- Placebo -4,- 5 mg/kg -iii- 10 mg/kg
`(n = 32)
`(n = 31)
`(n = 31)
`(n = 31) (cid:9)
`(n = 31) (cid:9)
`(n = 32)
`
`I -o-
`
`. . Eighteen of thirty-two (56%) patients in the 10 mg/kg arm achieved a clinical response. . The median time to onset of response in the Infliximab-treated group was 2 weeks. The median duration of response was 12 weeks; after 22 weeks there was no difference between either dose of Infliximab and placebo in the proportion of patients in response (Figure 2). New fistula(s) developed in approximately 15% of both Infliximab and placebo-treated patients. 0
`
`Figure 2. Response [fistula(s) closure] with Three Doses of Infliximab or Placebo
`
`Figure 2. Response [fistula(s) closure] with Three Doses of Infliximab or Placebo Seven of sixty (12%) evaluable Infliximab-treated patients, compared to one of thirty-one (3.5%) placebo-treated patients, developed an abscess in the area of fistulas between 8 and 16 weeks after the last infusion of Infliximab. Six of the Infliximab patients who developed an abscess had experienced a clinical response. (See
`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 Infliximab 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.
`
`Seven of sixty (12%) evaluable Infliximab-treated patients, compared to one of thirty-one (3.5%)
`placebo-treated patients, developed an abscess in the area of fistulas between 8 and 16 weeks after the
`last infusion of Infliximab. Six of the Infliximab patients who developed an abscess had experienced a
`ADVERSE REACTIONS,
`Infections).
`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 Infliximab 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.
`
`INDICATIONS AND USAGE:
`INDICATIONS AND USAGE:
`
`Infliximab is indicated for:
`
`Infliximab is indicated for: 1. treatment of moderately to severely active Crohn’s disease for the reduction of the signs and symptoms, in patients who have an inadequate response to conventional therapy.
`
`1.
`
`treatment of moderately to severely active Crohn's disease for the reduction of the signs and
`symptoms, in patients who have an inadequate response to conventional therapy.
`
`The safety and effkacy of therapy continued beyond a single dose have not been
`The safety and efficacy of therapy continued beyond a single dose have not been
`(See DOSAGE AND ADMINISTRATION).
`established
`established (See DOSAGE AND ADMINISTRATION).
`
`2.
`2.
`
`treatment of patients with fistulizing Crohn's disease for the reduction in the number of draining
`treatment of patients with fistulizing Crohn’s disease for the reduction in the number of draining enterocutaneous fistula(s).
`enterocutaneous fistula(s).
`
`The safety and effkacy of therapy continued beyond
`three doses have not been studied
`The safety and efficacy of therapy continued beyond three doses have not been studied
`
`12a August 1998 (cid:9)
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`Page 4 of
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`12a August 1998 Page 4 of
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`

`

`(See DOSAGE AND ADMINISTRATION).
`(See DOSAGE AND ADMINISTRATION).
`
`CONTRAINDICATIONS:
`
`CONTRAINDICATIONS: Infliximab should not be administered to patients with known hypersensitivity to any murine proteins or other component of the product. WARNINGS:
`
`Infliximab should not be administered to patients with known hypersensitivity to any murine proteins
`or other component of the product.
`
`WARNINGS:
`
`Hypersensitivity
`Hypersensitivity
`
`Infliximab has been associated with hypersensitivity reactions. Urticaria, dyspnea and hypotension
`have occurred in association with Infliximab infusion. Infliximab 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
`ADVERSE REACTIONS,
`Infusion-related Reactions).
`of a reaction (see ADVERSE REACTIONS, Infusion-related Reactions).
`
`Infliximab has been associated with hypersensitivity reactions. Urticaria, dyspnea and hypotension have occurred in association with Infliximab infusion. Infliximab 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
`
`Autoimmunity
`Autoimmunity
`
`Anti-TNF therapy may result in the formation of autoimmune antibodies and, rarely, in the
`development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like
`syndrome following treatment with Infliximab and is positive for antibodies against double-stranded
`ADVERSE REACTIONS, Auto-antibodies/Lupus-like
`DNA, treatment should be discontinued (see ADVERSE REACTIONS, Auto-antibodies/Lupus-like
`Syndrome).
`Syndrome). In clinical trials, patients who developed anti-double-stranded DNA (dsDNA) antibodies
`and/or symptoms suggestive of a lupus-like syndrome have had resolution of symptoms and
`disappearance of the anti-dsDNA after discontinuation of Infliximab therapy.
`
`Anti-TNF therapy may result in the formation of autoimmune antibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Infliximab and is positive for antibodies against double-stranded DNA, treatment should be discontinued (see
`In clinical trials, patients who developed anti-double-stranded DNA (dsDNA) antibodies and/or symptoms suggestive of a lupus-like syndrome have had resolution of symptoms and disappearance of the anti-dsDNA after discontinuation of Infliximab therapy.
`
`PRECAUTIONS:
`PRECAUTIONS:
`
`Immunosuppression
`Immunosuppression
`
`TNFa mediates inflammation and modulates cellular immune response; therefore, the possibility exists
`TNFa mediates inflammation and modulates cellular immune response; therefore, the possibility exists for anti-TNF therapies, including Infliximab, to affect normal immune responses.
`for anti-TNF therapies, including Infliximab, to affect normal immune responses.
`
`Malignancy/Infection
`Malignancy/Infection
`
`Patients with long duration of Crohn's disease and chronic exposure to immunosuppressant therapies
`ADVERSE REACTIONS,
`Patients with long duration of Crohn’s disease and chronic exposure to immunosuppressant therapies are more prone to develop lymphomas and infections (see
`are more prone to develop lymphomas and infections (see ADVERSE REACTIONS,
`Lymphoproliferative Disorders and Infections).
`Lymphoproliferative Disorders and Infections). The impact of Infliximab treatment on these
`The impact of Infliximab treatment on these phenomena is unknown.
`phenomena is unknown.
`
`Human Antichimeric Antibody
`(HACA) Development
`Human Antichimeric Antibody (HACA) Development
`
`One-hundred thirty-four of the 199 Crohn's disease patients treated with Infliximab were evaluated for
`HACA; 18 (13%) were HACA-positive (the majority at low titer, < 1:20). Patients who were HACA-
`ADVERSE REACTIONS, Znfision-
`positive were more likely to experience an infusion reaction (see ADVERSE REACTIONS, Infusion-
`related Reactions).
`related Reactions). The incidence of positive HACA responses was lower among Crohn's disease
`patients receiving immunosuppressant therapies such as 6-MP, AZA or corticosteroids [10/99 (10%)
`
`One-hundred thirty-four of the 199 Crohn’s disease patients treated with Infliximab were evaluated for HACA; 18 (13%) were HACA-positive (the majority at low titer, I 1:20). Patients who were HACA- positive were more likely to experience an infusion reaction (see
`The incidence of positive HACA responses was lower among Crohn’s disease patients receiving immunosuppressant therapies such as 6-MP, AZA or corticosteroids [lo/99 (10%) 12a August 1998 Page 5 of
`
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`of these patients developed positive HACA responses] than among those not receiving these agents
`of these patients developed positive HACA responses] than among those not receiving these agents _ [8/35 (23%) of these patients developed positive HACA responses].
`[8/35(23%) of these patients developed positive HACA responses].
`
`Drug Interactions
`Drug Interactions
`
`Specific studies on drug interactions with Infliximab have not been conducted. The majority of patients in Crohn’s disease clinical trials received one or more of the following concomitant medications: antibiotics, antivirals, corticosteroids, 6-MP/AZA and aminosalicylates, all medications commonly used in Crohn’s disease. Patients receiving immunosuppressants tended to experience fewer infusion reactions as compared to patients on no immunosuppressants (see
`
`Specific studies on drug interactions with Infliximab have not been conducted. The majority of
`patients in Crohn's disease clinical trials received one or more of the following concomitant
`medications: antibiotics, antivirals, corticosteroids, 6-MP/AZA and aminosalicylates, all medications
`commonly used in Crohn's disease. Patients receiving immunosuppressants tended to experience fewer
`PRECAUTIONS, HACA
`infusion reactions as compared to patients on no immunosuppressants (see PRECAUTIONS, HACA
`Development
`ADVERSE REACTIONS,
`Infusion-related Reactions).
`Development and ADVERSE REACTIONS, Infusion-related Reactions).
`
`Carcinogenesis, Mutagenesis
`and Impairment
`of Fertility
`Carcinogenesis, Mutagenesis and Impairment of Fertility
`
`Long-term studies in animals have not been performed to evaluate the carcinogenic potential or effects on potential impairment of fertility in male and female animals. No clastogenic or mutagenic effects of Infliximab were observed in the
`
`Long-term studies in animals have not been performed to evaluate the carcinogenic potential or effects
`on potential impairment of fertility in male and female animals. No clastogenic or mutagenic effects
`in vivo
`Salmonella-Escherichia
`coli
`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
`(Ames) assay, respectively. Chromosomal aberrations were not observed in an assay performed using human lymphocytes.
`human lymphocytes.
`
`Pregnancy Category C
`Pregnancy Category C
`
`Since Infliximab does not cross-react with TNFa in species other than humans and chimpanzees,
`animal reproduction studies have not been conducted with Infliximab. It is not known whether
`Infliximab can cause fetal harm when administered to a pregnant woman or can affect reproduction
`capacity. Infliximab should be given to a pregnant woman only if clearly needed. In a developmental
`toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional
`activity of mouse TNFa, no evidence of maternal toxicity, embryotoxicity or teratogenicity was
`observed.
`
`Since Infliximab does not cross-react with TNFa in species other than humans and chimpanzees, animal reproduction studies have not been conducted with Infliximab. It is not known whether Infliximab can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Infliximab should be given to a pregnant woman only if clearly needed. In a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFa, no evidence of maternal toxicity, embryotoxicity or teratogenicity was observed.
`
`Nursing Mothers
`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
`serious adverse reactions in nursing infants from Infliximab, 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.
`
`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 serious adverse reactions in nursing infants from Infliximab, 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.
`
`Pediatric Use
`Pediatric Use
`
`Safety and effectiveness of Infliximab in pediatric patients have not been established.
`
`Geriatric Use
`Geriatric Use
`
`Clinical studies of Infliximab did not include sufficient numbers of Crohn's disease patients aged 65
`and over to determine whether they respond differently from patients aged 18 to 65. As the impact of
`Infliximab treatment on the incidence of infections is unknown and there is a higher incidence of
`infections in the elderly population in general, caution should be used in treating the elderlyI4 (see
`
`Clinical studies of Infliximab did not include sufficient numbers of Crohn’s disease patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. As the impact of Infliximab treatment on the incidence of infections is unknown and there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderlyI (see 12a August 1998 Page 6 of
`
`12a August 1998 (cid:9)
`
`Page 6 of
`
`and
`mouse micronucleus test or the
`Safety and effectiveness of Infliximab in pediatric patients have not been established.
`

`

`ADVERSE REACTIONS,
`Infections).
`ADVERSE REACTIONS, Infections).
`
`ADVERSE REACTIONS:
`
`In clinical trials, a total of 533 patients were treated with Infliximab doses up to 20 mg/kg; 199 in
`Crohn's disease trials, 334 in investigational trials for other disease. Approximately one-third of the
`patients received only a single infusion of Infliximab while the remaining patients received multiple
`infusions, up to a maximum of five. One-hundred fifty-eight patients were followed for at least 2
`years, of whom only 30 patients were in Crohn's disease trials.
`
`In studies in Crohn's disease, approximately 5% of patients discontinued scheduled Infliximab
`infusions due to an adverse experience. The most commo