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. REMICADE is also indicated for the reduction in the number of draining enterocutaneous fistulae in patients with fistulizing Crohn's disease. There are insufficient safety and efficacy data for the use of REMICADE in Crohn's disease beyond the recommended duration.

There are reports of serious infections, including sepsis and tuberculosis, that may be life-threatening. So, if you are prone to or have a history of infections, currently have one, or develop one while taking REMICADE, tell your doctor right away. Also tell your doctor before beginning treatment if you have had recent close contact with, or if you have had past exposure to people with tuberculosis, or if you have any other reason to believe you may be at risk. There are also reports of serious infusion reactions with hives, difficulty breathing, and low blood pressure. If you have a de-myelinating disease such as multiple sclerosis, tell your doctor before you are treated. In rare cases, people with de-myelinating disease who were treated with REMICADE have seen their symptoms intensify. Up to one in four people experienced the following side effects in clinical studies: upper respiratory infections, headache, cough, sinusitis, nausea or mild reactions to the infusion such as rash or itchy skin.

Is REMICADE Right for You?

Crohn's disease is an autoimmune condition that affects the digestive tract. Research has shown that in Crohn's disease, the body is overproducing a substance known as tumor necrosis factor alpha
(TNF-alpha). REMICADE® (infliximab) works by neutralizing the biologic activity of this substance, which is an important cause of the inflammation processes of Crohn's disease. Because REMICADE neutralizes the TNF-alpha, patients may experience a reduction in their signs and symptoms of Crohn's disease.

Your doctor may decide that REMICADE is an appropriate treatment option for you.

Although results may vary, a single REMICADE infusion has been shown to reduce the signs and symptoms of Crohn's disease in patients with moderately to severely active Crohn's disease who have not responded well to conventional therapy. When given as a three-infusion course of therapy, REMICADE is also indicated for treatment of patients with fistulizing Crohn's disease for the reduction in the number of draining fistula(s).

The efficacy and safety for the use of REMICADE beyond the recommended duration has not been established.

REMICADE is NOT a cure for Crohn's disease. But for many patients, it can lessen the impact of Crohn's disease and help them return to a more normal, active life.

There are reports of serious infections, including sepsis and tuberculosis, that may be life-threatening. So, if you are prone to or have a history of infections, currently have one, or develop one while taking REMICADE, tell your doctor right away. Also tell your doctor before beginning treatment if you have had recent close contact with, or if you have had past exposure to people with tuberculosis, or if you have any other reason to believe you may be at risk. There are also reports of serious infusion reactions with hives, difficulty breathing, and low blood pressure. If you have a de-myelinating disease such as multiple sclerosis, tell your doctor before you are treated. In rare cases, people with de-myelinating disease who were treated with REMICADE have seen their symptoms intensify. Up to one in four people experienced the following side effects in clinical studies: upper respiratory infections, headache, cough, sinusitis, nausea or mild reactions to the infusion such as rash or itchy skin. (Please see the Full Prescribing Information.)

How REMICADE Works

Crohn's disease is an autoimmune condition that affects the digestive tract. Research has shown that in Crohn's disease, the body is overproducing a substance known as tumor necrosis factor alpha
(TNF-alpha). REMICADE® (infliximab) works by neutralizing the biologic activity of this substance, which is an important cause of the inflammation processes of Crohn's disease. Because REMICADE neutralizes the TNF-alpha, patients may experience a reduction in their signs and symptoms of Crohn's disease.

REMICADE has been shown in medical studies to heal the lining of the intestine, and a single dose has been shown to provide benefits for 8 to 12 weeks, on average.

What is TNF-alpha?
TNF-alpha is a substance that circulates in the bloodstream and plays an important role in the
inflammatory process. Overproduction of TNF-alpha may lead to some diseases associated with
inflammation, such as Crohn's disease and rheumatoid arthritis. Because REMICADE blocks
TNF-alpha in Crohn's patients, it is sometimes called an "anti-TNF-alpha antibody."

So what does REMICADE do in the body?
In Crohn's disease, the body produces more TNF-alpha than the body's natural receptors can lock
onto.

REMICADE helps control the symptoms of Crohn's disease by binding to TNF-alpha and neutralizing its action. REMICADE may also work by altering the function of the immune cells involved in Crohn's disease.1

Reference
1. Van Deventer SJH. Tumour necrosis factor and Crohn's disease. Gut. 1997;40:443-448.
 

How REMICADE Can Help You

Two important clinical studies have shown that REMICADE®(infliximab) can have important benefits for people with Crohn's disease. Of course, it's not possible to predict in advance how you will respond to treatment with REMICADE. It's important to discuss all of your treatment options with your doctor before deciding on any course of treatment.

Targan SR, Hanauer SB, van Deventer SJH, et. al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor (alpha) for Crohn's disease. N Engl J Med. 97;337.

In this study, 108 people who had moderately to severely active Crohn's disease who had failed other treatments were randomly divided into two groups. One group received REMICADE and one group received placebo (an inactive substance). Neither the patients nor their doctors knew who was getting REMICADE and who was getting placebo until the end of the study. Patients were allowed to continue taking stable doses of their regular medications during the study, such as corticosteroids and/or 6-MP.

Patients were evaluated 4 weeks after receiving a single dose of REMICADE to determine if they had achieved a significant improvement in signs and symptoms of Crohn's disease.

After 4 weeks, 82% of people who received the recommended dose of REMICADE had improvement in the signs and symptoms of their Crohn's disease, compared with only 16% of the people who received placebo.
 

After 4 weeks, 48% of people who received the recommended dose of REMICADE (more than half of those who showed improvement) experienced complete remission of their Crohn's disease.
Below is a case history about healing of colon ulcers.

Actual case study: Healing of colon ulcers with REMICADE

Remember, not everyone will experience these results.

Before treatment with REMICADE, showing colon lining with ulcers.
After 4 weeks of treatment with REMICADE, showing smooth, healed colon.
 

Present DH, Rutgeerts P, Targan S, Hanauer SB, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med. 99;340.

In this study, 94 Crohn's patients who had draining fistulas for at least 3 months were randomly divided into two groups. One group received REMICADE and one group received placebo (an inactive substance). Neither the patients nor their doctors knew who was getting REMICADE and who was getting placebo until the end of the study. Patients were allowed to continue taking stabilizing doses and their regular medications during the study, such as corticosteroids, 6-MP, and/or antibiotics. Patients were evaluated to determine if 50% or more of their draining fistulas closed (stopped draining) for at least 1 month.

• 68% of patients receiving the recommended dose of REMICADE had at least 50% of their fistulas
close for at least 1 month, compared with 26% of people who received placebo.

• 55% of patients receiving the recommended dose of REMICADE had all of their fistulas close for at least 1 month, compared with 13% of people who received placebo.

Actual case study: Healing of abdominal fistulas with REMICADE in a 61-year-old man who had open, draining fistulas for about 3 to 6 months.

Remember, not everyone will experience these results.

There are reports of serious infections, including sepsis and tuberculosis, that may be life-threatening. So, if you are prone to or have a history of infections, currently have one, or develop one while taking REMICADE, tell your doctor right away. Also tell your doctor before beginning treatment if you have had recent close contact with, or if you have had past exposure to people with tuberculosis, or if you have any other reason to believe you may be at risk. There are also reports of serious infusion reactions with hives, difficulty breathing, and low blood pressure. If you have a de-myelinating disease such as multiple sclerosis, tell your doctor before you are treated. In rare cases, people with de-myelinating disease who were treated with REMICADE have seen their symptoms intensify. Up to one in four people experienced the following side effects in clinical studies: upper respiratory infections, headache, cough, sinusitis, nausea or mild reactions to the infusion such as rash or itchy skin. (Please see the Full Prescribing Information.)
 

Talking To Your Doctor

How well do you communicate with your doctor? If you're like many of us, you may find that that
important question has slipped your mind until after you're already on your way home!

Also, you may find you've come to accept your condition as it is. Maybe you think there's nothing more that can be done. Maybe you think that you'll just have to "learn to live with it." However, new studies and new therapies are being evaluated all the time.

The only way to find out if REMICADE® (infliximab) or another treatment is best for you is to ask your doctor. Don't be embarrassed or afraid to bring up something you read about in a newspaper or magazine, or that you heard about on the news. You should expect to receive honest, well-considered answers to your questions from your doctor or healthcare professional. No question is ever "too silly" to ask where your health and well-being are concerned.
If you find it difficult to communicate with your doctor, prepare your questions ahead of time and bring them up at your next appointment. You should be able to ask any questions and discuss any concerns with your doctor. If you feel that your doctor's response is not adequate, you should feel free to seek out another medical opinion.
 

Questions About REMICADE

How is REMICADE® (infliximab) given?
There is something else that's different about REMICADE: it's a solution that is given by intravenous infusion (into a vein). Your REMICADE infusion may be given in your doctor's office, or at an infusion center, or in an outpatient setting your doctor selects. If you wish to receive your medication in a particular setting, talk to your doctor about your preferences.

How long does an infusion take?
The actual infusion takes 2 hours. You should plan on spending about 3 hours, which includes
preparation.

What can I expect when I go for my infusion appointment?
First, the nurse will weigh you in order to calculate the right dosage of REMICADE for you. The nurse will also check your vital signs–such as blood pressure, pulse rate, and temperature-before the infusion begins. Then, the nurse will make sure you are sitting comfortably and will prepare your arm for insertion of the catheter. (Note: While you are receiving the infusion–which takes approximately 2 hours–you will probably be required to remain seated. Be sure you use the bathroom facilities or make any urgent phone calls before the infusion begins.) You will feel a slight pinching, but only for a second. The catheter will be secured on your arm and the infusion will begin. If you are not comfortable, please let the nurse know.

What happens then?
During your infusion, the nurse will check on you at regular intervals. However, during the period of  infusion, you can simply relax, read a book, catch up on some work, watch TV, or listen to music. Just remember: the arm receiving the infusion may be restricted in movement.

What adverse events are associated with REMICADE?
There are reports of serious infections, including sepsis and tuberculosis, that may be life-threatening. So, if you are prone to or have a history of infections, currently have one, or develop one while taking REMICADE, tell your doctor right away. Also tell your doctor before beginning treatment if you have had recent close contact with, or if you have had past exposure to people with tuberculosis, or if you have any other reason to believe you may be at risk. There are also reports of serious infusion reactions with hives, difficulty breathing, and low blood pressure. If you have a de-myelinating disease such as multiple sclerosis, tell your doctor before you are treated. In rare cases, people with de-myelinating disease who were treated with REMICADE have seen their symptoms intensify. Up to one in four people experienced the following side effects in clinical studies: upper respiratory infections, headache, cough, sinusitis, nausea or mild reactions to the infusion such as rash or itchy skin. (Please see the Full Prescribing Information.)

Will I be able to drive after the infusion?1
The infusion is not sedating and you should be able to continue with your normal schedule as advised by your doctor.

How many doses are required?2
• For moderately to severely active Crohn's disease without fistulas, a single infusion is recommended

• For Crohn's patients with fistulas, three infusions (an initial infusion, then one 2 weeks later and one 6 weeks later) are recommended

Who should NOT get REMICADE?
If you know you are allergic to REMICADE or any of its components you should not receive this
medication. Your doctor can help determine if you fall into this category.

What about my other medications? Will I still need to take those?
Your doctor will determine exactly which medications you need to take. Most patients in the
REMICADE clinical studies remained on the medications they were already taking for Crohn's
disease–but started to see improvement in signs and symptoms when REMICADE was added to their medical regimen. Only your doctor can determine what is right for you. REMICADE is easily
incorporated into your treatment program. Specific studies on drug interactions with REMICADE have not been conducted. Be sure to let your doctor know all the medications you take, not just the ones you take for Crohn's disease.

Can I take REMICADE if I am pregnant?
Like many other drugs, REMICADE should be given to a pregnant woman if the benefit clearly
outweighs the risk, from your doctor's perspective. Consult your doctor if you are or plan to become
pregnant.

References
1. Data on file, Centocor, Inc., Malvern, PA.
2. REMICADE prescribing information, Centocor, Inc., Malvern, PA.

There are reports of serious infections, including sepsis and tuberculosis, that may be life-threatening. So, if you are prone to or have a history of infections, currently have one, or develop one while taking REMICADE, tell your doctor right away. Also tell your doctor before beginning treatment if you have had recent close contact with, or if you have had past exposure to people with tuberculosis, or if you have any other reason to believe you may be at risk. There are also reports of serious infusion reactions with hives, difficulty breathing, and low blood pressure. If you have a de-myelinating disease such as multiple sclerosis, tell your doctor before you are treated. In rare cases, people with de-myelinating disease who were treated with REMICADE have seen their symptoms intensify. Up to one in four people experienced the following side effects in clinical studies: upper respiratory infections, headache, cough, sinusitis, nausea or mild reactions to the infusion such as rash or itchy skin. (Please see the Full Prescribing Information.)
 

Medical Coverage

Because REMICADE® (infliximab) is given by IV in a doctor's office, infusion center, or hospital, it is generally covered by insurance plans, including Medicare. Coverage may vary by carrier or individual case.

If you have any questions about insurance coverage, please call your insurance carrier or Medicare first.
If you have problems getting coverage, or encounter any other problems related to medical coverage for REMICADE, call the REMICADE Patient Reimbursement Hotline.

REMICADE Patient Reimbursement Hotline
Phone: 1-800-964-8345
Fax: 1-800-281-7384
Hours: 8:30AM to 8PM, Mon - Fri (EST)
 

REMICADE Hotline

If you have a question about REMICADE® (infliximab), call us toll-free:

REMICADE Information Hotline
Phone: 1-888-779-9769
24 hours a day, 7 days a week

.
DESCRIPTION:
REMICADE© (infliximab) is a chimerie lgG1k monoclonal antibody with an approximate molecular weight of 149,100 daltons. It is composed of human constant and murine variable regions. lnfliximab binds specifically to human tumor necrosis factor alpha (TNF ?) with an association constantof 1019 M-1. lnfliximab 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 lnjection, 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
lnfiiximab neutralizes the biological activity of TNF? by binding with high affinity to the soluble and transmembrane forms of TNF? and inhibits binding of TNF? with its receptors.1-4 Infliximab does not neutralize TNF? (lymphotoxin ?), a related cytokine that utilizes the same receptors as TNF?. Biological activities attributed to TNF? 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 TNF? bound by infliximab can be lysed  in vitro by complement or effector cells.2 Infliximab inhibits the functional activity of TNF? in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils,3 B and T lymphocytes and epithelial cells.  Anti-TNF? 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 TNF?, and, when administered after disease onset, allows eroded joints to heal.

Pharmacodynamics
Elevated concentrations of TNF? have been found in the joints of rheumatoid arthritis papatients5 and the stools of Crohn s disease patients6 and correlate with elevated disease activity.  In rheumatoid arthritis, treatment with REMICADE reduced infiltration of infiammatory cells into inflamed areas of the joint as well as expression of molecules mediating celluiar adhesion [E-selectin, intercellular adhesion molecule-1 (ICAM-1 ) and vascular cell adhesion molecule-1 (VCAM-l)], 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 infiammatory cells and TNF? production in inflamed areas of the intestine, and reduced the proportion of mononuclear cells from the lamina propria able to express TNF? and interferon.4 After treatment with REMICADE, patients with rheumatoid arthritis or Crohn's dicesse exhibited decreased levels of serum IL-6 and C-reactive protein (CRP) compared to baseline.  Peripheral blood lymphocytes trom REMICADE treated patients showed no significant decrease in number or in proliferativi 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 rnaximum 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 disese 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:
Rheumatuid 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 durafion 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 ( <=1 0 mg/day) and/or nonsteroidal anti-infiammatory drugs was also permitted.

Clinical Response
All doses/schedules of REMICADE + MTX resulted in improvement in signs and symptoms as mesured by the American College of Rheumatology response criteria (ACR 20)7 through 54 weeks (Figure 1).

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 mq/kg q 8 weeks are shown in Table 1. Responses to the higher doses or more frequent administrations were similarly distributed.

a Visual Analog Scale (O=best, 10=worst)
b 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).

* p < 0.05 for each outcome compared to placebo

Health outcome measures were assessed by the SF-36 questionnaire. The eight subscale of the SF-36 were combined into two summary scales, the physical component summary (PCS) and the mental component surnmary (MCS).9 At week 54, patients treated wfth 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 MCS.

Radiographic Response
Structural damago 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 feet10.  Approximately 80% of patients had paired x-ray data. Results aro shown in Table 3.

*For comparison of each dose against placebo

Data use of REMICADE without concurrent MTX are limited (see Precautions, Immunogenicity).11,12

Active Crohn's Disease
The safety and efficacy of REMICADE were assesed 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 lndex (CDAI) >=220 and <=400]. All patients had experienced an inadeguate 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 this medications.

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 or 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 <l50), 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 REMICADE 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.

During the 12-week period following infusion, patients treated with REMICADE compared to placebo demonstrated improvement in outcomes measured by the lnfiammatory 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© (infliximab) 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/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 placebo 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 patients with fistulizing Crohn's disease with fistula(s) that were of at least 3 months duragon.14  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 modications. Fifty-two (55%) had multiple cutaneously draining fistulas, 90% of patients, had fistula(s) in the perianal area and 10% bad abdominal fistula(s).

Patients received 3 doses of placebo, 5 or 10 mq/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 >=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 or surgery for Crohns disease.

Eight of 31 (26%) patients in the placebo arm achieved a clinical response vs. 21 ci 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) devoloped in approximately 15% of both REMICADE- and placebo-treated patients.
 
 

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 REMICADE. 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 bave 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.

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 inadeguate response to methotrexate.

Crohn’s Disease
REMICAD 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 an inadeguate response to conventional therapy.

The safety and efficacy ai 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 oft terapy continued beyond doses have not been estlabished (see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS:
REMICADE should not be administered to patients with known hypersensitivity to arry 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 REMICADE.  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, INCLUOING LATENT TUBERCULOSIS.15 TREATMENT FOR TUBERCULOSIS SHOULD SE INITIATED PRIOR TO TREATMENT WITH REMICADE.

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, polyarlthralgias, 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 ci hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be availabie for immediate use in the event of a reaction (see ADVERSE REACTIONS, Infusion-related Reactions).

Neurologic Events
lnfliximab 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  autoantibodyes 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, Autoantibodies/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 devolop lymphomas (see ADVERSE REACTIONS, Malignancies/Lymphoproliferative Disease). The impact of treatment with REMICADE on these phenomena is unknown.

Immunagenicity
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, <l:20). Patients who were antibody-positive were more likely to experience an infusion reaction (see ADVERSE REACTIONS, lnfusion-related Reactions). Antibody development was lower among rheumatoid arthritis and Crohn's disease patients receiving immunosoppressart 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 REMICADE. Because immunogenicity analyses are product-specific, comparison of antibody 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-TNF terapy. It is recommended thst live vaccines not be given concurrently.
Drug Interaction
Specific drug interaction studies, including interactions with MTX, 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-infiammatory 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, lmmunogenicity and ADVERSE REACTIONS, lnfusion-related Reactions).

Carcinogonesis, Mutagenesis and lmpairment of Fertility
Long-term studies in animals have not been performed to evaluate the carcinogenic potential. No clastogenic or mutagenic effect  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 TNF? demonstraded 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 riproduction toxicity study conducted in mice using an analogous antibody that selectively inhibits the functioal activity of mouse TNF?.

Pregnancy Category B
Since infliximab does not cross-react with TNF? 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 TNF?. Doeses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Doeses 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 ere 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 discontinues the drug, taking into account the importance of the drug to the mother.

Pediatric Use
Safety and effectiveness of REMICADE in patients with juvenile rheumatoid artritis and in pediatric patients with Crohn’s disease have not been established.

Geriatric Use
In the ATTRACT study, no overall differences were observed in effectineness or safety in 72 patient 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.

lnfusion-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 ci 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, 1% were accompanied by cardiopulmonary reactions (primarily chest pain, hypotension, hypertension or dyspnea), <l % were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serius 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 anfibodies to infliximab and infusion reactions (see PRECAUTIONS, lmmunogenicity 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 manifestin 3 to 12 days following irfusion of which 6 were considerati serius. Signs and symptoms included mialgia 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 avents 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 adeguate 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 observed infrequently in clinical studios 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 sinusits, 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, collulitis 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© (infliximab) 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 INFECTlONS). Twelve percent of patients with  fistulizing Crohn's disease developed a new abscess 8 to l6 weeks after the last infusion of REMICADE (see CLINICAL STUDIES, Fistulizing Crohn’s Disease).

Autoantibodies/Lupus-like Syndrome
In the ATTRCT 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 dosa/schedule and development of ANA or anti-dsDNA.

Of Crohn’s disease patients treated with REMICADE who were evaluated for antinuclcear 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-posibve 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 PRECAU71ONS, Autoimmunity).

Malignancies/Lymphoproliferative 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 determirie whether REMICADE contributed to the development of these malignancies. The observed rates and incidences were similar to those expected for the populations studied16.17 (see PRECAUTIONS, Malignany).

Other Adverse Reactions
Adverse events occurring at a frequency of at least 5% in all patients treated with REMICADE are show in Table 4. Patients with Crohn's desease who were treated with REMICADE were more likely than patients with rheumatoid arthritis to experience adverse events associated with gastrointestinal symptoms.

	RHEUMATOID ARTHRITIS		CROHN'S DISEASE
	Placebo (n=l33)	REMICADE (n=555)	Placebo (n=56)	REMICADE (n=l99)
Avg. weeks of follow-up	35.9	41.2	14.7	27.0
Respiratory
Upper respiratory infection	17%	26%	9%	16%
Coughing	7%	13%	0%	5%
Sinusitis	4%	13%	2%	5%
Pharyngitis	6%	11%	5%	9%
Rhinitis	7%	9%	4%	6%
Bronchitis	5%	6%	2%	7%
Gastrointestinal
Nausea	18%	17%	4%	17%
Diarrhea	14%	13%	2%	3%
Abdominal pain	8%	10%	4%	12%
Vomiting	10%	7%	0%	9%
Dyspepsia	5%	6%	0%	5%
Other
Headache	14%	22%	21%	23%
Rash	5%	12%	5%	6%
Dizziness	10%	10%	9%	8%
Urinary tract infection	7%	8%	4%	3%
Fatigue	5%	8%	5%	11%
Fever	6%	8%	7%	10%
Pain	8%	8%	5%	9%
Back pain	3%	6%	4%	5%
Pruritus	0%	6%	2%	5%
Arthralgia	2%	6%	2%	5%
Chest pain	5%	5%	5%	6%

Serius adverse events (all occured at frequencies <2%) by body system in all patients treated with REMICADE are as follows:

Body as a whole: abdominal hernia, asthenia, chest pain, diaphragmatic hernia, edema, fall, pain
Blood: splenic infarction, splenomegaly
Cardiovascular: hypertension, hypotension, syncope
Cental & Peripheral Nervous: encephalopathy, dizzines, headache, spinal stenosis, upper motor neuron lesion
Autoimmunity: lupus erythematosus syndrome, worsening, rheumatoid arthritis, rheumatoid nodules
Ear and Hearing: ceruminosis
Eye and Vision: endophthalmits
Gastrointestinal: abdominal pain, appendicitis, Crohn's disease, diarrhea, gastdc ulcer, gastrointestinal  hemorrhage, intestinal obstruction, intestinal perforation, intestinal stenosis, nausea, pancreatitis, peritonitis, proctalgia, vomiting
Heart Rate and Rhythm: arrhythmia, atrioventricular block, bradycardia, cardiac arrest, palpitation, tachycardia
Liver and Biliary: biliary pain, cholecystitis, cholelithiasis, hepatitis cholestatic
Metabolic and Nutritional: dehydration, pancreati insufficiency, weight decrease
Musculoskeletal: arthralgia, arthritis, back pain, bone fracture, hemarthrosis, intervertebral disk herniation, joint cyst, joint degeneration, myalgia, osteoarthritis, osteoporosis, spondylolisthesis, symphyseolysis, tendon disorder, tendon injury
Myo-, Endo-, Periacardial and Coronory Valve: angina pectoris, cardiac failure, myocardial ischemia
Neoplasms: basal cell, breast, lymphoma, melanoma, rectal adenocarcinorm skin
Platelet, Bleeding and Clotting: thrombocytopenia
Psychiatric: anxiety, confusion ,delirium, depression, somnolence, suicide attempt
Red Blood Cell: anemia
Roproductive: endometriosis
Resistance Mechanism: abscess, bacterial infection, cellulitis, fever, fungal infction, herpes zoster, infection, infiammafion, sepsis
Respiratory: adult respiratory distress syndrome, bronchitis, cougting, dyspnea, pleural effusion, pleurisy,  pneumonia, pneumothorax, pulmonary edema, pulmonary infiltration, respiratory insufficiency, upper respiratory tract infection
Skin and Appendages: furunculosis, increased sweating, injection site infiammation, rash, ulceration Urinary: azotemia, dysuria, hydronephrosis, kidney infarction, pyelonephritis, renal calculus, renal failure, ureteral obstruction
Vascular (Extracardiac): brain infarchon, peripheral ischemia, pulmonary embolism, thrombophlebitis deep
White cell and Reticuloendothelial: leukopenia, lymphadenopathy, lymphangitis

A greater proportion of patients enrolled into the ATTRACT study who received REMICADE plus MTX experienced mild, transient elevations (<2 times the upper limit of normal) in AST or ALT (35% and 32% respectively) compared to patients treated with placebo with MTX (24% each). Six (l.8%) patients with REMICADE and MTX experienced more prolonged elevations in their ALT.

OVERDOSAGE:
Single doses up to 20 mg/kg have been administered without any direct toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropiate symptomatic treatment instituted immediately.

DOSAGE AND ADMINISTRATION:
Rheumatoid Arthritis
The recommended dose of REMICADE is 3mg/kg given as an intravenous infusion followed with additonal similar doses at 2 and 6 weeks after the first infusion then every 8 weeks thereafter. REMICADE should be given in combination with methotraxe. For patients who have an incomplete response, consideration may be given to adjusting the dose up to 10 mg/kg or treating as often as every 4 weeks.

Crohn’s Disease
The recommended dose of REMICADE is 5 mg/kg given as a single intravenous infusion for treatment of moderately to severely active Crohn's disease. In patients with fistulizing disease, an initial 5 mg/kg dose should be followed with additional 5 mg/kg doeses at 2 and 6 weeks after the first infusion.

There are insufficient safety and efficacy data for the ue of REMICAIDE in Crohn’s disease beyond the recommended duration (see WARNYNGS, Hypersensitivity; ADVERSE REACTIONS, Infusion-related Reactions; and INDICATIONS AND USAGE).

Preparation and administration instructions: Use aseptic technique.
REMICADE vials do not contain antibacterial preservatives.  Therefore, the vials after reconstitution should be used immediately, not re-entered or stored. The diluent to be used for reconstitution is 10 mL of Sterile Water for Injection, USP. The total dose of the reconstituted product must be further diluted to 250 mL with 0.9% Sodium Chloride Injection, USP. The infusion concentration should range between 0.4 mg/mL and 4 mg/mL. The REMICADE infusion should begin within 3 hours of preparation.

1 . Calculate the dose and the number of REMICADE vials needed. Each REMICADE vial contains 100 mg of infliximab.  Calculate the total volume of reconstituted REMICADE solution required.

2. Reconstitute each REMICADE vial with 10 mL of Sterile Water for Injection, USP, using a syringe equipped with a 21-gauge or smaller needle. Remove the flip-top from the vial and wipe the top with an alcohol swab. Lnsert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Do not use the vial if the vacuum is not present. Gently swirl the solution by rotating the vial to dissolve the lyophilized powder.  Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted solution to stand for 5 minutes. The solution shouil be colorless to light yellow and opalescent, and the solution may dovelop a few translucent particles as infliximab is a protein. Do not use if opaque particles, discoloration, or other foreign particies are present.

3. Diluite the total volume of the reconstituted REMICADE solution dose to 250 mL with 0.9% Sodium Chloride Injection, USP, by withdrawing a volume of 0.9% Scodium Chloride Injection, USP, equal to the volume of reconstituted REMICADE from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag. Slowly add the total volume of reconstituted REMICADE solution to the 250 mL infusion bottle or bag. Gently mix.

4. The infusion solution must be administered over a period of not less than 2 hours and must use an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2-?m or less). Any unused portion of the infusion solution should not be stored for reuse.

5. No physical biochemical compatibility studies have been conducted to evaluate the co-administration of REMICADE with other agents. REMICADE should not be infused concomitantly in the same intravenous line with other agents.

6. Parenteral drug products shouid be inspected visually for particulate matter and discoloration prior to  administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulares are observed, the soluton shouid not be used.

Storage
Store the lyophilized product under refrigeration at 2°C to 8°C (36°F to 46°F). Do not freeze. Do not use beyound the expiration date. This product contains no preservative.

HOW SUPPLIED:
REMICADE lyophilized concentrate for IV injection is supplied in individually-boxed single-use in the following strength:
NDC 57894-030-01 100 mg infliximab in a 20-mL vial

REFERENCES:
1 . Knight DM, Trinh H, Le J, et al. Construction and initial characterization of a mouse-human chimeric antiTNF antibody.  Molec lmmunol 1993;30:1443-1453.

2. Scalion BJ, Moore MA, Trinh H, et al.  Chimeric anti-TNF ? monoclonal antibody cA2 blinds recombinant transmembrane TNF? and activates immune effector functions.  Cytokine 1995;7:251-259.

3. Siegel SA, Shealy DJ, Nakada MT, et al. The mouse/uman chimeric monoclonal andbodty cA2 neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo.
 Cytochine 1995;7:15-25.

4. Data on file.

5. Chu CO, Field M, Feldmann M, et al. Localization of tumor necrosis factor ? in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis.
 Arthritis and Rheum 1991;34:1125-1132.

6. Braegger CP, Nicholls S, Murch SH, et al. Tumour necrosis factor alpha in stool as a marker of intestinal inflammation.  Lancet 1992;339:89-91.

7. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthrits Rheum 1995;38(6):727-735.

8. Fries JF, Spitz PW, Young DY. The dimension of health outcomes: the health assessment questionnaire, disability and pain scales. J Rheumatol 1982;9(5):789-793.

9. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form healt survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30(6):473-483.

10.Van der Heijde DM, van Leeuwen MA, van Riel PL, et al. Biannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis.
     Arthritis Rheum 1992;35(1):26-34.

11.Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of antitumor necrosis factor ? monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41(9):1552-1563.

12.Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-bind comparison of chimeric monoclonal antibody totumour necrosis alpha (cA2) vs. placebo in rheumatoid arthritis.
     Lancet l994;344(8930):1105-1110.

13.Targan SR, Hanauer SR, van Deventer SJH, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor ? for Crohn's disease. N Engl J Med 1997;337(15):1029-1035.

14.Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment fistulas in patients with Crohn’s disease. N Engl J Med 1999;340:1398-1405.

15.American Thoracic Society, Centers for Desease Control and Prevention. Targeted tuberculin testing and treatment of latent tuborculosis infection.  Am J Respir Crit Care Med 2000;161:S221-S247.

16.Greenstein,AJ, Mullin GE, Strauchen JA, et al. Lymphoma in infiamatory bowel disease.
 Cancer  1992;69:1119-1121.

17.Jones M, Symmons D, Finn J, et al. Does exposure to immunosuppressive therapy increase the 10 year malignancy and mortality risk in rheumatoid arthritis? A matched cohort study.
 Br J Rheum 1996;35:738-745.
 

© Centocor, Inc. 2000
Malvern, PA 19355, USA
1-800-457-6399

License #l242
Revised 1 December 2000
IN00160

Infliximab è un anticorpo monoclonale in grado di neutralizzare il TNF (Tumor Necrosis Factor).
In uno studio randomizzato, 94 pazienti affetti da morbo di Crohn e fistola addominale o perianale da almeno 3 mesi, sono stati trattati con Infliximab.
L'end-point primario era costituito dalla riduzione del 50% o più delle fistole.
Circa il 60% dei pazienti trattati con Infliximab ha raggiunto l'obiettivo terapeutico, contro il 26% del gruppo che aveva ricevuto il placebo. Per quanto riguarda l'incidenza di effetti indesiderati non ci sono state differenze significative tra gruppi sottoposti a Infliximab o placebo. (Xagena 2000)

Il Morbo di Crohn è una malattia infiammatoria intestinale di origine sconosciuta, caratterizzata da un'infiammazione che interessa la parete intestinale in tutto il suo spessore e da lesioni granulomatose della mucosa intestinale.
A differenza della colite ulcerosa la mucosa intestinale è interessata in modo discontinuo: segmenti di mucosa gravemente danneggiati si alternano ad altri in cui la mucosa ha un aspetto normale.
La terapia del Morbo di Crohn è stata finora empirica; vengono utilizzati: corticosteroidi, immunosoppressori, antibiotici. Nei casi più gravi si ricorre alla resezione chirurgica. Tuttavia l'impiego della chirurgia non è risolutivo: l'80% dei pazienti va incontro a distanza di un anno a recidive. Infliximab è un anticorpo monoclonale chimerico, umano/murino, diretto contro il Tumor Necrosis Factor Alpha (Tnf-alfa).
Il Tnf-alfa svolge un ruolo chiave nel processo infiammatorio che è alla base del Morbo di Crohn.
Infliximab è un farmaco molto potente ed il suo utilizzo è riservato alle forme gravi, refrattarie alla terapia convenzionale. Le fistole enterocutanee rappresentano una grave complicanza del Morbo di Crohn e colpiscono circa 1/3 dei pazienti. Lo studio ha coinvolto 94 pazienti con Morbo di Crohn fistolizzato. 31 sono stati trattati con placebo, 31 pazienti con tre infusioni di Infliximab di 5 mg/Kg, 32 pazienti con Infliximab 10 mg/Kg, a zero, due e sei settimane.
L'efficacia è stata valutata come riduzione = 50% del numero di fistole secernenti.
Con il dosaggio da 5 mg/Kg, la percentuale di efficacia, dopo 6 settimane, è stata del 68%.
Con il dosaggio da 10 mg/Kg, la percentuale di efficacia, dopo 6 settimane, è stata del 56%
Infliximab si è quindi rivelato un trattamento efficace delle fistole nei pazienti con Morbo di Crohn.
(Present D H et al, N Engl J Med 1999; 340: 1398-1405)

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