REMICADE® safety in Crohn's disease (CD) across clinical trials

Luminal CD


Fistulizing CD


In Targan, incidence of adverse events was generaly similar among the groupsIn Targan, incidence of adverse events was generaly similar among the groups
Variable Placebo One dose of
Two doses of
No. of patients evaluated 25 102 29
Average length of follow-up—wk 6.9 10.4 12.4
Adverse effect—no. of patients (%)
Adverse effect 15 (60) 76 (75) 23 (79)
Headache 5 (20) 19 (19) 3 (10)
Nausea 2 (8) 11 (11) 5 (17)
Upper respiratory tract infection 3 (12) 8 (8) 4 (14)
Fatigue 1 (4) 6 (6) 3 (10)
Myalgia 1 (4) 4 (4) 3 (10)
Rhinitis 1 (4) 3 (3) 3 (10)
Pain 0 4 (4) 3 (10)
Pruritus 1 (4) 1 (1) 4 (14)
Chest pain 1 (4) 2 (2) 3 (10)
Vomiting 0 2 (2) 3 (10)
Dyspnea 0 1 (1) 3 (10)
Adverse effects that occurred in 10 percent or more of patients in any of the groups were reported.
Patients who did not have a clinical response after the first infusion were given a second infusion of REMICADE® in a dose of 10 mg/kg and followed for an additional 12 weeks.

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In ACCENT I: Safety data through Week 54In ACCENT I: Safety data through Week 54
  Group I
Group II
5 mg/kg
Group III
10 mg/kg
REMICADE® exposure over 54 weeks, mean (SD)
Number of Infusions 2.2 (1.5) 6.7 (1.9) 6.8 (2.1) 5.3 (2.9)
Total dose (mg/kg) 10.7 (7.6) 36 (11.1) 55.5 (21.1) 34.3 (23.3)
Adverse events leading to discontinuation 5 (3%) 29 (15%) 16 (8%) 50 (9%)
Serious adverse events        
All events 55 (29%) 54 (28%) 43 (22%) 152 (27%)
Reasonably related 13 (7%) 15 (8%) 11 (6%) 39 (7%)
Infection requiring antimicrobial treatment 70 (37%) 64 (33%) 52 (27%) 186 (32%)
Serious infection 8 (4%) 8 (4%) 6 (3%) 22 (4%)
Intestinal stenosis 6 (3%) 3 (2%) 5 (3%) 14 (2%)
Infusion reactions 17 (9%) 44 (23%) 36 (19%) 97 (17%)
Serum-sickness-like reactions 3 (2%) 5 (3%) 6 (3%) 14 (2%)
92 (49%) of 188 patients crossed over to episodic retreatment and received two or more REMICADE® infusions.
Defined as any adverse experience that occurred during or within 1 h after infusion. Reported infusion reactions occurred during maintenance infusions (Initial infusion excluded).
Defined as features occurring 1-14 days after reinfusion of REMICADE®, including delayed hypersensitivity reactions, myalgia, arthralgia, fever, and/or rash.

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Safety data through Week 54Safety data through Week 54
  AZA + placebo
+ placebo
Patients with any AE, n (%) 144
Serious AEs, n (%) 43
AEs leading to study drug
discontinuation, n (%)
Serious infections, n (%) 9
Number of patients with infusion
reactions (%)
Total no. of infusions/no. of infusions with infusion reactions (%) 862/10
Results from SONIC, a multicenter, randomized, double-blind, controlled, phase IIIb trial of 508 patients with moderately to severely active CD (baseline Crohn's Disease Activity Index [CDAI] ≥220 and ≤450). At baseline, mean CDAI score for all patients was 287; median duration of CD ranged from 2.2 to 2.4 years. Patients were randomly assigned to 1 of 3 treatment groups through Week 30: in the primary study phase, patients received REMICADE® 5 mg/kg or placebo infusions at Weeks 0, 2, 6, 14, and 22; patients also received azathioprine (AZA) capsules at a dose of 2.5 mg/kg/day or placebo capsules daily through Week 30. Patients completing treatment through Week 30 (main study) were eligible to enter the study extension if, in the opinion of the investigator, the patient could benefit from continued treatment. Patients eligible for participation in the extension (N=280) continued to receive their initial treatment through Week 50. The Week 50 analysis included patients who did not enter the study extension. These patients were assumed non-responders and not to be in steroid-free remission at Week 50. The primary endpoint of the study was the proportion of patients in corticosteroid-free remission at Week 26. Secondary endpoints included mucosal healing at Week 26 and corticosteroid-free remission at Week 50. Monitoring for adverse events was performed through Week 54.
All treated subjects.
For patients with mild to moderate reactions who do not tolerate infusion following appropriate intervention or have severe reactions, REMICADE® should be discontinued.
  • In the primary phase:
    • 1 patient treated with REMICADE® and AZA developed tuberculosis3
    • 2 patients treated with AZA monotherapy developed colon cancer1
    • 1 patient treated with AZA monotherapy died of sepsis following colectomy1
  • No deaths, malignancies, or reports of TB were observed during the study extension in patients taking REMICADE®4

Azathioprine (AZA) is not approved by the Food and Drug Administration (FDA) for the treatment of Crohn's disease andi its contribution to the effectiveness of use in combination with REMICADE® (infliximab) has not been established. The use of AZA in combination with REMICADE® should take into account the potential risks associated with combination therapy and monotherapy

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In Accent II: Safety data through Week 54In Accent II: Safety data through Week 54
Variable Placebo Maintenance (n=144) REMICADE® Maintenance (n=138) Total
P Value
Extent of REMICADE® exposure over 54-wk period
No. of REMICADE® infusions 4.3 ± 1.7 7.5 ± 1.3 5.9 ± 2.2 <0.001
Total dose—mg/kg 21.4 ± 8.3 41.1 ± 10.9 31.1 ± 13.8 <0.001
Adverse events leading to discontinuation—no. of patients (%) 12 (8) 5 (4) 17 (6) 0.1
Serious adverse events—no. of patients (%)      
All events 33 (23) 19 (14) 52 (18) 0.05
Reasonably related events 9 (6) 3 (2) 12 (4) 0.09
Infections—no. of patients (%)        
Infections requiring antimicrobial
39 (27) 47 (34) 86 (30) 0.20
Serious infections 9 (6)|| 4 (3) 13 (5) 0.18
New fistula related abscesses
—no. of patients (%)
25 (17) 17 (12) 42 (15) 0.25
Infusion reactions
—no. of patients (%)#
24 (17) 22 (16) 46 (16)  
  During induction 11 (8) 9 (7) 20 (7)  
  During maintenance 4 (3) 13 (9) n/a 0.02
  During treatment after crossover** 14 (23) 3 (9) 17 (18)  
Development of
antinuclear antibodies—no. of patients/total no. (%)††
24/132 (18.2) 56/122 (45.9) 80/254 (31.5) <0.001
Development of antibodies against double-stranded DNA—no. of patients/total no. (%)‡‡ 8/127 (6.3) 27/116 (23.3) 35/243 (14.4) <0.001
Plus-minus values are means ± SD.
P values are for the comparison between the placebo maintenance and REMICADE® maintenance groups.
Events deemed by the investigator to be possibly, probably, or definitely related to the study agent (or that had an unknown relation) were recorded as "reasonably related."
The analysis does not include one patient who was found to have a positive skin test with purified protein derivative (who was asymptomatic and had negative finding on chest radiography) before the Week 30 infusion. Isoniazid therapy was initiated, and the patient subsequently received all remaining study infusions.
The analysis includes three patients with an intraabdominal abscess, one patient with parastomal and retroperitoneal abscesses, and one patient with parastomal and perianal abscesses.
The analysis includes one patient with an ischiorectal abscess and one patient with a perianal abscess.
Some patients had infusion reactions during more than one period.
A total of 60 patients in the placebo maintenance group crossed over to receive 5 mg of REMICADE® per kilogram, and 35 patients in the REMICADE® maintenance group crossed over to receive 10 mg of REMICADE® per kilogram.
Among patients with antinuclear antibodies who were evaluated at baseline and at Week 54, 132 were assigned to the placebo maintenance group and 122 were assigned to the REMICADE® maintenance group.
Among patients with antibodies against double-stranded DNA who were evaluated at baseline and at Week 54, 127 were assigned to the placebo maintenance group and 116 were assigned to the REMICADE® maintenance group.

Serious and sometimes fatal side effects have been reported with REMICADE®. Infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens (e.g., TB, histoplasmosis) have been reported. Lymphoma, including cases of fatal hepatosplenic T-cell lymphoma (HSTCL), and other malignancies have been reported, including in children and young adult patients. Due to the risk of HSTCL, carefully assess the risk/benefit especially if the patient has Crohn's disease or ulcerative colitis, is male, and is receiving azathioprine or 6-mercaptopurine treatment. REMICADE® is contraindicated in patients with severe hypersensitivity reactions to REMICADE® and certain patients with congestive heart failure. Other serious side effects reported include melanoma and Merkel cell carcinoma, hepatitis B reactivation, hepatotoxicity, hematological events, hypersensitivity, neurological events, and lupus-like syndrome. Please see related and other Important Safety Information.

  1. Targan SR, Hanauer SB, van Deventer SJH, et al; for the Crohn's Disease cA2 Study Group. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. N Engl J Med. 1997;337:1029-1035.
  2. Hanauer SB, Feagan BG, Lichtenstein GR, et al, and the ACCENT I Study Group. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 2004;359:1541-1549.
  3. Colombel JF, Sandborn WJ, Reinisch W, et al; for the SONIC Study Group. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362:1383-1395.
  4. Data on file. Janssen Biotech, Inc.
  5. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 2004;350:876-885.

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REMICADE® is indicated for:

Crohn's Disease
  • Reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn's disease (CD) who have had an inadequate response to conventional therapy
  • Reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing CD
Pediatric Crohn's Disease
  • Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age or older with moderately to severely active CD who have had an inadequate response to conventional therapy
Ulcerative Colitis
  • Reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy
Pediatric Ulcerative Colitis
  • Reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active UC who have had an inadequate response to conventional therapy
Rheumatoid Arthritis
  • Reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis (RA) in combination with methotrexate (MTX)
Psoriatic Arthritis
  • Reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis (PsA)
Ankylosing Spondylitis
  • Reducing signs and symptoms in patients with active ankylosing spondylitis (AS)
Plaque Psoriasis
  • The treatment of adult patients with chronic severe (ie, extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate



Patients treated with REMICADE® (infliximab) are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious infection or sepsis.

Reported infections include:

  • Active tuberculosis (TB), including reactivation of latent TB. Patients frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before and during treatment with REMICADE®.1,2 Treatment for latent infection should be initiated prior to treatment with REMICADE®.
  • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis and pneumocystosis. Patients may present with disseminated, rather than localized, disease. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
  • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

The risks and benefits of treatment with REMICADE® should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Closely monitor patients for the development of signs and symptoms of infection during and after treatment with REMICADE®, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

Risk of infection may be higher in patients greater than 65 years of age, pediatric patients, patients with co-morbid conditions and/or patients taking concomitant immunosuppressant therapy. In clinical trials, other serious infections observed in patients treated with REMICADE® included pneumonia, cellulitis, abscess, and skin ulceration.


Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including REMICADE®. Approximately half of these cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months after the first dose of therapy. Most of the patients were receiving concomitant immunosuppressants.

Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers, including REMICADE®. These cases have had a very aggressive disease course and have been fatal. All reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of treatment with REMICADE®, especially in these patient types.

In clinical trials of all TNF inhibitors, more cases of lymphoma were observed compared with controls and the expected rate in the general population. However, patients with Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for developing lymphoma. In clinical trials of some TNF inhibitors, including REMICADE®, more cases of other malignancies were observed compared with controls. The rate of these malignancies among patients treated with REMICADE® was similar to that expected in the general population whereas the rate in control patients was lower than expected. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use. As the potential role of TNF inhibitors in the development of malignancies is not known, caution should be exercised when considering treatment of patients with a current or a past history of malignancy or other risk factors such as chronic obstructive pulmonary disease (COPD).

Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including REMICADE®. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.


REMICADE® is contraindicated in patients with moderate to severe (NYHA Class III/IV) congestive heart failure (CHF) at doses greater than 5 mg/kg. Higher mortality rates at the 10 mg/kg dose and higher rates of cardiovascular events at the 5 mg/kg dose have been observed in these patients. REMICADE® should be used with caution and only after consideration of other treatment options. Patients should be monitored closely. Discontinue REMICADE® if new or worsening CHF symptoms appear. REMICADE® should not be (re)administered to patients who have experienced a severe hypersensitivity reaction or to patients with hypersensitivity to murine proteins or other components of the product.


TNF inhibitors, including REMICADE®, have been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients should be tested for HBV infection before initiating REMICADE®. For patients who test positive, consult a physician with expertise in the treatment of hepatitis B. Exercise caution when prescribing REMICADE® for patients identified as carriers of HBV and monitor closely for active HBV infection during and following termination of therapy with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and initiate antiviral therapy with appropriate supportive treatment. Exercise caution when considering resumption of REMICADE® and monitor patients closely.


Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported rarely in patients receiving REMICADE® postmarketing. Some cases were fatal or required liver transplant. Aminotransferase elevations were not noted prior to discovery of liver injury in many cases. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of normal) develop, REMICADE® should be discontinued, and a thorough investigation of the abnormality should be undertaken.


Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise caution in patients who have ongoing or a history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs and symptoms of blood dyscrasias or infection. Consider discontinuation of REMICADE® in patients who develop significant hematologic abnormalities.


REMICADE® has been associated with hypersensitivity reactions that differ in their time of onset. Acute urticaria, dyspnea, and hypotension have occurred in association with infusions of REMICADE®. Serious infusion reactions including anaphylaxis were infrequent. Medications for the treatment of hypersensitivity reactions should be available.


TNF inhibitors, including REMICADE®, have been associated in rare cases with CNS manifestation of systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when considering REMICADE® in patients with these disorders and consider discontinuation if these disorders develop.


Treatment with REMICADE® may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome. Discontinue treatment if symptoms of a lupus-like syndrome develop.


In clinical trials, the most common REMICADE® adverse reactions occurring in >10% of patients included infections (eg, upper respiratory, sinusitis, and pharyngitis),
infusion-related reactions, headache, and abdominal pain.


Concomitant use of REMICADE® with anakinra, abatacept, tocilizumab, or other biologics used to treat the same conditions as REMICADE® is not recommended because of the possibility of an increased risk of infection. Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.


Live vaccines or therapeutic infectious agents should not be given with REMICADE® due to the possibility of clinical infections, including disseminated infections.

Bring pediatric patients up to date with all vaccinations prior to initiating REMICADE®. Exercise caution in the administration of live vaccines to infants born to female patients treated with REMICADE® during pregnancy.

For more information, please see full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion. (Requires Adobe® Reader®. Click here to download.)


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

2. See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.