Infliximab

1 INDICATIONS AND USAGE REMICADE is a tumor necrosis factor (TNF) blocker indicated for: Crohn’s Disease : reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy. ( 1.1 ) reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease. ( 1.1 ) Pediatric Crohn’s Disease : reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active disease who have had an inadequate response to conventional therapy. ( 1.2 ) 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 disease who have had an inadequate response to conventional therapy. ( 1.3 ) 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 disease who have had an inadequate response to conventional therapy. ( 1.4 ) Rheumatoid Arthritis in combination with methotrexate : reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active disease. ( 1.5 ) Ankylosing Spondylitis : reducing signs and symptoms in adult patients with active disease. ( 1.6 ) Psoriatic Arthritis : reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in adult patients. ( 1.7 ) Plaque Psoriasis : treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. ( 1.8 ) 1.1 Crohn’s Disease REMICADE is indicated for: 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. 1.2 Pediatric Crohn’s Disease REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active CD who have had an inadequate response to conventional therapy. 1.3 Ulcerative Colitis REMICADE is indicated for 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. 1.4 Pediatric Ulcerative Colitis REMICADE is indicated for 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. 1.5 Rheumatoid Arthritis REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis (RA). 1.6 Ankylosing Spondylitis REMICADE is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis (AS). 1.7 Psoriatic Arthritis REMICADE is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in adult patients with psoriatic arthritis (PsA). 1.8 Plaque Psoriasis REMICADE is indicated for the treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis (Ps) who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. REMICADE should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warning and Warnings and Precautions (5) ] .

5 WARNINGS AND PRECAUTIONS Serious infections – do not give REMICADE during an active infection. If an infection develops, monitor carefully and stop REMICADE if infection becomes serious. ( 5.1 ) Invasive fungal infections – for patients who develop a systemic illness on REMICADE, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic ( 5.1 ) Malignancies – the incidence of malignancies, including invasive cervical cancer and lymphoma, was greater in REMICADE-treated patients than in controls. 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. ( 5.2 ) Hepatitis B virus reactivation – test for HBV infection before starting REMICADE. Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop REMICADE and begin anti-viral therapy. ( 5.3 ) Hepatotoxicity – severe hepatic reactions, some fatal or necessitating liver transplantation. Stop REMICADE in cases of jaundice and/or marked liver enzyme elevations. ( 5.4 ) Heart failure – new onset or worsening symptoms may occur. ( 4 , 5.5 ) Cytopenias – advise patients to seek immediate medical attention if signs and symptoms develop, and consider stopping REMICADE. ( 5.6 ) Hypersensitivity – serious infusion reactions including anaphylaxis or serum sickness-like reactions may occur. ( 5.7 ) Cardiovascular and Cerebrovascular Reactions – Cerebrovascular accidents, myocardial infarctions (some fatal), and arrhythmias have been reported during and within 24 hours of initiation of REMICADE infusion. Monitor patients during REMICADE infusion and if serious reaction occurs, discontinue infusion. ( 5.8 ) Demyelinating disease – exacerbation or new onset may occur. ( 5.9 ) Lupus-like syndrome – stop REMICADE if syndrome develops. ( 5.12 ) Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents – Prior to initiating REMICADE bring pediatric and adult patients up to date with all vaccinations. Live vaccines or therapeutic infectious agents should not be given with REMICADE. At least a six month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab ( 5.13 ). 5.1 Serious Infections Patients treated with REMICADE are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis, salmonellosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. Treatment with REMICADE should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients: with chronic or recurrent infection; who have been exposed to tuberculosis; with a history of an opportunistic infection; who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or with underlying conditions that may predispose them to infection. Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving REMICADE, including patients who have previously received treatment for latent or active tuberculosis. Cases of active tuberculosis have also occurred in patients being treated with REMICADE during treatment for latent tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating REMICADE and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Induration of 5 mm or greater with tuberculin skin testing should be considered a positive test result when assessing if treatment for latent tuberculosis is needed prior to initiating REMICADE, even for patients previously vaccinated with Bacille Calmette-Guérin (BCG). Anti-tuberculosis therapy should also be considered prior to initiation of REMICADE in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Tuberculosis should be strongly considered in patients who develop a new infection during REMICADE treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. Monitoring Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with REMICADE, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with REMICADE. REMICADE should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with REMICADE should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated. Invasive Fungal Infections For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. 5.2 Malignancies Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF blockers (initiation of therapy ≤18 years of age), 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 (range 1 to 84 months) after the first dose of TNF blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports. Lymphomas In the controlled portions of clinical trials of all the TNF blockers, more cases of lymphoma have been observed among patients receiving a TNF blocker compared with control patients. In the controlled and open-label portions of REMICADE clinical trials, 5 patients developed lymphomas among 5707 patients treated with REMICADE (median duration of follow-up 1.0 years) vs. 0 lymphomas in 1600 control patients (median duration of follow-up 0.4 years). In RA patients, 2 lymphomas were observed for a rate of 0.08 cases per 100 patient-years of follow-up, which is approximately three-fold higher than expected in the general population. In the combined clinical trial population for RA, CD, PsA, AS, UC, and Ps, 5 lymphomas were observed for a rate of 0.10 cases per 100 patient-years of follow-up, which is approximately four-fold higher than expected in the general population. Patients with CD, RA or Ps, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Cases of acute and chronic leukemia have been reported with postmarketing TNF blocker use in RA and other diseases. Even in the absence of TNF blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Hepatosplenic T-cell Lymphoma (HSTCL) Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), 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. Almost all patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. The majority of reported REMICADE cases have occurred in patients with CD or UC and most were in adolescent and young adult males. It is uncertain whether the occurrence of HSTCL is related to TNF blockers or TNF blockers in combination with these other immunosuppressants. When treating patients, consideration of whether to use REMICADE alone or in combination with other immunosuppressants such as azathioprine or 6-mercaptopurine should take into account a possibility that there is a higher risk of HSTCL with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with REMICADE monotherapy from the clinical trial data [see Warnings and Precautions (5.7) and Adverse Reactions (6.1) ] . Skin Cancer Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including REMICADE [see Adverse Reactions (6.3) ] . Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. Cervical Cancer A population-based retrospective cohort study using data from Swedish national health registries found a 2 to 3 fold increase in the incidence of invasive cervical cancer in women with RA treated with REMICADE compared to biologics-naïve patients or the general population, particularly those over 60 years of age. A causal relationship between REMICADE and cervical cancer cannot be excluded. Periodic screening should continue in women treated with REMICADE [see Adverse Reactions (6.3) ] . Other Malignancies In the controlled portions of clinical trials of some TNF blockers including REMICADE, more malignancies (excluding lymphoma and nonmelanoma skin cancer [NMSC]) have been observed in patients receiving those TNF blockers compared with control patients. During the controlled portions of REMICADE trials in patients with moderately to severely active RA, CD, PsA, AS, UC, and Ps, 14 patients were diagnosed with malignancies (excluding lymphoma and NMSC) among 4019 REMICADE-treated patients vs. 1 among 1597 control patients (at a rate of 0.52/100 patient-years among REMICADE-treated patients vs. a rate of 0.11/100 patient-years among control patients), with median duration of follow-up 0.5 years for REMICADE-treated patients and 0.4 years for control patients. Of these, the most common malignancies were breast, colorectal, and melanoma. The rate of malignancies among REMICADE-treated patients was similar to that expected in the general population whereas the rate in control patients was lower than expected. In a clinical trial exploring the use of REMICADE in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies, the majority of lung or head and neck origin, were reported in REMICADE-treated patients compared with control patients. All patients had a history of heavy smoking [see Adverse Reactions (6.1) ] . Prescribers should exercise caution when considering the use of REMICADE in patients with moderate to severe COPD. Ps patients should be monitored for nonmelanoma skin cancers (NMSCs), particularly those patients who have had prior prolonged phototherapy treatment. In the maintenance portion of clinical trials for REMICADE, NMSCs were more common in patients with previous phototherapy [see Adverse Reactions (6.1) ] . The potential role of TNF blockers in the development of malignancies is not known [see Adverse Reactions (6.1) ]. Rates in clinical trials for REMICADE cannot be compared to rates in clinical trials of other TNF blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering REMICADE treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving REMICADE. 5.3 Hepatitis B Virus Reactivation Use of TNF blockers, including REMICADE, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients should be tested for HBV infection before initiating TNF blocker therapy, including REMICADE. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF blocker therapy in this situation and monitor patients closely. 5.4 Hepatotoxicity Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported in postmarketing data in patients receiving REMICADE. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 year after initiation of REMICADE; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥5 times the upper limit of normal) develop, REMICADE should be discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving REMICADE without progression to severe hepatic injury [see Adverse Reactions (6.1) ] . 5.5 Heart Failure The use of REMICADE at doses >5 mg/kg is contraindicated in patients with moderate or severe heart failure. A randomized, double-blind, placebo-controlled study evaluated the use of REMICADE (5 mg/kg or 10 mg/kg at Weeks 0, 2, and 6) in patients with moderate or severe heart failure [New York Heart Association (NYHA) Functional Class III/IV]. Compared to patients who received placebo, there was a higher rate of mortality and a higher risk of hospitalization at Week 28 due to heart failure in patients who received the 10 mg/kg REMICADE dose, and higher rates of cardiovascular adverse events in patients who received REMICADE doses of 5 mg/kg and 10 mg/kg. There have been post-marketing reports of new onset and worsening heart failure, with and without identifiable precipitating factors (e.g., pre-existing cardiovascular disease), in REMICADE-treated patients. Some of these patients have been under 50 years of age. If a decision is made to administer REMICADE (≤ 5 mg/kg) to patients with moderate or severe heart failure or to administer REMICADE (any approved dose) to patients with mild heart failure, they should be closely monitored during therapy, and REMICADE should be discontinued if new or worsening symptoms of heart failure appear [see Contraindications (4) and Adverse Reactions (6.1) ] . 5.6 Hematologic Reactions Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving REMICADE. The causal relationship to REMICADE therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with REMICADE who have ongoing or a history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on REMICADE. Discontinuation of REMICADE therapy should be considered in patients who develop significant hematologic abnormalities. 5.7 Hypersensitivity REMICADE has been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions (including anaphylaxis, urticaria, dyspnea, and/or hypotension), have occurred during or within 2 hours of REMICADE infusion. However, in some cases, serum sickness-like reactions have been observed in patients after initial REMICADE therapy (i.e., as early as after the second dose), and when REMICADE therapy was reinstituted following an extended period without REMICADE treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with a marked increase in antibodies to infliximab, loss of detectable serum concentrations of infliximab, and possible loss of drug efficacy. REMICADE should be discontinued for severe hypersensitivity 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 Dosage and Administration (2.10) and Adverse Reactions (6.1) ] . In RA, CD and Ps clinical trials, re-administration of REMICADE after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment [see Adverse Reactions (6.1) ] . In general, the benefit-risk of re-administration of REMICADE after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where REMICADE maintenance therapy for Ps is interrupted, REMICADE should be reinitiated as a single dose followed by maintenance therapy. 5.8 Cardiovascular and Cerebrovascular Reactions During and After Infusion Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of REMICADE infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of REMICADE. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms [see Adverse Reactions (6) ] . 5.9 Neurologic Reactions REMICADE and other agents that inhibit TNF have been associated with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of REMICADE in patients with these neurologic disorders and should consider discontinuation of REMICADE if these disorders develop. 5.10 Concurrent Administration with Other Biological Products Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNF blocker, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with the concurrent use of etanercept and anakinra therapy, similar toxicities may also result from the concurrent use of anakinra and other TNF blockers. Therefore, the concurrent use of REMICADE and anakinra is not recommended. In clinical studies, concurrent administration of TNF blockers and abatacept have been associated with an increased risk of infections including serious infections compared with TNF blockers alone, without increased clinical benefit. Therefore, the concurrent use of REMICADE and abatacept is not recommended [see Drug Interactions (7.1) ] . There is insufficient information regarding the concurrent use of REMICADE with other biological products used to treat the same conditions as REMICADE. The concurrent use of REMICADE with these biological products is not recommended because of the possibility of an increased risk of infection [see Drug Interactions (7.1) ] . 5.11 Switching Between Biological Disease-Modifying Antirheumatic Drugs (DMARDs) Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection. 5.12 Autoimmunity Treatment with REMICADE may result in the formation of autoantibodies and 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 (6.1) ] . 5.13 Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents Vaccinations Prior to initiating REMICADE in pediatric and adult patients, update vaccinations in accordance with current vaccination guidelines. Live Vaccines and Therapeutic Infectious Agents In patients receiving TNF blockers, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with REMICADE is not recommended. Fatal outcome due to disseminated BCG infection has been reported in an infant who received a BCG vaccine after in utero exposure to infliximab. Infliximab is known to cross the placenta and has been detected up to 6 months following birth. At least a six month waiting period following birth is recommended before the administration of any live vaccine to infants exposed in utero to infliximab. Other uses of therapeutic infectious agents such as live attenuated bacteria (e.g., BCG bladder instillation for the treatment of cancer) could result in clinical infections, including disseminated infections. It is recommended that therapeutic infectious agents not be given concurrently with REMICADE.

6 ADVERSE REACTIONS Most common adverse reactions (>10%) – infections (e.g. upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Adults The data described herein reflect exposure to REMICADE in 4779 adult patients (1304 patients with RA, 1106 patients with CD, 202 with AS, 293 with PsA, 484 with UC, 1373 with Ps, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond 1 year. [For information on adverse reactions in pediatric patients see Adverse Reactions (6.1) ]. One of the most-common reasons for discontinuation of treatment was infusion-related reactions (e.g., dyspnea, flushing, headache and rash). Infusion-Related Reactions Adverse Reactions During or Shortly After Infusion An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In all the clinical studies, approximately 20% of REMICADE-treated patients experienced an infusion reaction compared with 10% of placebo-treated patients. Of REMICADE-treated patients who had an infusion reaction during the induction period, 27% experienced an infusion reaction during the maintenance period. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period. Among all 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), and <1% were accompanied by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary reactions. Serious infusion reactions occurred in <1% of patients and included anaphylaxis, convulsions, erythematous rash and hypotension. Approximately 3% of patients discontinued REMICADE because of infusion reactions, and all patients recovered with treatment and/or discontinuation of the infusion. REMICADE infusions beyond the initial infusion were not associated with a higher incidence of reactions. The infusion reaction rates remained stable in Ps through 1 year in Ps Study I. In psoriasis Study II, the rates were variable over time and somewhat higher following the final infusion than after the initial infusion. Across the 3 Ps studies, the percent of total infusions resulting in infusion reactions (i.e., an adverse event occurring within 1 hour) was 7% in the 3 mg/kg group, 4% in the 5 mg/kg group, and 1% in the placebo group. Patients who became positive for antibodies to infliximab were more likely (approximately two-to three-fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions [see Adverse Reactions (6.2) and Drug Interactions (7.3) ] . Infusion Reactions Following Re-administration In a clinical trial of patients with moderate to severe Ps designed to assess the efficacy of long-term maintenance therapy versus re-treatment with an induction regimen of REMICADE following disease flare, 4% (8/219) of patients in the re-treatment induction therapy arm experienced serious infusion reactions versus 1 to <3 × ULN ≥3 × ULN ≥5 × ULN Placebo REMICADE Placebo REMICADE Placebo REMICADE Rheumatoid arthritis Placebo patients received methotrexate while REMICADE patients received both REMICADE and methotrexate. Median follow-up was 58 weeks. 24% 34% 3% 4% <1% <1% Crohn's disease Placebo patients in the 2 Phase 3 trials in CD received an initial dose of 5 mg/kg REMICADE at study start and were on placebo in the maintenance phase. Patients who were randomized to the placebo maintenance group and then later crossed over to REMICADE are included in the REMICADE group in ALT analysis. Median follow-up was 54 weeks. 34% 39% 4% 5% 0% 2% Ulcerative colitis Median follow-up was 30 weeks. Specifically, the median duration of follow-up was 30 weeks for placebo and 31 weeks for REMICADE. 12% 17% 1% 2% <1% <1% Ankylosing spondylitis Median follow-up was 24 weeks for the placebo group and 102 weeks for the REMICADE group. 15% 51% 0% 10% 0% 4% Psoriatic arthritis Median follow-up was 39 weeks for the REMICADE group and 18 weeks for the placebo group. 16% 50% 0% 7% 0% 2% Plaque psoriasis ALT values are obtained in 2 Phase 3 Ps studies with median follow-up of 50 weeks for REMICADE and 16 weeks for placebo. 24% 49% 16 weeks. In a PsA study in which 191 patients received 5 mg/kg with or without MTX, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. Antibody development was lower among RA and CD patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX. Patients who were antibody-positive were more likely to have higher rates of clearance, have reduced efficacy, and to experience an infusion reaction than were patients who were antibody negative [see Adverse Reactions (6.1) ] . In the Ps Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the Ps Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year and in Study III in patients treated with 5 mg/kg induction (14.1%–23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in Ps patients as compared to patients with other diseases treated with REMICADE over the long term is not known. Immunogenicity in Pediatric Patients with Crohn's Disease In Study Peds Crohn's, in which all patients received stable doses of 6-MP, AZA, or MTX, excluding inconclusive samples, 3 of 24 patients had antibodies to infliximab. Although 105 patients were tested for antibodies to infliximab, 81 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample. Immunogenicity in Pediatric Patients with Ulcerative Colitis In the pediatric UC trial, 58 patients were evaluated for antibodies to infliximab using the EIA as well as the drug-tolerant ECLIA. With the EIA, 4 of 58 (7%) patients had antibodies to infliximab. With the ECLIA, 30 of 58 (52%) patients had antibodies to infliximab. The higher incidence of antibodies to infliximab by the ECLIA method was due to the 60-fold higher sensitivity compared to the EIA method. While EIA-positive patients generally had undetectable trough infliximab concentrations, ECLIA-positive patients could have detectable trough concentrations of infliximab because the ECLIA assay is more sensitive and drug-tolerant. 6.3 Postmarketing Experience Adverse reactions, some with fatal outcomes, have been identified during post approval use of REMICADE in adult and pediatric patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Postmarketing Adverse Reactions in Adults and Pediatric Patients Neutropenia [see Warnings and Precautions (5.6) ] , agranulocytosis (including infants exposed in utero to infliximab), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura. Interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and rapidly progressive disease). Pericardial effusion, systemic and cutaneous vasculitis. Erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, linear IgA bullous dermatosis (LABD), acute generalized exanthematous pustulosis (AGEP), worsening psoriasis (all subtypes including pustular, primarily palmoplantar), lichenoid reactions. Peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy) transverse myelitis, and neuropathies (additional neurologic reactions have also been observed) [see Warnings and Precautions (5.9) ] . Acute liver failure, jaundice, hepatitis, and cholestasis [see Warnings and Precautions (5.4) ] . Serious infections [see Warnings and Precautions (5.1) ] and vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant exposed in utero to infliximab [see Warnings and Precautions (5.13) ]. Malignancies, including leukemia, melanoma, Merkel cell carcinoma, and cervical cancer [see Warnings and Precautions (5.2) ] . Anaphylactic reactions, including anaphylactic shock, laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with REMICADE administration. Transient visual loss have been reported in association with REMICADE during or within 2 hours of infusion. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal), and arrhythmia occurring within 24 hours of initiation of infusion have also been reported [see Warnings and Precautions (5.8) ] . New onset immune disorders (e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease). Postmarketing Serious Adverse Reactions in Pediatric Patients The following serious adverse reactions have been reported in the post-marketing experience in pediatric patients: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, hypersensitivity reactions, malignancies, including hepatosplenic T-cell lymphomas [see Boxed Warning and Warnings and Precautions (5.2) ] , transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.

7 DRUG INTERACTIONS Other Biological Products – increased risk of serious infections. ( 7.1 ) 7.1 Other Biological Products The combination of REMICADE with other biological products used to treat the same conditions as REMICADE is not recommended [see Warnings and Precautions (5.10) ] . An increased risk of serious infections was seen in clinical studies of other TNF blockers used in combination with anakinra or abatacept, with no added clinical benefit. Because of the nature of the adverse reactions seen with these combinations with TNF blocker therapy, similar toxicities may also result from the combination of anakinra or abatacept with other TNF blockers. Therefore, the combination of REMICADE and anakinra or abatacept is not recommended [see Warnings and Precautions (5.10) ] . The concomitant use of tocilizumab with biological DMARDs such as TNF antagonists, including REMICADE, should be avoided because of the possibility of increased immunosuppression and increased risk of infection. 7.2 Methotrexate and Other Concomitant Medications Specific drug interaction studies, including interactions with methotrexate (MTX), have not been conducted. The majority of patients in RA or CD clinical studies received one or more concomitant medications. In RA, concomitant medications besides MTX were nonsteroidal anti-inflammatory agents (NSAIDs), folic acid, corticosteroids and/or narcotics. Concomitant CD medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA and aminosalicylates. In PsA clinical trials, concomitant medications included MTX in approximately half of the patients as well as NSAIDs, folic acid and corticosteroids. Concomitant MTX use may decrease the incidence of anti-infliximab antibody production and increase infliximab concentrations. 7.3 Immunosuppressants Patients with CD who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants [see Adverse Reactions (6.1) ] . Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of CD including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates. 7.4 Cytochrome P450 Substrates The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-1, IL-6, IL-10, IFN) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as infliximab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of REMICADE in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed. 7.5 Live Vaccines/Therapeutic Infectious Agents It is recommended that live vaccines not be given concurrently with REMICADE. It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab for at least 6 months following birth [see Warnings and Precautions (5.13) ] . It is recommended that therapeutic infectious agents not be given concurrently with REMICADE [see Warnings and Precautions (5.13) ] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available observational studies in pregnant women exposed to REMICADE showed no increased risk of major malformations among live births as compared to those exposed to non-biologics. However, findings on other birth and maternal outcomes were not consistent across studies of different study design and conduct (see Data ) . Monoclonal antibodies such as infliximab are transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant (see Clinical Considerations ) . Because infliximab does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with REMICADE. In a developmental study conducted in mice using an analogous antibody, no evidence of maternal toxicity or fetal harm was observed (see Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that there is an increased risk of adverse pregnancy outcomes in women with inflammatory bowel disease or rheumatoid arthritis associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2.5 kg) and small for gestational age at birth. Fetal/Neonatal Adverse Reactions As with other IgG antibodies, infliximab crosses the placenta. Infliximab has been detected in the serum of infants up to 6 months following birth. Consequently, these infants may be at increased risk of infection, including disseminated infection which can become fatal. At least a six month waiting period following birth is recommended before the administration of live vaccines (e.g., BCG vaccine or other live vaccines, such as the rotavirus vaccine) to these infants [see Warnings and Precautions (5.13) ] . Cases of agranulocytosis in infants exposed in utero have also been reported [see Adverse Reactions (6.3) ] . Data Human Data Two prospective cohort studies were conducted assessing birth outcomes as well as the health status of infants up to the age of one year in women exposed to REMICADE compared to non-biologic comparators including methotrexate, azathioprine, 6-mercaptopurine and systemic corticosteroids used for the treatment of similar diseases. The first study was conducted in an IBD pregnancy registry in the United States and assessed pregnancy outcomes in 294 women with inflammatory bowel disease exposed to REMICADE during pregnancy compared with 515 women on a non-biologic treatment. REMICADE exposure was not associated with increased rates of major congenital malformations, miscarriage/stillbirth, infants of low birth weight, small for gestational age, or infection in the first year of life. The second study among IBD and non-IBD patients in Sweden, Finland, and Denmark compared 97, 7, and 166 women exposed to REMICADE to 2,693, 2,499 and 1,268 women on non-biologic systemic therapy, respectively. In this study, comparing pooled data across the three countries, exposure to REMICADE was not associated with increased rates of congenital anomalies or infant death. REMICADE in combination with immunosuppressants (mainly systemic corticosteroids and azathioprine) was associated with increased rates of preterm birth, small for gestational age, low birth weight, and infant hospitalization for infection compared with non-biologic systemic treatment. Although the study did not show any associations with REMICADE monotherapy, the analyses could have been underpowered to detect an association. There were additional methodological limitations with these studies that may account for the study findings in both studies: the concomitant use of other medications or treatments was not controlled and disease severity was not assessed; in the U.S. study, patient reported outcomes were collected without clinical validation. These methodological limitations hinder interpretation of the study results. Animal Data Because infliximab products do not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab. An embryofetal development study was conducted in pregnant mice using cV1q anti-mouse TNFα, an analogous antibody that selectively inhibits the functional activity of mouse TNFα. This antibody administered in mice, during the period of organogenesis on gestation days (GDs) 6 and 12, at IV doses up to 40 mg/kg produced no evidence of maternal toxicity, fetal mortality, or structural abnormalities. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Analyses of fetal samples on GD 14 indicated placental transfer of the antibody and exposure of the fetuses during organogenesis. In a peri- and post-natal development study in mice, no maternal toxicity or adverse developmental effects in offspring were observed when dams were administered IV doses of 10 or 40 mg/kg of the analogous antibody on GDs 6, 12 and 18 and lactation days 3, 9 and 15. 8.2 Lactation Risk Summary Published literature show that infliximab is present at low levels in human milk. Systemic exposure in a breastfed infant is expected to be low because infliximab is largely degraded in the gastrointestinal tract. A U.S. multi-center study of 168 women treated with infliximab for inflammatory bowel disease (breast milk samples obtained, n=29) showed that infants exposed to infliximab through breast milk had no increase in rates of infections and developed normally. There are no data on the effects of infliximab on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for REMICADE and any potential adverse effects on the breastfed child from REMICADE or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of REMICADE have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of CD and UC [ see Dosage and Administration (2.2 , 2.4) and Adverse Reactions (6.1) ] . However, the safety and effectiveness of REMICADE in pediatric patients <6 years of age with CD or UC have not been established. The safety and effectiveness of REMICADE in the treatment of pediatric patients with Ps and juvenile rheumatoid arthritis (JRA) have not been established. Pediatric Crohn's Disease The safety and effectiveness of REMICADE have been established for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active CD who have had an inadequate response to conventional therapy. The use of REMICADE for this indication is supported by evidence from a randomized, open-label pediatric CD study in 112 pediatric patients aged 6 years and older [see Clinical Studies (14.2) ]. REMICADE has been studied only in combination with conventional immunosuppressive therapy in pediatric CD. The longer term (greater than 1 year) safety and effectiveness of REMICADE in pediatric CD patients have not been established in clinical trials. Postmarketing cases of HSTCL have been reported in pediatric patients treated with TNF blockers including REMICADE. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when REMICADE is used in combination with other immunosuppressants in pediatric CD patients [see Boxed Warning and Warnings and Precautions (5.2) ]. Pediatric Ulcerative Colitis The safety and effectiveness of REMICADE for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active UC who have had an inadequate response to conventional therapy have been established. The use of REMICADE for this indication is supported by evidence from adequate and well-controlled studies of REMICADE in adults with additional safety and pharmacokinetic data from an open-label pediatric UC study in 60 pediatric patients aged 6 years and older [see Dosage and Administration (2.4) , Adverse Reactions (6.1) , and Clinical Studies (14.4) ] . The effectiveness of REMICADE in inducing and maintaining mucosal healing in pediatric UC was not established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at the Week 8 endoscopy, the induction phase was open-label and lacked a control group. Only 9 patients had an optional endoscopy at Week 54. Approximately half of the patients were on concomitant immunomodulators (AZA, 6-MP, MTX) at study start. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when REMICADE is used in combination with other immunosuppressants in pediatric UC patients [see Boxed Warning and Warnings and Precautions (5.2) ] . The longer term (greater than 1 year) safety and effectiveness of REMICADE in pediatric UC patients have not been established in clinical trials. Juvenile Rheumatoid Arthritis (JRA) The safety and effectiveness of REMICADE in the treatment of pediatric patients with juvenile rheumatoid arthritis (JRA) have not been established. The safety and efficacy of REMICADE in patients with JRA were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (≤0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or disease modifying antirheumatic drugs (DMARDs) was permitted. Doses of 3 mg/kg REMICADE or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed-over to receive 6 mg/kg REMICADE at Weeks 14, 16, and 20, and then every 8 weeks through Week 44. Patients who completed the study continued to receive open-label treatment with REMICADE for up to 2 years in a companion extension study. The study failed to establish the efficacy of REMICADE in the treatment of JRA. Key observations in the study included a high placebo response rate and a higher rate of immunogenicity than what has been observed in adults. Additionally, a higher rate of clearance of infliximab was observed than had been observed in adults. Population pharmacokinetic analysis showed that in pediatric patients with JRA with a body weight of up to 35 kg receiving 6 mg/kg REMICADE and pediatric patients with JRA with body weight greater than 35 kg up to adult body weight receiving 3 mg/kg REMICADE, the steady state area under the concentration curve (AUC ss ) was similar to that observed in adults receiving 3 mg/kg of REMICADE. A total of 60 patients with JRA were treated with doses of 3 mg/kg and 57 patients were treated with doses of 6 mg/kg. The proportion of patients with infusion reactions who received 3 mg/kg REMICADE was 35% (21/60) over 52 weeks compared with 18% (10/57) in patients who received 6 mg/kg over 38 weeks. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg REMICADE group, 4 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg REMICADE group, 2 patients had a serious infusion reaction, 1 of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received REMICADE by rapid infusion (duration of less than 2 hours). Antibodies to infliximab developed in 38% (20/53) of patients who received 3 mg/kg REMICADE compared with 12% (6/49) of patients who received 6 mg/kg. A total of 68% (41/60) of patients who received 3 mg/kg REMICADE in combination with MTX experienced an infection over 52 weeks compared with 65% (37/57) of patients who received 6 mg/kg REMICADE in combination with MTX over 38 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient. 8.5 Geriatric Use Of the total number of REMICADE-treated patients in RA and Ps clinical studies, 256 (9.6%) were 65 years old and over, while 17 (0.6%) were 75 years old and over. In these trials, no overall differences in safety or effectiveness were observed between geriatric patients (patients ≥ 65 years old) and younger adult patients (patients 18 to 65 years old). However, the incidence of serious adverse reactions in geriatric patients was higher in both REMICADE and control groups compared to younger adult patients. Of the total number of REMICADE-treated patients in CD, UC, AS, and PsA clinical studies, 76 (3.2%) were 65 years old and over, while 9 (0.4%) were 75 years old and over. In the CD, UC, AS, and PsA studies, there were insufficient numbers of geriatric patients to determine whether they respond differently from younger adults . The incidence of serious infections in REMICADE-treated geriatric patients was greater than in REMICADE-treated younger adult patients; therefore close monitoring of geriatric patients for the development of serious infections is recommended [see Warnings and Precautions (5.1) and Adverse Reactions (6.1) ] .

8.1 Pregnancy Risk Summary Available observational studies in pregnant women exposed to REMICADE showed no increased risk of major malformations among live births as compared to those exposed to non-biologics. However, findings on other birth and maternal outcomes were not consistent across studies of different study design and conduct (see Data ) . Monoclonal antibodies such as infliximab are transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant (see Clinical Considerations ) . Because infliximab does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with REMICADE. In a developmental study conducted in mice using an analogous antibody, no evidence of maternal toxicity or fetal harm was observed (see Data ) . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that there is an increased risk of adverse pregnancy outcomes in women with inflammatory bowel disease or rheumatoid arthritis associated with increased disease activity. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2.5 kg) and small for gestational age at birth. Fetal/Neonatal Adverse Reactions As with other IgG antibodies, infliximab crosses the placenta. Infliximab has been detected in the serum of infants up to 6 months following birth. Consequently, these infants may be at increased risk of infection, including disseminated infection which can become fatal. At least a six month waiting period following birth is recommended before the administration of live vaccines (e.g., BCG vaccine or other live vaccines, such as the rotavirus vaccine) to these infants [see Warnings and Precautions (5.13) ] . Cases of agranulocytosis in infants exposed in utero have also been reported [see Adverse Reactions (6.3) ] . Data Human Data Two prospective cohort studies were conducted assessing birth outcomes as well as the health status of infants up to the age of one year in women exposed to REMICADE compared to non-biologic comparators including methotrexate, azathioprine, 6-mercaptopurine and systemic corticosteroids used for the treatment of similar diseases. The first study was conducted in an IBD pregnancy registry in the United States and assessed pregnancy outcomes in 294 women with inflammatory bowel disease exposed to REMICADE during pregnancy compared with 515 women on a non-biologic treatment. REMICADE exposure was not associated with increased rates of major congenital malformations, miscarriage/stillbirth, infants of low birth weight, small for gestational age, or infection in the first year of life. The second study among IBD and non-IBD patients in Sweden, Finland, and Denmark compared 97, 7, and 166 women exposed to REMICADE to 2,693, 2,499 and 1,268 women on non-biologic systemic therapy, respectively. In this study, comparing pooled data across the three countries, exposure to REMICADE was not associated with increased rates of congenital anomalies or infant death. REMICADE in combination with immunosuppressants (mainly systemic corticosteroids and azathioprine) was associated with increased rates of preterm birth, small for gestational age, low birth weight, and infant hospitalization for infection compared with non-biologic systemic treatment. Although the study did not show any associations with REMICADE monotherapy, the analyses could have been underpowered to detect an association. There were additional methodological limitations with these studies that may account for the study findings in both studies: the concomitant use of other medications or treatments was not controlled and disease severity was not assessed; in the U.S. study, patient reported outcomes were collected without clinical validation. These methodological limitations hinder interpretation of the study results. Animal Data Because infliximab products do not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab. An embryofetal development study was conducted in pregnant mice using cV1q anti-mouse TNFα, an analogous antibody that selectively inhibits the functional activity of mouse TNFα. This antibody administered in mice, during the period of organogenesis on gestation days (GDs) 6 and 12, at IV doses up to 40 mg/kg produced no evidence of maternal toxicity, fetal mortality, or structural abnormalities. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Analyses of fetal samples on GD 14 indicated placental transfer of the antibody and exposure of the fetuses during organogenesis. In a peri- and post-natal development study in mice, no maternal toxicity or adverse developmental effects in offspring were observed when dams were administered IV doses of 10 or 40 mg/kg of the analogous antibody on GDs 6, 12 and 18 and lactation days 3, 9 and 15.

8.4 Pediatric Use The safety and effectiveness of REMICADE have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of CD and UC [ see Dosage and Administration (2.2 , 2.4) and Adverse Reactions (6.1) ] . However, the safety and effectiveness of REMICADE in pediatric patients <6 years of age with CD or UC have not been established. The safety and effectiveness of REMICADE in the treatment of pediatric patients with Ps and juvenile rheumatoid arthritis (JRA) have not been established. Pediatric Crohn's Disease The safety and effectiveness of REMICADE have been established for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active CD who have had an inadequate response to conventional therapy. The use of REMICADE for this indication is supported by evidence from a randomized, open-label pediatric CD study in 112 pediatric patients aged 6 years and older [see Clinical Studies (14.2) ]. REMICADE has been studied only in combination with conventional immunosuppressive therapy in pediatric CD. The longer term (greater than 1 year) safety and effectiveness of REMICADE in pediatric CD patients have not been established in clinical trials. Postmarketing cases of HSTCL have been reported in pediatric patients treated with TNF blockers including REMICADE. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when REMICADE is used in combination with other immunosuppressants in pediatric CD patients [see Boxed Warning and Warnings and Precautions (5.2) ]. Pediatric Ulcerative Colitis The safety and effectiveness of REMICADE for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active UC who have had an inadequate response to conventional therapy have been established. The use of REMICADE for this indication is supported by evidence from adequate and well-controlled studies of REMICADE in adults with additional safety and pharmacokinetic data from an open-label pediatric UC study in 60 pediatric patients aged 6 years and older [see Dosage and Administration (2.4) , Adverse Reactions (6.1) , and Clinical Studies (14.4) ] . The effectiveness of REMICADE in inducing and maintaining mucosal healing in pediatric UC was not established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at the Week 8 endoscopy, the induction phase was open-label and lacked a control group. Only 9 patients had an optional endoscopy at Week 54. Approximately half of the patients were on concomitant immunomodulators (AZA, 6-MP, MTX) at study start. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when REMICADE is used in combination with other immunosuppressants in pediatric UC patients [see Boxed Warning and Warnings and Precautions (5.2) ] . The longer term (greater than 1 year) safety and effectiveness of REMICADE in pediatric UC patients have not been established in clinical trials. Juvenile Rheumatoid Arthritis (JRA) The safety and effectiveness of REMICADE in the treatment of pediatric patients with juvenile rheumatoid arthritis (JRA) have not been established. The safety and efficacy of REMICADE in patients with JRA were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (≤0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or disease modifying antirheumatic drugs (DMARDs) was permitted. Doses of 3 mg/kg REMICADE or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed-over to receive 6 mg/kg REMICADE at Weeks 14, 16, and 20, and then every 8 weeks through Week 44. Patients who completed the study continued to receive open-label treatment with REMICADE for up to 2 years in a companion extension study. The study failed to establish the efficacy of REMICADE in the treatment of JRA. Key observations in the study included a high placebo response rate and a higher rate of immunogenicity than what has been observed in adults. Additionally, a higher rate of clearance of infliximab was observed than had been observed in adults. Population pharmacokinetic analysis showed that in pediatric patients with JRA with a body weight of up to 35 kg receiving 6 mg/kg REMICADE and pediatric patients with JRA with body weight greater than 35 kg up to adult body weight receiving 3 mg/kg REMICADE, the steady state area under the concentration curve (AUC ss ) was similar to that observed in adults receiving 3 mg/kg of REMICADE. A total of 60 patients with JRA were treated with doses of 3 mg/kg and 57 patients were treated with doses of 6 mg/kg. The proportion of patients with infusion reactions who received 3 mg/kg REMICADE was 35% (21/60) over 52 weeks compared with 18% (10/57) in patients who received 6 mg/kg over 38 weeks. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg REMICADE group, 4 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg REMICADE group, 2 patients had a serious infusion reaction, 1 of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received REMICADE by rapid infusion (duration of less than 2 hours). Antibodies to infliximab developed in 38% (20/53) of patients who received 3 mg/kg REMICADE compared with 12% (6/49) of patients who received 6 mg/kg. A total of 68% (41/60) of patients who received 3 mg/kg REMICADE in combination with MTX experienced an infection over 52 weeks compared with 65% (37/57) of patients who received 6 mg/kg REMICADE in combination with MTX over 38 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient.