- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
- 11. Legal category
Rheumatoid arthritisRemicade, in combination with methotrexate, is indicated for the reduction of signs and symptoms as well as the improvement in physical function in:• adult patients with active disease when the response to disease-modifying anti-rheumatic drugs (DMARDs), including methotrexate, has been inadequate.• adult patients with severe, active and progressive disease not previously treated with methotrexate or other DMARDs.In these patient populations, a reduction in the rate of the progression of joint damage, as measured by X-ray, has been demonstrated (see section 5.1).
Adult Crohn's diseaseRemicade is indicated for:• treatment of moderately to severely active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who are intolerant to or have medical contraindications for such therapies. • treatment of fistulising, active Crohn's disease, in adult patients who have not responded despite a full and adequate course of therapy with conventional treatment (including antibiotics, drainage and immunosuppressive therapy).
Paediatric Crohn's diseaseRemicade is indicated for treatment of severe, active Crohn's disease, in children and adolescents aged 6 to 17 years, who have not responded to conventional therapy including a corticosteroid, an immunomodulator and primary nutrition therapy; or who are intolerant to or have contraindications for such therapies. Remicade has been studied only in combination with conventional immunosuppressive therapy.
Ulcerative colitisRemicade is indicated for treatment of moderately to severely active ulcerative colitis in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies.
Paediatric ulcerative colitisRemicade is indicated for treatment of severely active ulcerative colitis, in children and adolescents aged 6 to 17 years, who have had an inadequate response to conventional therapy including corticosteroids and 6-MP or AZA, or who are intolerant to or have medical contraindications for such therapies.
Ankylosing spondylitisRemicade is indicated for treatment of severe, active ankylosing spondylitis, in adult patients who have responded inadequately to conventional therapy.
Psoriatic arthritisRemicade is indicated for treatment of active and progressive psoriatic arthritis in adult patients when the response to previous DMARD therapy has been inadequate.Remicade should be administered• in combination with methotrexate• or alone in patients who show intolerance to methotrexate or for whom methotrexate is contraindicatedRemicade has been shown to improve physical function in patients with psoriatic arthritis, and to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease (see section 5.1).
PsoriasisRemicade is indicated for treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including cyclosporine, methotrexate or PUVA (see section 5.1).
Adults (≥ 18 years)
Rheumatoid arthritis3 mg/kg given as an intravenous infusion followed by additional 3 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Remicade must be given concomitantly with methotrexate.Available data suggest that the clinical response is usually achieved within 12 weeks of treatment. If a patient has an inadequate response or loses response after this period, consideration may be given to increase the dose step-wise by approximately 1.5 mg/kg, up to a maximum of 7.5 mg/kg every 8 weeks. Alternatively, administration of 3 mg/kg as often as every 4 weeks may be considered. If adequate response is achieved, patients should be continued on the selected dose or dose frequency. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within the first 12 weeks of treatment or after dose adjustment.
Moderately to severely active Crohn's disease5 mg/kg given as an intravenous infusion followed by an additional 5 mg/kg infusion 2 weeks after the first infusion. If a patient does not respond after 2 doses, no additional treatment with infliximab should be given. Available data do not support further infliximab treatment, in patients not responding within 6 weeks of the initial infusion. In responding patients, the alternative strategies for continued treatment are:• Maintenance: Additional infusion of 5 mg/kg at 6 weeks after the initial dose, followed by infusions every 8 weeks or • Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur (see 'Re-administration' below and section 4.4). Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who lost response indicate that some patients may regain response with dose escalation (see section 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.
Fistulising, active Crohn's disease5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusions at 2 and 6 weeks after the first infusion. If a patient does not respond after 3 doses, no additional treatment with infliximab should be given.In responding patients, the alternative strategies for continued treatment are:• Maintenance: Additional infusions of 5 mg/kg every 8 weeks or • Re-administration: Infusion of 5 mg/kg if signs and symptoms of the disease recur followed by infusions of 5 mg/kg every 8 weeks (see 'Re-administration' below and section 4.4).Although comparative data are lacking, limited data in patients who initially responded to 5 mg/kg but who lost response indicate that some patients may regain response with dose escalation (see section 5.1). Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment.In Crohn's disease, experience with re-administration if signs and symptoms of disease recur is limited and comparative data on the benefit/risk of the alternative strategies for continued treatment are lacking.
Ulcerative colitis5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Available data suggest that the clinical response is usually achieved within 14 weeks of treatment, i.e. three doses. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit within this time period.
Ankylosing spondylitis5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 6 to 8 weeks. If a patient does not respond by 6 weeks (i.e. after 2 doses), no additional treatment with infliximab should be given.
Psoriatic arthritis5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter.
Psoriasis5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. If a patient shows no response after 14 weeks (i.e. after 4 doses), no additional treatment with infliximab should be given.
Re-administration for Crohn's disease and rheumatoid arthritisIf the signs and symptoms of disease recur, Remicade can be re-administered within 16 weeks following the last infusion. In clinical studies, delayed hypersensitivity reactions have been uncommon and have occurred after Remicade-free intervals of less than 1 year (see sections 4.4 and 4.8). The safety and efficacy of re-administration after a Remicade-free interval of more than 16 weeks has not been established. This applies to both Crohn's disease patients and rheumatoid arthritis patients.
Re-administration for ulcerative colitisThe safety and efficacy of re-administration, other than every 8 weeks, has not been established (see sections 4.4 and 4.8).Re-administration for ankylosing spondylitisThe safety and efficacy of re-administration, other than every 6 to 8 weeks, has not been established (see sections 4.4 and 4.8).
Re-administration for psoriatic arthritisThe safety and efficacy of re-administration, other than every 8 weeks, has not been established (see sections 4.4 and 4.8).
Re-administration for psoriasisLimited experience from re-treatment with one single Remicade dose in psoriasis after an interval of 20 weeks suggests reduced efficacy and a higher incidence of mild to moderate infusion reactions when compared to the initial induction regimen (see section 5.1).Limited experience from re-treatment following disease flare by a re-induction regimen suggests a higher incidence of infusion reactions, including serious ones, when compared to 8-weekly maintenance treatment (see section 4.8).
Re-administration across indicationsIn case maintenance therapy is interrupted, and there is a need to restart treatment, use of a re-induction regimen is not recommended (see section 4.8). In this situation, Remicade should be re-initiated as a single dose followed by the maintenance dose recommendations described above.
Elderly patients (≥ 65 years)Specific studies of Remicade in elderly patients have not been conducted. No major age-related differences in clearance or volume of distribution were observed in clinical studies. No dose adjustment is required (see section 5.2). For more information about the safety of Remicade in elderly patients see sections 4.4 and 4.8.
Impaired renal and/or hepatic functionRemicade has not been studied in these patient populations. No dose recommendations can be made (see section 5.2).
Crohn's disease (6 to 17 years)5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximab treatment in children and adolescents not responding within the first 10 weeks of treatment (see section 5.1).Some patients may require a shorter dosing interval to maintain clinical benefit, while for others a longer dosing interval may be sufficient. Patients who have had their dose interval shortened to less than 8 weeks may be at greater risk for adverse reactions. Continued therapy with a shortened interval should be carefully considered in those patients who show no evidence of additional therapeutic benefit after a change in dosing interval.The safety and efficacy of Remicade have not been studied in children with Crohn's disease below the age of 6 years. Currently available pharmacokinetic data are described in section 5.2 but no recommendation on a posology can be made in children younger than 6 years.
Ulcerative colitis (6 to 17 years)5 mg/kg given as an intravenous infusion followed by additional 5 mg/kg infusion doses at 2 and 6 weeks after the first infusion, then every 8 weeks thereafter. Available data do not support further infliximab treatment in paediatric patients not responding within the first 8 weeks of treatment (see section 5.1).The safety and efficacy of Remicade have not been studied in children with ulcerative colitis below the age of 6 years. Currently available pharmacokinetic data are described in section 5.2 but no recommendation on a posology can be made in children younger than 6 years.
PsoriasisThe safety and efficacy of Remicade in children and adolescents younger than 18 years in the indication psoriasis have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.
Juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitisThe safety and efficacy of Remicade in children and adolescents younger than 18 years in the indications juvenile idiopathic arthritis, psoriatic arthritis and ankylosing spondylitis have not been established. Currently available data are described in section 5.2 but no recommendation on a posology can be made.
Juvenile rheumatoid arthritisThe safety and efficacy of Remicade in children and adolescents younger than 18 years in the indication juvenile rheumatoid arthritis have not been established. Currently available data are described in sections 4.8 and 5.2 but no recommendation on a posology can be made.
Impaired renal and/or hepatic functionRemicade has not been studied in these patient populations. No dose recommendations can be made (see section 5.2).
Method of administrationRemicade should be administered intravenously over a 2 hour period. All patients administered Remicade are to be observed for at least 1-2 hours post-infusion for acute infusion-related reactions. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol and infusion rate may be slowed in order to decrease the risk of infusion-related reactions especially if infusion-related reactions have occurred previously (see section 4.4).
Shortened infusions across adult indicationsIn carefully selected adult patients who have tolerated at least 3 initial 2-hour infusions of Remicade (induction phase) and are receiving maintenance therapy, consideration may be given to administering subsequent infusions over a period of not less than 1 hour. If an infusion reaction occurs in association with a shortened infusion, a slower infusion rate may be considered for future infusions if treatment is to be continued. Shortened infusions at doses > 6 mg/kg have not been studied (see section 4.8).For preparation and administration instructions, see section 6.6.
Infusion reactions and hypersensitivityInfliximab has been associated with acute infusion-related reactions, including anaphylactic shock, and delayed hypersensitivity reactions (see section 4.8). Acute infusion reactions including anaphylactic reactions may develop during (within seconds) or within a few hours following infusion. If acute infusion reactions occur, the infusion must be interrupted immediately. Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available. Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol to prevent mild and transient effects.Antibodies to infliximab may develop and have been associated with an increased frequency of infusion reactions. A low proportion of the infusion reactions was serious allergic reactions. An association between development of antibodies to infliximab and reduced duration of response has also been observed. Concomitant administration of immunomodulators has been associated with lower incidence of antibodies to infliximab and a reduction in the frequency of infusion reactions. The effect of concomitant immunomodulator therapy was more profound in episodically-treated patients than in patients given maintenance therapy. Patients who discontinue immunosuppressants prior to or during Remicade treatment are at greater risk of developing these antibodies. Antibodies to infliximab cannot always be detected in serum samples. If serious reactions occur, symptomatic treatment must be given and further Remicade infusions must not be administered (see section 4.8).In clinical studies, delayed hypersensitivity reactions have been reported. Available data suggest an increased risk for delayed hypersensitivity with increasing Remicade-free interval. Patients should be advised to seek immediate medical advice if they experience any delayed adverse event (see section 4.8). If patients are re-treated after a prolonged period, they must be closely monitored for signs and symptoms of delayed hypersensitivity.
InfectionsPatients must be monitored closely for infections including tuberculosis before, during and after treatment with Remicade. Because the elimination of infliximab may take up to six months, monitoring should be continued throughout this period. Further treatment with Remicade must not be given if a patient develops a serious infection or sepsis.Caution should be exercised when considering the use of Remicade in patients with chronic infection or a history of recurrent infections, including concomitant immunosuppressive therapy. Patients should be advised of and avoid exposure to potential risk factors for infection as appropriate.Tumour necrosis factor alpha (TNFα) mediates inflammation and modulates cellular immune responses. Experimental data show that TNFα is essential for the clearing of intracellular infections. Clinical experience shows that host defence against infection is compromised in some patients treated with infliximab. It should be noted that suppression of TNFα may mask symptoms of infection such as fever. Early recognition of atypical clinical presentations of serious infections and of typical clinical presentation of rare and unusual infections is critical in order to minimise delays in diagnosis and treatment.Patients taking TNF-blockers are more susceptible to serious infections. Tuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral, and other opportunistic infections have been observed in patients treated with infliximab. Some of these infections have been fatal; the most frequently reported opportunistic infections with a mortality rate of > 5% include pneumocystosis, candidiasis, listeriosis and aspergillosis. Patients who develop a new infection while undergoing treatment with Remicade, should be monitored closely and undergo a complete diagnostic evaluation. Administration of Remicade should be discontinued if a patient develops a new serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated until the infection is controlled.
TuberculosisThere have been reports of active tuberculosis in patients receiving Remicade. It should be noted that in the majority of these reports tuberculosis was extrapulmonary, presenting as either local or disseminated disease. Before starting treatment with Remicade, all patients must be evaluated for both active and inactive ('latent') tuberculosis. This evaluation should include a detailed medical history with personal history of tuberculosis or possible previous contact with tuberculosis and previous and/or current immunosuppressive therapy. Appropriate screening tests, i.e. tuberculin skin test and chest X-ray, should be performed in all patients (local recommendations may apply). It is recommended that the conduct of these tests should be recorded in the patient's alert card. Prescribers are reminded of the risk of false negative tuberculin skin test results, especially in patients who are severely ill or immunocompromised. If active tuberculosis is diagnosed, Remicade therapy must not be initiated (see section 4.3).If latent tuberculosis is suspected, a physician with expertise in the treatment of tuberculosis should be consulted. In all situations described below, the benefit/risk balance of Remicade therapy should be very carefully considered.If inactive ('latent') tuberculosis is diagnosed, treatment for latent tuberculosis must be started with anti-tuberculosis therapy before the initiation of Remicade, and in accordance with local recommendations. In patients who have several or significant risk factors for tuberculosis and have a negative test for latent tuberculosis, anti-tuberculosis therapy should be considered before the initiation of Remicade. Use of anti-tuberculosis therapy should also be considered before the initiation of Remicade in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.Some cases of active tuberculosis have been reported in patients treated with Remicade during and after treatment for latent tuberculosis.All patients should be informed to seek medical advice if signs/symptoms suggestive of tuberculosis (e.g. persistent cough, wasting/weight loss, low-grade fever) appear during or after Remicade treatment.
Invasive fungal infectionsIn patients treated with Remicade, an invasive fungal infection such as aspergillosis, candidiasis, pneumocystosis, histoplasmosis, coccidioidomycosis or blastomycosis should be suspected if they develop a serious systemic illness, and a physician with expertise in the diagnosis and treatment of invasive fungal infections should be consulted at an early stage when investigating these patients. Invasive fungal infections may present as disseminated rather than localised disease, and antigen and antibody testing may be negative in some patients with active infection. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed taking into account both the risk for severe fungal infection and the risks of antifungal therapy.For patients who have resided in or travelled to regions where invasive fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of Remicade treatment should be carefully considered before initiation of Remicade therapy.
Fistulising Crohn's diseasePatients with fistulising Crohn's disease with acute suppurative fistulas must not initiate Remicade therapy until a source for possible infection, specifically abscess, has been excluded (see section 4.3).
Hepatitis B (HBV) reactivationReactivation of hepatitis B has occurred in patients receiving a TNF-antagonist including infliximab, who are chronic carriers of this virus. Some cases have had fatal outcome. Patients should be tested for HBV infection before initiating treatment with Remicade. For patients who test positive for HBV infection, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Carriers of HBV who require treatment with Remicade should be closely monitored for signs and symptoms of active HBV infection throughout therapy and for several months following termination of therapy. Adequate data of treating patients who are carriers of HBV with antiviral therapy in conjunction with TNF-antagonist therapy to prevent HBV reactivation are not available. In patients who develop HBV reactivation, Remicade should be stopped and effective antiviral therapy with appropriate supportive treatment should be initiated.
Hepatobiliary eventsVery rare cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have been observed in the post-marketing experience of Remicade. Isolated cases of liver failure resulting in liver transplantation or death have occurred. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or ALT elevations ≥ 5 times the upper limit of normal develop(s), Remicade should be discontinued, and a thorough investigation of the abnormality should be undertaken.
Concurrent administration of TNF-alpha inhibitor and anakinraSerious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of Remicade and anakinra is not recommended.
Concurrent administration of TNF-alpha inhibitor and abataceptIn clinical studies concurrent administration of TNF-antagonists and abatacept has been associated with an increased risk of infections including serious infections compared to TNF-antagonists alone, without increased clinical benefit. The combination of Remicade and abatacept is not recommended.
Concurrent administration with other biological therapeuticsThere is insufficient information regarding the concomitant use of infliximab with other biological therapeutics used to treat the same conditions as infliximab. The concomitant use of infliximab with these biologics is not recommended because of the possibility of an increased risk of infection, and other potential pharmacological interactions.
Switching between biological DMARDSCare should be taken and patients should continue to be monitored when switching from one biologic to another, since overlapping biological activity may further increase the risk for adverse events, including infection.
Live vaccines/therapeutic infectious agentsIn patients receiving anti-TNF therapy, 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 could result in clinical infections, including disseminated infections. It is recommended that live vaccines not be given concurrently with Remicade.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.
Autoimmune processesThe relative deficiency of TNFα caused by anti-TNF therapy may result in the initiation of an autoimmune process. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Remicade and is positive for antibodies against double-stranded DNA, further treatment with Remicade must not be given (see section 4.8).
Neurological eventsUse of TNF-blocking agents, including infliximab, has been associated with cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. In patients with pre-existing or recent onset of demyelinating disorders, the benefits and risks of anti-TNF treatment should be carefully considered before initiation of Remicade therapy. Discontinuation of Remicade should be considered if these disorders develop.
Malignancies and lymphoproliferative disordersIn the controlled portions of clinical studies of TNF-blocking agents, more cases of malignancies including lymphoma have been observed among patients receiving a TNF blocker compared with control patients. During clinical studies of Remicade across all approved indications the incidence of lymphoma in Remicade-treated patients was higher than expected in the general population, but the occurrence of lymphoma was rare. In the post-marketing setting, cases of leukaemia have been reported in patients treated with a TNF-antagonist. There is an increased background risk for lymphoma and leukaemia in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates risk estimation.In an exploratory clinical study evaluating the use of Remicade in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies were reported in Remicade-treated patients compared with control patients. All patients had a history of heavy smoking. Caution should be exercised in considering treatment of patients with increased risk for malignancy due to heavy smoking.With the current knowledge, a risk for the development of lymphomas or other malignancies in patients treated with a TNF-blocking agent cannot be excluded (see section 4.8). Caution should be exercised when considering TNF-blocking therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy.Caution should also be exercised in patients with psoriasis and a medical history of extensive immunosuppressant therapy or prolonged PUVA treatment.Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-blocking agents (initiation of therapy ≤ 18 years of age), including Remicade in the post-marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in patients treated with TNF-blockers cannot be excluded.Rare post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Almost all patients had received treatment with AZA or 6-MP concomitantly with or immediately prior to a TNF-blocker. The vast majority of Remicade cases have occurred in patients with Crohn's disease or ulcerative colitis and most were reported in adolescent or young adult males. The potential risk with the combination of AZA or 6-MP and Remicade should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with Remicade cannot be excluded (see section 4.8).Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including Remicade (see section 4.8). Periodic skin examination is recommended, particularly for patients with risk factors for skin cancer.All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations. With current data it is not known if infliximab treatment influences the risk for developing dysplasia or colon cancer (see section 4.8). Since the possibility of increased risk of cancer development in patients with newly diagnosed dysplasia treated with Remicade is not established, the risk and benefits to the individual patients must be carefully reviewed and consideration should be given to discontinuation of therapy.
Heart failureRemicade should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored and Remicade must not be continued in patients who develop new or worsening symptoms of heart failure (see sections 4.3 and 4.8).
Haematologic reactionsThere have been reports of pancytopenia, leucopenia, neutropenia, and thrombocytopenia in patients receiving TNF-blockers, including Remicade. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor). Discontinuation of Remicade therapy should be considered in patients with confirmed significant haematologic abnormalities.
OthersThere is limited safety experience of Remicade treatment in patients who have undergone surgical procedures, including arthroplasty. The long half-life of infliximab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on Remicade should be closely monitored for infections, and appropriate actions should be taken. Failure to respond to treatment for Crohn's disease may indicate the presence of a fixed fibrotic stricture that may require surgical treatment. There is no evidence to suggest that infliximab worsens or causes fibrotic strictures.
Elderly patients (≥ 65 years)The incidence of serious infections in Remicade-treated patients 65 years and older was greater than in those under 65 years of age. Some of those had a fatal outcome. Particular attention regarding the risk for infection should be paid when treating the elderly (see section 4.8).
InfectionsIn clinical studies, infections have been reported in a higher proportion of paediatric patients compared to adult patients (see section 4.8).
VaccinationsIt is recommended that paediatric patients, if possible, be brought up to date with all vaccinations in agreement with current vaccination guidelines prior to initiating Remicade therapy.
Malignancies and lymphoproliferative disordersMalignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNF-blocking agents (initiation of therapy ≤ 18 years of age), including Remicade in the post-marketing setting. Approximately half the cases were lymphomas. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression. A risk for the development of malignancies in children and adolescents treated with TNF-blockers cannot be excluded.Rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with TNF-blocking agents including infliximab. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Almost all patients had received treatment with AZA or 6-MP concomitantly with or immediately prior to a TNF-blocker. The vast majority of Remicade cases have occurred in patients with Crohn's disease or ulcerative colitis and most were reported in adolescent or young adult males. The potential risk with the combination of AZA or 6-MP and Remicade should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with Remicade cannot be excluded (see section 4.8).
Women of childbearing potentialWomen of childbearing potential must use adequate contraception to prevent pregnancy and continue its use for at least 6 months after the last Remicade treatment.
PregnancyThe moderate number (approximately 450) of prospectively collected pregnancies exposed to infliximab with known outcomes, including a limited number (approximately 230) exposed during the first trimester, does not indicate unexpected effects on pregnancy outcome. Due to its inhibition of TNFα, infliximab administered during pregnancy could affect normal immune responses in the newborn. In a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα, there was no indication of maternal toxicity, embryotoxicity or teratogenicity (see section 5.3). The available clinical experience is too limited to exclude a risk, and administration of infliximab is therefore not recommended during pregnancy. Infliximab crosses the placenta and has been detected up to 6 months in the serum of infants born to women treated with infliximab during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of live vaccines to infants exposed to infliximab in utero is not recommended for 6 months following the mother's last infliximab infusion during pregnancy (see sections 4.4 and 4.5).
Breast-feedingIt is unknown whether infliximab is excreted in human milk or absorbed systemically after ingestion. Because human immunoglobulins are excreted in milk, women must not breast feed for at least 6 months after Remicade treatment.
FertilityThere are insufficient preclinical data to draw conclusions on the effects of infliximab on fertility and general reproductive function (see section 5.3).
Summary of the safety profileUpper respiratory tract infection was the most common adverse drug reaction (ADR) reported in clinical trials, occurring in 25.3% of infliximab-treated patients compared with 16.5% of control patients. The most serious ADRs associated with the use of TNF blockers that have been reported for Remicade include HBV reactivation, CHF, serious infections (including sepsis, opportunistic infections and TB), serum sickness (delayed hypersensitivity reactions), haematologic reactions, systemic lupus erythematosus/lupus-like syndrome, demyelinating disorders, hepatobiliary events, lymphoma, HSTCL, leukaemia, Merkel cell carcinoma, melanoma, paediatric malignancy, sarcoidosis/sarcoid-like reaction, intestinal or perianal abscess (in Crohn's disease), and serious infusion reactions (see section 4.4).
Tabulated list of adverse reactionsTable 1 lists ADRs based on experience from clinical studies as well as adverse reactions, some with fatal outcome, reported from post-marketing experience. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Undesirable effects in clinical studies and from post-marketing experience
|Infections and infestations|
|Very Common:||Viral infection (e.g. influenza, herpes virus infection).|
|Common:||Bacterial infections (e.g. sepsis, cellulitis, abscess).|
|Uncommon:||Tuberculosis, fungal infections (e.g. candidiasis).|
|Rare:||Meningitis, opportunistic infections (such as invasive fungal infections [pneumocystosis, histoplasmosis, aspergillosis, coccidioidomycosis, cryptococcosis, blastomycosis], bacterial infections [atypical mycobacterial, listeriosis, salmonellosis], and viral infections [cytomegalovirus]), parasitic infections, hepatitis B reactivation.|
|Neoplasms benign, malignant and unspecified (including cysts and polyps)|
|Rare:||Lymphoma, non-Hodgkin's lymphoma, Hodgkin's disease, leukaemia, melanoma.|
|Not known:||Hepatosplenic T-cell lymphoma (primarily in adolescents and young adults with Crohn's disease and ulcerative colitis), Merkel cell carcinoma.|
|Blood and lymphatic system disorders|
|Common:||Neutropenia, leucopenia, anaemia, lymphadenopathy.|
|Uncommon:||Thrombocytopenia, lymphopenia, lymphocytosis.|
|Rare:||Agranulocytosis, thrombotic thrombocytopenic purpura, pancytopenia, haemolytic anaemia, idiopathic thrombocytopenic purpura.|
|Immune system disorders|
|Common:||Allergic respiratory symptom.|
|Uncommon:||Anaphylactic reaction, lupus-like syndrome, serum sickness or serum sickness-like reaction.|
|Rare:||Anaphylactic shock, vasculitis, sarcoid-like reaction.|
|Uncommon:||Amnesia, agitation, confusion, somnolence, nervousness.|
|Nervous system disorders|
|Common:||Vertigo, dizziness, hypoaesthesia, paraesthesia.|
|Rare:||Transverse myelitis, central nervous system demyelinating disorders (multiple sclerosis-like disease and optic neuritis), peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy).|
|Uncommon:||Keratitis, periorbital oedema, hordeolum.|
|Not known:||Transient visual loss occurring during or within two hours of infusion.|
|Uncommon:||Cardiac failure (new onset or worsening), arrhythmia, syncope, bradycardia.|
|Rare:||Cyanosis, pericardial effusion.|
|Not known:||Myocardial ischaemia/myocardial infarction occurring during or within two hours of infusion.|
|Common:||Hypotension, hypertension, ecchymosis, hot flush, flushing.|
|Uncommon:||Peripheral ischaemia, thrombophlebitis, haematoma.|
|Rare:||Circulatory failure, petechia, vasospasm.|
|Respiratory, thoracic and mediastinal disorders|
|Very common:||Upper respiratory tract infection, sinusitis.|
|Common:||Lower respiratory tract infection (e.g. bronchitis, pneumonia), dyspnoea, epistaxis.|
|Uncommon:||Pulmonary oedema, bronchospasm, pleurisy, pleural effusion.|
|Rare:||Interstitial lung disease (including rapidly progressive disease, lung fibrosis and pneumonitis).|
|Very common:||Abdominal pain, nausea.|
|Common:||Gastrointestinal haemorrhage, diarrhoea, dyspepsia, gastroesophageal reflux, constipation.|
|Uncommon:||Intestinal perforation, intestinal stenosis, diverticulitis, pancreatitis, cheilitis.|
|Common:||Hepatic function abnormal, transaminases increased.|
|Uncommon:||Hepatitis, hepatocellular damage, cholecystitis.|
|Rare:||Autoimmune hepatitis, jaundice.|
|Not known:||Liver failure.|
|Skin and subcutaneous tissue disorders|
|Common:||New onset or worsening psoriasis including pustular psoriasis (primarily palm & soles), urticaria, rash, pruritus, hyperhidrosis, dry skin, fungal dermatitis, eczema, alopecia.|
|Uncommon:||Bullous eruption, onychomycosis, seborrhoea, rosacea, skin papilloma, hyperkeratosis, abnormal skin pigmentation.|
|Rare:||Toxic epidermal necrolysis, Stevens-Johnson Syndrome, erythema multiforme, furunculosis.|
|Not known:||Worsening of symptoms of dermatomyositis.|
|Musculoskeletal and connective tissue disorders|
|Common:||Arthralgia, myalgia, back pain.|
|Renal and urinary disorders|
|Common:||Urinary tract infection.|
|Reproductive system and breast disorders|
|General disorders and administration site conditions|
|Very common:||Infusion-related reaction, pain.|
|Common:||Chest pain, fatigue, fever, injection site reaction, chills, oedema.|
|Rare:||Complement factor abnormal.|
Infusion-related reactionsAn infusion-related reaction was defined in clinical studies as any adverse event occurring during an infusion or within 1 hour after an infusion. In Phase III clinical studies, 18% of infliximab-treated patients compared with 5% of placebo-treated patients experienced an infusion-related reaction. Overall, a higher proportion of patients receiving infliximab monotherapy experienced an infusion-related reaction compared to patients receiving infliximab with concomitant immunomodulators. Approximately 3% of patients discontinued treatment due to infusion-related reactions and all patients recovered with or without medical therapy. Of infliximab-treated patients who had an infusion reaction during the induction period, through week 6, 27% experienced an infusion reaction during the maintenance period, week 7 through week 54. Of patients who did not have an infusion reaction during the induction period, 9% experienced an infusion reaction during the maintenance period.In a clinical study of patients with rheumatoid arthritis (ASPIRE), infusions were to be administered over 2 hours for the first 3 infusions. The duration of subsequent infusions could be shortened to not less than 40 minutes in patients who did not experience serious infusion reactions. In this trial, sixty six percent of the patients (686 out of 1,040) received at least one shortened infusion of 90 minutes or less and 44% of the patients (454 out of 1,040) received at least one shortened infusion of 60 minutes or less. Of the infliximab-treated patients who received at least one shortened infusion, infusion-related reactions occurred in 15% of patients and serious infusion reactions occurred in 0.4% of patients.In a clinical study of patients with Crohn's disease (SONIC), infusion-related reactions occurred in 16.6% (27/163) of patients receiving infliximab monotherapy, 5% (9/179) of patients receiving infliximab in combination with AZA, and 5.6% (9/161) of patients receiving AZA monotherapy. One serious infusion reaction (< 1%) occurred in a patient on infliximab monotherapy. In post-marketing experience, cases of anaphylactic-like reactions, including laryngeal/pharyngeal oedema and severe bronchospasm, and seizure have been associated with Remicade administration. Exceedingly rare cases of transient visual loss and myocardial ischaemia/infarction occurring during or within 2 hours of Remicade infusion have also been reported (see section 4.4).
Infusion reactions following re-administration of RemicadeA clinical study in patients with moderate to severe psoriasis was designed to assess the efficacy and safety of long-term maintenance therapy versus re-treatment with an induction regimen of Remicade (maximum of four infusions at 0, 2, 6 and 14 weeks) following disease flare. Patients did not receive any concomitant immunosuppressant therapy. In the re-treatment arm, 4% (8/219) of patients experienced a serious infusion reaction versus < 1% (1/222) on maintenance therapy. The majority of serious infusion reactions occurred during the second infusion at week 2. The interval between the last maintenance dose and the first re-induction dose ranged from 35-231 days. Symptoms included, but were not limited to, dyspnea, urticaria, facial oedema, and hypotension. In all cases, Remicade treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
Delayed hypersensitivityIn clinical studies delayed hypersensitivity reactions have been uncommon and have occurred after Remicade-free intervals of less than 1 year. In the psoriasis studies, delayed hypersensitivity reactions occurred early in the treatment course. Signs and symptoms included myalgia and/or arthralgia with fever and/or rash, with some patients experiencing pruritus, facial, hand or lip oedema, dysphagia, urticaria, sore throat and headache.There are insufficient data on the incidence of delayed hypersensitivity reactions after Remicade-free intervals of more than 1 year but limited data from clinical studies suggest an increased risk for delayed hypersensitivity with increasing Remicade-free interval (see section 4.4).In a 1-year clinical study with repeated infusions in patients with Crohn's disease (ACCENT I study), the incidence of serum sickness-like reactions was 2.4%.
ImmunogenicityPatients who developed antibodies to infliximab were more likely (approximately 2-3 fold) to develop infusion-related reactions. Use of concomitant immunosuppressant agents appeared to reduce the frequency of infusion-related reactions.In clinical studies using single and multiple infliximab doses ranging from 1 to 20 mg/kg, antibodies to infliximab were detected in 14% of patients with any immunosuppressant therapy, and in 24% of patients without immunosuppressant therapy. In rheumatoid arthritis patients who received the recommended repeated treatment dose regimens with methotrexate, 8% of patients developed antibodies to infliximab. In psoriatic arthritis patients who received 5 mg/kg with and without methotrexate, antibodies occurred overall in 15% of patients (antibodies occurred in 4% of patients receiving methotrexate and in 26% of patients not receiving methotrexate at baseline). In Crohn's disease patients who received maintenance treatment, antibodies to infliximab occurred overall in 3.3% of patients receiving immunosuppressants and in 13.3% of patients not receiving immunosuppressants. The antibody incidence was 2-3 fold higher for patients treated episodically. Due to methodological limitations, a negative assay did not exclude the presence of antibodies to infliximab. Some patients who developed high titres of antibodies to infliximab had evidence of reduced efficacy. In psoriasis patients treated with infliximab as a maintenance regimen in the absence of concomitant immunomodulators, approximately 28% developed antibodies to infliximab (see section 4.4: Infusion reactions and hypersensitivity).
InfectionsTuberculosis, bacterial infections, including sepsis and pneumonia, invasive fungal, viral, and other opportunistic infections have been observed in patients receiving Remicade. Some of these infections have been fatal; the most frequently reported opportunistic infections with a mortality rate of > 5% include pneumocystosis, candidiasis, listeriosis and aspergillosis (see section 4.4).In clinical studies 36% of infliximab-treated patients were treated for infections compared with 25% of placebo-treated patients. In rheumatoid arthritis clinical studies, the incidence of serious infections including pneumonia was higher in infliximab plus methotrexate treated patients compared with methotrexate alone especially at doses of 6 mg/kg or greater (see section 4.4).In post-marketing spontaneous reporting, infections are the most common serious adverse event. Some of the cases have resulted in a fatal outcome. Nearly 50% of reported deaths have been associated with infection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis and tuberculosis with extra-pulmonary location have been reported (see section 4.4).
Malignancies and lymphoproliferative disordersIn clinical studies with infliximab in which 5,780 patients were treated, representing 5,494 patient years, 5 cases of lymphomas and 26 non-lymphoma malignancies were detected as compared with no lymphomas and 1 non-lymphoma malignancy in 1,600 placebo-treated patients representing 941 patient years.In long-term safety follow-up of clinical studies with infliximab of up to 5 years, representing 6,234 patients-years (3,210 patients), 5 cases of lymphoma and 38 cases of non-lymphoma malignancies were reported.Cases of malignancies, including lymphoma, have also been reported in the post-marketing setting (see section 4.4).In an exploratory clinical study involving patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 adult patients were treated with Remicade at doses similar to those used in rheumatoid arthritis and Crohn's disease. Nine of these patients developed malignancies, including 1 lymphoma. The median duration of follow-up was 0.8 years (incidence 5.7% [95% CI 2.65% - 10.6%]. There was one reported malignancy amongst 77 control patients (median duration of follow-up 0.8 years; incidence 1.3% [95% CI 0.03% - 7.0%]). The majority of the malignancies developed in the lung or head and neck. In addition, rare post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with Remicade with the vast majority of cases occurring in Crohn's disease and ulcerative colitis, and most of whom were adolescent or young adult males (see section 4.4).
Heart failureIn a Phase II study aimed at evaluating Remicade in congestive heart failure (CHF), higher incidence of mortality due to worsening of heart failure were seen in patients treated with Remicade, especially those treated with the higher dose of 10 mg/kg (i.e. twice the maximum approved dose). In this study 150 patients with NYHA Class III-IV CHF (left ventricular ejection fraction ≤ 35%) were treated with 3 infusions of Remicade 5 mg/kg, 10 mg/kg, or placebo over 6 weeks. At 38 weeks, 9 of 101 patients treated with Remicade (2 at 5 mg/kg and 7 at 10 mg/kg) died compared to one death among the 49 patients on placebo.There have been post-marketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking Remicade. There have also been rare post-marketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age.
Hepatobiliary eventsIn clinical studies, mild or moderate elevations of ALT and AST have been observed in patients receiving Remicade without progression to severe hepatic injury. Elevations of ALT ≥ 5 x Upper Limit of Normal (ULN) have been observed (see Table 2). Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving Remicade than in controls, both when Remicade was given as monotherapy and when it was used in combination with other immunosuppressive agents. Most aminotransferase abnormalities were transient; however, a small number of patients experienced more prolonged elevations. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of Remicade, or modification of concomitant therapy. In post-marketing surveillance, very rare cases of jaundice and hepatitis, some with features of autoimmune hepatitis, have been reported in patients receiving Remicade (see section 4.4).
Proportion of patients with increased ALT activity in clinical studies
|Indication||Number of patients3||Median follow-up (wks)4||≥ 3 x ULN||≥ 5 x ULN|
|Paediatric Crohn's disease||N/A||139||N/A||53.0||N/A||4.4%||N/A||1.5%|
|Paediatric Ulcerative colitis||N/A||60||N/A||49.4||N/A||6.7%||N/A||1.7%|
Antinuclear antibodies (ANA)/Anti-double-stranded DNA (dsDNA) antibodiesApproximately half of infliximab-treated patients in clinical studies who were ANA negative at baseline developed a positive ANA during the study compared with approximately one fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately 17% of infliximab-treated patients compared with 0% of placebo-treated patients. At the last evaluation, 57% of infliximab-treated patients remained anti-dsDNA positive. Reports of lupus and lupus-like syndromes, however, remain uncommon (see section 4.4).
Juvenile rheumatoid arthritis patientsRemicade was studied in a clinical study in 120 patients (age range: 4-17 years old) with active juvenile rheumatoid arthritis despite methotrexate. Patients received 3 or 6 mg/kg infliximab as a 3-dose induction regimen (weeks 0, 2, 6 or weeks 14, 16, 20 respectively) followed by maintenance therapy every 8 weeks, in combination with methotrexate.Infusion reactionsInfusion reactions occurred in 35% of patients with juvenile rheumatoid arthritis receiving 3 mg/kg compared with 17.5% of patients receiving 6 mg/kg. In the 3 mg/kg Remicade group, 4 out of 60 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 group, 2 out of 57 patients had a serious infusion reaction, one of whom had a possible anaphylactic reaction (see section 4.4). ImmunogenicityAntibodies to infliximab developed in 38% of patients receiving 3 mg/kg compared with 12% of patients receiving 6 mg/kg. The antibody titres were notably higher for the 3 mg/kg compared to the 6 mg/kg group.InfectionsInfections occurred in 68% (41/60) of children receiving 3 mg/kg over 52 weeks, 65% (37/57) of children receiving infliximab 6 mg/kg over 38 weeks and 47% (28/60) of children receiving placebo over 14 weeks (see section 4.4).
Paediatric Crohn's disease patientsThe following adverse events were reported more commonly in paediatric Crohn's disease patients in the REACH study (see section 5.1) than in adult Crohn's disease patients: anaemia (10.7%), blood in stool (9.7%), leucopenia (8.7%), flushing (8.7%), viral infection (7.8%), neutropenia (6.8%), bone fracture (6.8%), bacterial infection (5.8%), and respiratory tract allergic reaction (5.8%). Other special considerations are discussed below.Infusion-related reactionsIn REACH, 17.5% of randomised patients experienced 1 or more infusion reactions. There were no serious infusion reactions, and 2 subjects in REACH had non-serious anaphylactic reactions.ImmunogenicityAntibodies to infliximab were detected in 3 (2.9%) paediatric patients.InfectionsIn the REACH study, infections were reported in 56.3% of randomised subjects treated with infliximab. Infections were reported more frequently for subjects who received q8 week as opposed to q12 week infusions (73.6% and 38.0%, respectively), while serious infections were reported for 3 subjects in the q8 week and 4 subjects in the q12 week maintenance treatment group. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was abscess. Three cases of pneumonia (1 serious) and 2 cases of herpes zoster (both non-serious) were reported.
Paediatric ulcerative colitis patientsOverall, the adverse reactions reported in the paediatric ulcerative colitis trial (C0168T72) and adult ulcerative colitis (ACT 1 and ACT 2) studies were generally consistent. In C0168T72, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache. The most common adverse event was worsening of ulcerative colitis, the incidence of which was higher in patients on the q12 week vs. the q8 week dosing regimen.Infusion-related reactionsOverall, 8 (13.3%) of 60 treated patients experienced one or more infusion reactions, with 4 of 22 (18.2%) in the q8 week and 3 of 23 (13.0%) in the q12 week treatment maintenance group. No serious infusion reactions were reported. All infusion reactions were mild or moderate in intensity.ImmunogenicityAntibodies to infliximab were detected in 4 (7.7%) patients through week 54.InfectionsInfections were reported in 31 (51.7%) of 60 treated patients in C0168T72 and 22 (36.7%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in C0168T72 was similar to that in the paediatric Crohn's disease study (REACH) but higher than the proportion in the adults ulcerative colitis studies (ACT 1 and ACT 2). The overall incidence of infections in C0168T72 was 13/22 (59%) in the every 8 week maintenance treatment group and 14/23 (60.9%) in the every 12 week maintenance treatment group. Upper respiratory tract infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently reported respiratory system infections. Serious infections were reported in 12% (7/60) of all treated patients.In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group (45/60 [75.0%]) vs.15/60 [25.0%]). While the numbers of patients in each subgroup are too small to make any definitive conclusions about the effect of age on safety events, there were higher proportions of patients with serious adverse events and discontinuation due to adverse events in the younger age group than in the older age group. While the proportion of patients with infections was also higher in the younger age group, for serious infections, the proportions were similar in the two age groups. Overall proportions of adverse events and infusion reactions were similar between the 6 to 11 and 12 to 17 year age groups.
Post-marketing experiencePost-marketing spontaneous serious adverse events with infliximab in the paediatric population have included malignancies including hepatosplenic T-cell lymphomas, transient hepatic enzyme abnormalities, lupus-like syndromes, and positive auto-antibodies (see sections 4.4 and 4.8).
Additional information on special populations
Elderly patients (≥ 65 years)In rheumatoid arthritis clinical studies, the incidence of serious infections was greater in infliximab plus methotrexate treated patients 65 years and older (11.3%) than in those under 65 years of age (4.6%). In patients treated with methotrexate alone, the incidence of serious infections was 5.2% in patients 65 years and older compared to 2.7% in patients under 65 (see section 4.4).
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Mechanism of actionInfliximab is a chimeric human-murine monoclonal antibody that binds with high affinity to both soluble and transmembrane forms of TNFα but not to lymphotoxin α (TNFß).
Pharmacodynamic effectsInfliximab inhibits the functional activity of TNFα in a wide variety of in vitro bioassays. Infliximab prevented disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα and when administered after disease onset, it allowed eroded joints to heal. In vivo, infliximab rapidly forms stable complexes with human TNFα, a process that parallels the loss of TNFα bioactivity.Elevated concentrations of TNFα have been found in the joints of rheumatoid arthritis patients and correlate with elevated disease activity. In rheumatoid arthritis, treatment with infliximab reduced infiltration of inflammatory cells into inflamed areas of the joint as well as expression of molecules mediating cellular adhesion, chemoattraction and tissue degradation. After infliximab treatment, patients exhibited decreased levels of serum interleukin 6 (IL-6) and C-reactive protein (CRP), and increased haemoglobin levels in rheumatoid arthritis patients with reduced haemoglobin levels, compared with baseline. Peripheral blood lymphocytes further showed no significant decrease in number or in proliferative responses to in vitro mitogenic stimulation when compared with untreated patients' cells. In psoriasis patients, treatment with infliximab resulted in decreases in epidermal inflammation and normalization of keratinocyte differentiation in psoriatic plaques. In psoriatic arthritis, short term treatment with Remicade reduced the number of T-cells and blood vessels in the synovium and psoriatic skin.Histological evaluation of colonic biopsies, obtained before and 4 weeks after administration of infliximab, revealed a substantial reduction in detectable TNFα. Infliximab treatment of Crohn's disease patients was also associated with a substantial reduction of the commonly elevated serum inflammatory marker, CRP. Total peripheral white blood cell counts were minimally affected in infliximab-treated patients, although changes in lymphocytes, monocytes and neutrophils reflected shifts towards normal ranges. Peripheral blood mononuclear cells (PBMC) from infliximab-treated patients showed undiminished proliferative responsiveness to stimuli compared with untreated patients, and no substantial changes in cytokine production by stimulated PBMC were observed following treatment with infliximab. Analysis of lamina propria mononuclear cells obtained by biopsy of the intestinal mucosa showed that infliximab treatment caused a reduction in the number of cells capable of expressing TNFα and interferonγ. Additional histological studies provided evidence that treatment with infliximab reduces the infiltration of inflammatory cells into affected areas of the intestine and the presence of inflammation markers at these sites. Endoscopic studies of intestinal mucosa have shown evidence of mucosal healing in infliximab treated patients.
Clinical efficacy and safety
Adult rheumatoid arthritisThe efficacy of infliximab was assessed in two multicentre, randomised, double-blind, pivotal clinical studies: ATTRACT and ASPIRE. In both studies concurrent use of stable doses of folic acid, oral corticosteroids (≤ 10 mg/day) and/or non-steroidal anti-inflammatory drugs (NSAIDs) was permitted.The primary endpoints were the reduction of signs and symptoms as assessed by the American College of Rheumatology criteria (ACR20 for ATTRACT, landmark ACR-N for ASPIRE), the prevention of structural joint damage, and the improvement in physical function. A reduction in signs and symptoms was defined to be at least a 20% improvement (ACR20) in both tender and swollen joint counts, and in 3 of the following 5 criteria: (1) evaluator's global assessment, (2) patient's global assessment, (3) functional/disability measure, (4) visual analogue pain scale and (5) erythrocyte sedimentation rate or C-reactive protein. ACR-N uses the same criteria as the ACR20, calculated by taking the lowest percent improvement in swollen joint count, tender joint count, and the median of the remaining 5 components of the ACR response. Structural joint damage (erosions and joint space narrowing) in both hands and feet was measured by the change from baseline in the total van der Heijde-modified Sharp score (0-440). The Health Assessment Questionnaire (HAQ; scale 0-3) was used to measure patients' average change from baseline scores over time, in physical function. The ATTRACT study evaluated responses at 30, 54 and 102 weeks in a placebo-controlled study of 428 patients with active rheumatoid arthritis despite treatment with methotrexate. Approximately 50% of patients were in functional Class III. Patients received placebo, 3 mg/kg or 10 mg/kg infliximab at weeks 0, 2 and 6, and then every 4 or 8 weeks thereafter. All patients were on stable methotrexate doses (median 15 mg/wk) for 6 months prior to enrolment and were to remain on stable doses throughout the study.Results from week 54 (ACR20, total van der Heijde-modified Sharp score and HAQ) are shown in Table 3. Higher degrees of clinical response (ACR50 and ACR70) were observed in all infliximab groups at 30 and 54 weeks compared with methotrexate alone. A reduction in the rate of the progression of structural joint damage (erosions and joint space narrowing) was observed in all infliximab groups at 54 weeks (Table 3).The effects observed at 54 weeks were maintained through 102 weeks. Due to a number of treatment withdrawals, the magnitude of the effect difference between infliximab and the methotrexate alone group cannot be defined.
Effects on ACR20, Structural Joint Damage and Physical Function at week 54, ATTRACT
|Controla||3 mg/kg q 8 wks||3 mg/kg q 4 wks||10 mg/kg q 8 wks||10 mg/kg q 4 wks||All infliximabb|
|Patients with ACR20 response/Patients evaluated (%)||15/88 (17%)||36/86 (42%)||41/86 (48%)||51/87 (59%)||48/81 (59%)||176/340 (52%)|
|Total scored (van der Heijde-modified Sharp score)|
|Change from baseline (Mean ± SDc )||7.0 ± 10.3||1.3 ± 6.0||1.6 ± 8.5||0.2 ± 3.6||-0.7 ± 3.8||0.6 ± 5.9|
|Median (Interquartile range)||4.0 (0.5,9.7)||0.5 (-1.5,3.0)||0.1 (-2.5,3.0)||0.5 (-1.5,2.0)||-0.5 (-3.0,1.5)||0.0 (-1.8,2.0)|
|Patients with no deterioration/patients evaluated (%)c||13/64 (20%)||34/71 (48%)||35/71 (49%)||37/77 (48%)||44/66 (67%)||150/285 (53%)|
|HAQ change from baseline over timee (patients evaluated)||87||86||85||87||81||339|
|Mean ± SDc||0.2 ± 0.3||0.4 ± 0.3||0.5 ± 0.4||0.5 ± 0.5||0.4 ± 0.4||0.4 ± 0.4|
Effects on ACRn, Structural Joint Damage and Physical Function at week 54, ASPIRE
|Infliximab + MTX|
|Placebo + MTX||3 mg/kg||6 mg/kg||Combined|
|Percentage ACR improvement|
|Mean ± SDa||24.8 ± 59.7||37.3 ± 52.8||42.0 ± 47.3||39.6 ± 50.1|
|Change from baseline in total van der Heijde-modified Sharp scoreb|
|Mean ± SDa||3.70 ± 9.61||0.42 ± 5.82||0.51 ± 5.55||0.46 ± 5.68|
|Improvement from baseline in HAQ averaged over time from week 30 to week 54c|
|Mean ± SDd||0.68 ± 0.63||0.80 ± 0.65||0.88 ± 0.65||0.84 ± 0.65|
Adult Crohn's disease
Induction treatment in moderately to severely active Crohn's diseaseThe efficacy of a single dose treatment with infliximab was assessed in 108 patients with active Crohn's disease (Crohn's Disease Activity Index (CDAI) ≥ 220 ≤ 400) in a randomised, double-blinded, placebo-controlled, dose-response study. Of these 108 patients, 27 were treated with the recommended dosage of infliximab 5 mg/kg. All patients had experienced an inadequate response to prior conventional therapies. Concurrent use of stable doses of conventional therapies was permitted, and 92% of patients continued to receive these therapies.The primary endpoint was the proportion of patients who experienced a clinical response, defined as a decrease in CDAI by ≥ 70 points from baseline at the 4-week evaluation and without an increase in the use of medicinal products or surgery for Crohn's disease. Patients who responded at week 4 were followed to week 12. Secondary endpoints included the proportion of patients in clinical remission at week 4 (CDAI < 150) and clinical response over time.At week 4, following administration of a single dose, 22/27 (81%) of infliximab-treated patients receiving a 5 mg/kg dose achieved a clinical response vs. 4/25 (16%) of the placebo-treated patients (p < 0.001). Also at week 4, 13/27 (48%) of infliximab-treated patients achieved a clinical remission (CDAI < 150) vs. 1/25 (4%) of placebo-treated patients. A response was observed within 2 weeks, with a maximum response at 4 weeks. At the last observation at 12 weeks, 13/27 (48%) of infliximab-treated patients were still responding.
Maintenance treatment in moderately to severely active Crohn's disease in adultsThe efficacy of repeated infusions with infliximab was studied in a 1-year clinical study (ACCENT I).A total of 573 patients with moderately to severely active Crohn's disease (CDAI ≥ 220 ≤ 400) received a single infusion of 5 mg/kg at week 0. 178 of the 580 enrolled patients (30.7%) were defined as having severe disease (CDAI score > 300 and concomitant corticosteroid and/or immunosuppressants) corresponding to the population defined in the indication (see section 4.1). At week 2, all patients were assessed for clinical response and randomised to one of 3 treatment groups; a placebo maintenance group, 5 mg/kg maintenance group and 10 mg/kg maintenance group. All 3 groups received repeated infusions at week 2, 6 and every 8 weeks thereafter.Of the 573 patients randomised, 335 (58%) achieved clinical response by week 2. These patients were classified as week-2 responders and were included in the primary analysis (see Table 5). Among patients classified as non-responders at week 2, 32% (26/81) in the placebo maintenance group and 42% (68/163) in the infliximab group achieved clinical response by week 6. There was no difference between groups in the number of late responders thereafter. The co-primary endpoints were the proportion of patients in clinical remission (CDAI < 150) at week 30 and time to loss of response through week 54. Corticosteroid tapering was permitted after week 6.
Effects on response and remission rate, data from ACCENT I (week-2 responders)
|ACCENT I (week-2 responders) % of Patients|
|Placebo Maintenance (n = 110)||Infliximab Maintenance 5 mg/kg (n = 113) (p value)||Infliximab Maintenance 10 mg/kg (n = 112) (p value)|
|Median time to loss of response through week 54||19 weeks||38 weeks (0.002)||>54 weeks (<0.001)|
|Clinical Responsea||27.3||51.3 (<0.001)||59.1 (<0.001)|
|Clinical Remission||20.9||38.9 (0.003)||45.5 (<0.001)|
|Steroid-Free Remission||10.7 (6/56)||31.0 (18/58) (0.008)||36.8 (21/57) (0.001)|
|Clinical Responsea||15.5||38.1 (<0.001)||47.7 (<0.001)|
|Clinical Remission||13.6||28.3 (0.007)||38.4 (<0.001)|
|Sustained Steroid-Free Remissionb||5.7 (3/53)||17.9 (10/56) (0.075)||28.6 (16/56) (0.002)|
Percent of patients achieving corticosteroid-free clinical remission at week 26, SONIC
|AZA Monotherapy||Infliximab Monotherapy||Infliximab + AZA Combination Therapy|
|All randomised patients||30.0% (51/170)||44.4% (75/169) (p = 0.006)*||56.8% (96/169) (p < 0.001)*|
Induction treatment in fistulising active Crohn's diseaseThe efficacy was assessed in a randomised, double-blinded, placebo-controlled study in 94 patients with fistulising Crohn's disease who had fistulae that were of at least 3 months' duration. Thirty one of these patients were treated with infliximab 5 mg/kg. Approximately 93% of the patients had previously received antibiotic or immunosuppressive therapy.Concurrent use of stable doses of conventional therapies was permitted, and 83% of patients continued to receive at least one of these therapies. Patients received three doses of either placebo or infliximab at weeks 0, 2 and 6. Patients 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 fistulae draining upon gentle compression on at least two consecutive visits (4 weeks apart), without an increase in the use of medicinal products or surgery for Crohn's disease.Sixty eight percent (21/31) of infliximab-treated patients receiving a 5 mg/kg dose regimen achieved a clinical response vs. 26% (8/31) placebo-treated patients (p = 0.002). The median time to onset of response in the infliximab-treated group was 2 weeks. The median duration of response was 12 weeks. Additionally, closure of all fistulae was achieved in 55% of infliximab-treated patients compared with 13% of placebo-treated patients (p = 0.001).
Maintenance treatment in fistulising active Crohn's diseaseThe efficacy of repeated infusions with infliximab in patients with fistulising Crohn's disease was studied in a 1-year clinical study (ACCENT II). A total of 306 patients received 3 doses of infliximab 5 mg/kg at week 0, 2 and 6. At baseline, 87% of the patients had perianal fistulae, 14% had abdominal fistulae, 9% had rectovaginal fistulae. The median CDAI score was 180. At week 14, 282 patients were assessed for clinical response and randomised to receive either placebo or 5 mg/kg infliximab every 8 weeks through week 46. Week-14 responders (195/282) were analyzed for the primary endpoint, which was time from randomisation to loss of response (see Table 7). Corticosteroid tapering was permitted after week 6.
Effects on response rate, data from ACCENT II (week-14 responders)
|ACCENT II (week-14 responders)|
|Placebo Maintenance (n = 99)||Infliximab Maintenance (5 mg/kg) (n = 96)||p-value|
|Median time to loss of response through week 54||14 weeks||> 40 weeks||< 0.001|
|Fistula Response (%) a||23.5||46.2||0.001|
|Complete fistula response (%) b||19.4||36.3||0.009|
Adult ulcerative colitisThe safety and efficacy of Remicade were assessed in two (ACT 1 and ACT 2) randomised, double-blind, placebo-controlled clinical studies in adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12; Endoscopy subscore ≥ 2) with an inadequate response to conventional therapies [oral corticosteroids, aminosalicylates and/or immunomodulators (6-MP, AZA)]. Concomitant stable doses of oral aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted. In both studies, patients were randomised to receive either placebo, 5 mg/kg Remicade, or 10 mg/kg Remicade at weeks 0, 2, 6, 14 and 22, and in ACT 1 at weeks 30, 38 and 46. Corticosteroid taper was permitted after week 8.
Effects on clinical response, clinical remission and mucosal healing at weeks 8 and 30.
Combined data from ACT 1 & 2
|Placebo||5 mg/kg||10 mg/kg||Combined|
|Percentage of subjects in clinical response and in sustained clinical response|
|Clinical response at week 8a||33.2%||66.9%||65.3%||66.1%|
|Clinical response at week 30a||27.9%||49.6%||55.4%||52.5%|
|Sustained response (clinical response at both week 8 and week 30)a||19.3%||45.0%||49.6%||47.3%|
|Percentage of subjects in clinical remission and sustained remission|
|Clinical remission at week 8a||10.2%||36.4%||29.8%||33.1%|
|Clinical remission at week 30a||13.1%||29.8%||36.4%||33.1%|
|Sustained remission (in remission at both week 8 and week 30)a||5.3%||19.0%||24.4%||21.7%|
|Percentage of subjects with mucosal healing|
|Mucosal healing at week 8a||32.4%||61.2%||60.3%||60.7%|
|Mucosal healing at week 30a||27.5%||48.3%||52.9%||50.6%|
Adult ankylosing spondylitisEfficacy and safety of infliximab were assessed in two multicenter, double-blind, placebo-controlled studies in patients with active ankylosing spondylitis (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] score ≥ 4 and spinal pain ≥ 4 on a scale of 1-10). In the first study (P01522), which had a 3 month double-blind phase, 70 patients received either 5 mg/kg infliximab or placebo at weeks 0, 2, 6 (35 patients in each group). At week 12, placebo patients were switched to infliximab 5 mg/kg every 6 weeks up to week 54. After the first year of the study, 53 patients continued into an open-label extension to week 102. In the second clinical study (ASSERT), 279 patients were randomised to receive either placebo (Group 1, n = 78) or 5 mg/kg infliximab (Group 2, n = 201) at 0, 2 and 6 weeks and every 6 weeks to week 24. Thereafter, all subjects continued on infliximab every 6 weeks to week 96. Group 1 received 5 mg/kg infliximab. In group 2, starting with the week 36 infusion, patients who had a BASDAI ≥ 3 at 2 consecutive visits, received 7.5 mg/kg infliximab every 6 weeks thereafter through week 96. In ASSERT, improvement in signs and symptoms was observed as early as week 2. At week 24, the number of ASAS 20 responders was 15/78 (19%) in the placebo group, and 123/201 (61%) in the 5 mg/kg infliximab group (p < 0.001). There were 95 subjects from group 2 who continued on 5 mg/kg every 6 weeks. At 102 weeks there were 80 subjects still on infliximab treatment and among those, 71 (89%) were ASAS 20 responders.In P01522, improvement in signs and symptoms was also observed as early as week 2. At week 12, the number of BASDAI 50 responders were 3/35 (9%) in the placebo group, and 20/35 (57%) in the 5 mg/kg group (p < 0.01). There were 53 subjects who continued on 5 mg/kg every 6 weeks. At 102 weeks there were 49 subjects still on infliximab treatment and among those, 30 (61%) were BASDAI 50 responders. In both studies, physical function and quality of life as measured by the BASFI and the physical component score of the SF-36 were also improved significantly.
Adult psoriatic arthritisEfficacy and safety were assessed in two multicenter, double-blind, placebo-controlled studies in patients with active psoriatic arthritis. In the first clinical study (IMPACT), efficacy and safety of infliximab were studied in 104 patients with active polyarticular psoriatic arthritis. During the 16-week double-blind phase, patients received either 5 mg/kg infliximab or placebo at weeks 0, 2, 6, and 14 (52 patients in each group). Starting at week 16, placebo patients were switched to infliximab and all patients subsequently received 5 mg/kg infliximab every 8 weeks up to week 46. After the first year of the study, 78 patients continued into an open-label extension to week 98.In the second clinical study (IMPACT 2), efficacy and safety of infliximab were studied in 200 patients with active psoriatic arthritis (≥ 5 swollen joints and ≥ 5 tender joints). Forty six percent of patients continued on stable doses of methotrexate (≤ 25 mg/week). During the 24-week double-blind phase, patients received either 5 mg/kg infliximab or placebo at weeks 0, 2, 6, 14, and 22 (100 patients in each group). At week 16, 47 placebo patients with < 10% improvement from baseline in both swollen and tender joint counts were switched to infliximab induction (early escape). At week 24, all placebo-treated patients crossed over to infliximab induction. Dosing continued for all patients through week 46.Key efficacy results for IMPACT and IMPACT 2 are shown in Table 9 below:
Effects on ACR and PASI in IMPACT and IMPACT 2
|Placebo (week 16)||Infliximab (week 16)||Infliximab (week 98)||Placebo (week 24)||Infliximab (week 24)||Infliximab (week 54)|
|ACR response (% of patients)|
|ACR 20 response*||5(10%)||34 (65%)||48 (62%)||16 (16%)||54 (54%)||53 (53%)|
|ACR 50 response*||0(0%)||24 (46%)||35 (45%)||4 (4%)||41(41%)||33 (33%)|
|ACR 70 response*||0(0%)||15 (29%)||27 (35%)||2 (2%)||27 (27%)||20 (20%)|
|PASI response (% of patients)b|
|PASI 75 response**||1 (1%)||50 (60%)||40 (48.8%)|
Adult psoriasisThe efficacy of infliximab was assessed in two multicenter, randomised, double-blind studies: SPIRIT and EXPRESS. Patients in both studies had plaque psoriasis (Body Surface Area [BSA] ≥ 10% and Psoriasis Area and Severity Index [PASI] score ≥ 12). The primary endpoint in both studies was the percent of patients who achieved ≥ 75% improvement in PASI from baseline at week 10.SPIRIT evaluated the efficacy of infliximab induction therapy in 249 patients with plaque psoriasis that had previously received PUVA or systemic therapy. Patients received either 3 or 5 mg/kg infliximab or placebo infusions at weeks 0, 2 and 6. Patients with a PGA score ≥ 3 were eligible to receive an additional infusion of the same treatment at week 26. In SPIRIT, the proportion of patients achieving PASI 75 at week 10 was 71.7% in the 3 mg/kg infliximab group, 87.9% in the 5 mg/kg infliximab group, and 5.9% in the placebo group (p < 0.001). By week 26, twenty weeks after the last induction dose, 30% of patients in the 5 mg/kg group and 13.8% of patients in the 3 mg/kg group were PASI 75 responders. Between weeks 6 and 26, symptoms of psoriasis gradually returned with a median time to disease relapse of > 20 weeks. No rebound was observed. EXPRESS evaluated the efficacy of infliximab induction and maintenance therapy in 378 patients with plaque psoriasis. Patients received 5 mg/kg infliximab- or placebo-infusions at weeks 0, 2 and 6 followed by maintenance therapy every 8 weeks through week 22 in the placebo group and through week 46 in the infliximab group. At week 24, the placebo group crossed over to infliximab induction therapy (5 mg/kg) followed by infliximab maintenance therapy (5 mg/kg). Nail psoriasis was assessed using the Nail Psoriasis Severity Index (NAPSI). Prior therapy with PUVA, methotrexate, cyclosporin, or acitretin had been received by 71.4% of patients, although they were not necessarily therapy resistant. Key results are presented in Table 10. In infliximab treated subjects, significant PASI 50 responses were apparent at the first visit (week 2) and PASI 75 responses by the second visit (week 6). Efficacy was similar in the subgroup of patients that were exposed to previous systemic therapies compared to the overall study population.
Summary of PASI response, PGA response and percent of patients with all nails cleared at weeks 10, 24 and 50. EXPRESS
|Placebo → Infliximab 5 mg/kg (at week 24)||Infliximab 5 mg/kg|
|≥ 90% improvement||1 (1.3%)||172 (57.1%)a|
|≥ 75% improvement||2 (2.6%)||242 (80.4%)a|
|≥ 50% improvement||6 (7.8%)||274 (91.0%)|
|PGA of cleared (0) or minimal (1)||3 (3.9%)||242 (82.9%)ab|
|PGA of cleared (0), minimal (1), or mild (2)||14 (18.2%)||275 (94.2%)ab|
|≥ 90% improvement||1 (1.3%)||161 (58.3%)a|
|≥ 75% improvement||3 (3.9%)||227 (82.2%)a|
|≥ 50% improvement||5 (6.5%)||248 (89.9%)|
|PGA of cleared (0) or minimal (1)||2 (2.6%)||203 (73.6%)a|
|PGA of cleared (0), minimal (1), or mild (2)||15 (19.5%)||246 (89.1%)a|
|≥ 90% improvement||34 (50.0%)||127 (45.2%)|
|≥ 75% improvement||52 (76.5%)||170 (60.5%)|
|≥ 50% improvement||61 (89.7%)||193 (68.7%)|
|PGA of cleared (0) or minimal (1)||46 (67.6%)||149 (53.0%)|
|PGA of cleared (0), minimal (1), or mild (2)||59 (86.8%)||189 (67.3%)|
|All nails cleared c|
|Week 10||1/65(1.5%)||16/235 (6.8% )|
|Week 24||3/65 (4.6%)||58/223 (26,0%) a|
|Week 50||27/64 (42.2%)||92/226 (40.7%)|
Paediatric Crohn's disease (6 to17 years)In the REACH study, 112 patients (6 to 17 years, median age 13.0 years) with moderate to severe, active Crohn's disease (median paediatric CDAI of 40) and an inadequate response to conventional therapies were to receive 5 mg/kg infliximab at weeks 0, 2, and 6. All patients were required to be on a stable dose of 6-MP, AZA or MTX (35% were also receiving corticosteroids at baseline). Patients assessed by the investigator to be in clinical response at week 10 were randomised and received 5 mg/kg infliximab at either q8 weeks or q12 weeks as a maintenance treatment regimen. If response was lost during maintenance treatment, crossing over to a higher dose (10 mg/kg) and/or shorter dosing interval (q8 weeks) was allowed. Thirty two (32) evaluable paediatric patients crossed over (9 subjects in the q8 weeks and 23 subjects in the q12 weeks maintenance groups). Twenty four of these patients (75.0%) regained clinical response after crossing over. The proportion of subjects in clinical response at week 10 was 88.4% (99/112). The proportion of subjects achieving clinical remission at week 10 was 58.9% (66/112). At week 30, the proportion of subjects in clinical remission was higher in the q8 week (59.6%, 31/52) than the q12 week maintenance treatment group (35.3%, 18/51; p = 0.013). At week 54, the figures were 55.8% (29/52) and 23.5% (12/51) in the q8 weeks and q12 weeks maintenance groups, respectively (p < 0.001).Data about fistulas were derived from PCDAI scores. Of the 22 subjects that had fistulas at baseline, 63.6% (14/22), 59.1% (13/22) and 68.2% (15/22) were in complete fistula response at week 10, 30 and 54, respectively, in the combined q8 weeks and q12 weeks maintenance groups.In addition, statistically and clinically significant improvements in quality of life and height, as well as a significant reduction in corticosteroid use, were observed versus baseline.
Paediatric ulcerative colitis (6 to 17 years)The safety and efficacy of infliximab were assessed in a multicenter, randomised, open-label, parallel-group clinical study (C0168T72) in 60 paediatric patients aged 6 through 17 years (median age 14.5 years) with moderately to severely active ulcerative colitis (Mayo score of 6 to 12; endoscopic subscore ≥ 2) with an inadequate response to conventional therapies. At baseline 53% of patients were receiving immunomodulator therapy (6-MP, AZA and/or MTX) and 62% of patients were receiving corticosteroids. Discontinuation of immunomodulators and corticosteroid taper were permitted after week 0.All patients received an induction regimen of 5 mg/kg infliximab at weeks 0, 2, and 6. Patients who did not respond to infliximab at week 8 (n = 15) received no further drug and returned for safety follow-up. At week 8, 45 patients were randomised and received 5 mg/kg infliximab at either q8 weeks or q12 weeks as a maintenance treatment regimen.The proportion of patients in clinical response at week 8 was 73.3% (44/60). Clinical response at week 8 was similar between those with or without concomitant immunomodulator use at baseline. Clinical remission at week 8 was 33.3% (17/51) as measured by the Paediatric Ulcerative Colitis Activity Index (PUCAI) score.At week 54, the proportion of patients in clinical remission as measured by the PUCAI score was 38% (8/21) in the q8 week maintenance group and 18% (4/22) in the q12 week maintenance treatment group. For patients receiving corticosteroids at baseline, the proportion of patients in remission and not receiving corticosteroids at week 54 was 38.5% (5/13) for the q8 week and 0% (0/13) for the q12 week maintenance treatment group.In this study, there were more patients in the 12 to 17 year age group than in the 6 to 11 year age group (45/60 vs.15/60). While the numbers of patients in each subgroup are too small to draw definitive conclusions about the effect of age, there was a higher number of patients in the younger age group who stepped up in dose or discontinued treatment due to inadequate efficacy.
Other paediatric indicationsThe European Medicines Agency has waived the obligation to submit the results of studies with Remicade in all subsets of the paediatric population in rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis and Crohn's disease (see section 4.2 for information on paediatric use).
Paediatric populationPopulation pharmacokinetic analysis based on data obtained from patients with ulcerative colitis (N = 60), Crohn's disease (N = 112), juvenile rheumatoid arthritis (N = 117) and Kawasaki disease (N = 16) with an overall age range from 2 months to 17 years indicated that exposure to infliximab was dependent on body weight in a non-linear way. Following administration of 5 mg/kg Remicade every 8 weeks, the predicted median steady-state infliximab exposure (area under concentration-time curve at steady state, AUCss) in paediatric patients aged 6 years to 17 years was approximately 20% lower than the predicted median steady-state drug exposure in adults. The median AUCss in paediatric patients aged 2 years to less than 6 years was predicted to be approximately 40% lower than that in adults, although the number of patients supporting this estimate is limited.
Before reconstitution:3 years at 2 °C 8 °C.Remicade may be stored at temperatures up to a maximum of 25 °C for a single period of up to 6 months, but not exceeding the original expiry date. The new expiry date must be written on the carton. Upon removal from refrigerated storage, Remicade must not be returned to refrigerated storage.
After reconstitution:Chemical and physical in use stability of the reconstituted solution has been demonstrated for 24 hours at 25 °C. From a microbiological point of view, the product should be used as soon as possible but within 3 hours of reconstitution and dilution. If not used immediately, in use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2 °C to 8 °C.
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