Dosage & Administration
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Remicade Prescribing Information
WARNING: SERIOUS INFECTIONS and MALIGNANCY
- Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis) and infections due to other opportunistic pathogens. ()
5.1 Serious InfectionsPatients 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.
TuberculosisCases 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.
MonitoringPatients 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 InfectionsFor 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.
- Discontinue REMICADE if a patient develops a serious infection.
- Perform test for latent TB; if positive, start treatment for TB prior to starting REMICADE. Monitor all patients for active TB during treatment, even if initial latent TB test is negative. ()
5.1 Serious InfectionsPatients 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.
TuberculosisCases 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.
MonitoringPatients 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 InfectionsFor 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.
- Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including REMICADE. ()
5.2 MalignanciesMalignancies, 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.
LymphomasIn 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 CancerMelanoma 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 CancerA 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 MalignanciesIn 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. - Postmarketing cases of fatal hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF blockers including REMICADE. Almost all had received azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. The majority of REMICADE cases were reported in patients with Crohn's disease or ulcerative colitis, most of whom were adolescent or young adult males. ()
5.2 MalignanciesMalignancies, 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.
LymphomasIn 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 CancerMelanoma 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 CancerA 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 MalignanciesIn 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.
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 Crohn's DiseaseREMICADE 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.
- reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease. ()
1.1 Crohn's DiseaseREMICADE 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.
- 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. (
- 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 Pediatric Crohn's DiseaseREMICADE 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.
- 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 Ulcerative ColitisREMICADE 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.
- 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 Pediatric Ulcerative ColitisREMICADE 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.
- 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 Rheumatoid ArthritisREMICADE, 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).
- Ankylosing Spondylitis: reducing signs and symptoms in adult patients with active disease. ()
1.6 Ankylosing SpondylitisREMICADE is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis (AS).
- Psoriatic Arthritis: reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in adult patients. ()
1.7 Psoriatic ArthritisREMICADE 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).
- 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 Plaque PsoriasisREMICADE 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
[seeBoxed Warning and Warnings and Precautions (5)].
- Prior to treatment, ensure appropriate personnel and medication are available to treat reactions (e.g., hypersensitivity) that occur during infusion and shortly after infusion. ()
2.11 Reconstitution, Dilution, and Administration InstructionsREMICADE is intended for use under the guidance and supervision of a healthcare provider. The supplied lyophilized powder must be reconstituted and diluted prior to administration. The infusion solution should be prepared and administered by a trained medical professional using aseptic technique by the following procedure:
- Calculate the dose, total volume of reconstituted REMICADE solution required and the number of REMICADE vials needed. More than one vial may be needed for a full dose.
- Reconstitute each 100 mg REMICADE vial with 10 mL of Sterile Water for Injection, USP, to obtain a concentration of 10 mg/mL, using a syringe equipped with a 21-gauge or smaller needle as follows:
- Remove the flip-top from the vial and wipe the top with an alcohol swab.
- Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the lyophilized powder, which has a cake-like appearance. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual.
- Allow the reconstituted solution to stand for 5 minutes. Visually inspect the reconstituted solution for particulate matter and discoloration. The reconstituted solution should be colorless to light yellow and opalescent, and the solution may develop a few translucent particles as infliximab is a protein. Do not use if the lyophilized powder has not fully dissolved or if opaque particles, discoloration, or other foreign particles are present. Do not store unused reconstituted REMICADE solution.
- Dilute the total volume of the reconstituted REMICADE solution to 250 mLFor volumes greater than 250 mL, either use a larger infusion bag (e.g. 500 mL) or multiple 250 mL infusion bags to ensure that the concentration of the infusion solution does not exceed 4 mg/mL.with sterile 0.9% Sodium Chloride Injection, USP, (do not dilute with any other diluent) as follows:
- Withdraw a volume from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag equal to thetotalvolume of reconstituted REMICADE required for a dose. Slowly add the total volume of reconstituted REMICADE solution from the vial(s) to the 250 mL infusion bottle or bag.
- Discard any unused portion of the reconstituted REMICADE solution remaining in the vial(s).
- Gently invert the bag to mix the solution. The resulting infusion concentration should range between 0.4 mg/mL (minimum recommended concentration) and 4 mg/mL (maximum recommended concentration) of infliximab.
- Withdraw a volume from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag equal to the
- The REMICADE infusion should begin within 3 hours of reconstitution and dilution. The infusion must be administered intravenously for at least 2 hours with an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 µm or less).
- Given that the vials do not contain antibacterial preservatives, discard any unused portion of the infusion solution (do not store for reuse).
No physical biochemical compatibility studies have been conducted to evaluate the co-administration of REMICADE with other agents. REMICADE should not be infused concomitantly in the same intravenous line with other agents.
- REMICADE is administered by intravenous infusion for at least 2 hours with an in-line filter ()
2.11 Reconstitution, Dilution, and Administration InstructionsREMICADE is intended for use under the guidance and supervision of a healthcare provider. The supplied lyophilized powder must be reconstituted and diluted prior to administration. The infusion solution should be prepared and administered by a trained medical professional using aseptic technique by the following procedure:
- Calculate the dose, total volume of reconstituted REMICADE solution required and the number of REMICADE vials needed. More than one vial may be needed for a full dose.
- Reconstitute each 100 mg REMICADE vial with 10 mL of Sterile Water for Injection, USP, to obtain a concentration of 10 mg/mL, using a syringe equipped with a 21-gauge or smaller needle as follows:
- Remove the flip-top from the vial and wipe the top with an alcohol swab.
- Insert the syringe needle into the vial through the center of the rubber stopper and direct the stream of Sterile Water for Injection, USP, to the glass wall of the vial. Gently swirl the solution by rotating the vial to dissolve the lyophilized powder, which has a cake-like appearance. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual.
- Allow the reconstituted solution to stand for 5 minutes. Visually inspect the reconstituted solution for particulate matter and discoloration. The reconstituted solution should be colorless to light yellow and opalescent, and the solution may develop a few translucent particles as infliximab is a protein. Do not use if the lyophilized powder has not fully dissolved or if opaque particles, discoloration, or other foreign particles are present. Do not store unused reconstituted REMICADE solution.
- Dilute the total volume of the reconstituted REMICADE solution to 250 mLFor volumes greater than 250 mL, either use a larger infusion bag (e.g. 500 mL) or multiple 250 mL infusion bags to ensure that the concentration of the infusion solution does not exceed 4 mg/mL.with sterile 0.9% Sodium Chloride Injection, USP, (do not dilute with any other diluent) as follows:
- Withdraw a volume from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag equal to thetotalvolume of reconstituted REMICADE required for a dose. Slowly add the total volume of reconstituted REMICADE solution from the vial(s) to the 250 mL infusion bottle or bag.
- Discard any unused portion of the reconstituted REMICADE solution remaining in the vial(s).
- Gently invert the bag to mix the solution. The resulting infusion concentration should range between 0.4 mg/mL (minimum recommended concentration) and 4 mg/mL (maximum recommended concentration) of infliximab.
- Withdraw a volume from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or bag equal to the
- The REMICADE infusion should begin within 3 hours of reconstitution and dilution. The infusion must be administered intravenously for at least 2 hours with an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 µm or less).
- Given that the vials do not contain antibacterial preservatives, discard any unused portion of the infusion solution (do not store for reuse).
No physical biochemical compatibility studies have been conducted to evaluate the co-administration of REMICADE with other agents. REMICADE should not be infused concomitantly in the same intravenous line with other agents.
- Crohn's Disease: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some adult patients who initially respond to treatment may benefit from increasing the dose to 10 mg/kg every 8 weeks if they later lose their response. ()
2.1 Dosage in Adult Crohn's DiseaseThe recommended dosage of REMICADE is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adults with moderately to severely active CD or fistulizing CD. For adult patients who respond and then lose their response, consideration may be given to treatment with 10 mg/kg every 8 weeks. Patients who do not respond by Week 14 are unlikely to respond with continued dosing and consideration should be given to discontinue REMICADE in these patients.
- Pediatric Crohn's Disease (≥ 6 years old): 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. ()
2.2 Dosage in Pediatric Crohn's DiseaseThe recommended dosage of REMICADE for pediatric patients 6 years and older with moderately to severely active CD is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks.
- Ulcerative Colitis: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. ()
2.3 Dosage in Adult Ulcerative ColitisThe recommended dosage of REMICADE is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of adult patients with moderately to severely active UC.
- Pediatric Ulcerative Colitis (≥ 6 years old): 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. ()
2.4 Dosage in Pediatric Ulcerative ColitisThe recommended dosage of REMICADE for pediatric patients 6 years and older with moderately to severely active UC is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks.
- Rheumatoid Arthritis: In conjunction with methotrexate, 3 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some patients may benefit from increasing the dose up to 10 mg/kg every 8 weeks or treating as often as every 4 weeks. ()
2.5 Dosage in Rheumatoid ArthritisThe recommended dosage of REMICADE is 3 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 3 mg/kg every 8 weeks thereafter for the treatment of moderately to severely active RA. REMICADE should be given in combination with methotrexate. For patients who have an incomplete response, consideration may be given to adjusting the dosage up to 10 mg/kg every 8 weeks or treating as often as every 4 weeks bearing in mind that risk of serious infections is increased at higher doses per infusion or more frequent dosing
[seeAdverse Reactions (6.1)]. - Ankylosing Spondylitis: 5 mg/kg at 0, 2 and 6 weeks, then every 6 weeks. ()
2.6 Dosage in Ankylosing SpondylitisThe recommended dosage of REMICADE is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 6 weeks thereafter for the treatment of active AS.
- Psoriatic ArthritisandPlaque Psoriasis: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. (,
2.7 Dosage in Psoriatic ArthritisThe recommended dosage of REMICADE is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of PsA. REMICADE can be used with or without methotrexate.
)2.8 Dosage in Plaque PsoriasisThe recommended dosage of REMICADE in adult patients is 5 mg/kg given as an intravenous induction regimen at 0, 2 and 6 weeks followed by a maintenance regimen of 5 mg/kg every 8 weeks thereafter for the treatment of chronic severe (i.e., extensive and/or disabling) Ps.
For injection: 100 mg of infliximab as a white lyophilized powder in a single-dose vial for reconstitution and dilution.
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
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.
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.
Monoclonal antibodies such as infliximab are transferred across the placenta during the third trimester of pregnancy and may affect immune response in the
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.
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
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.
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.
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.
The use of REMICADE at doses >5 mg/kg is contraindicated in patients with moderate or severe 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
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.
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.
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
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% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, REMICADE treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
In Ps studies, approximately 1% of REMICADE-treated patients experienced a possible delayed hypersensitivity reaction, generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash. These reactions generally occurred within 2 weeks after repeat infusion.
In REMICADE clinical studies, treated infections were reported in 36% of REMICADE-treated patients (average of 51 weeks of follow-up) and in 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. Among REMICADE-treated patients, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal), and 1 case each of pneumocystosis, nocardiosis and cytomegalovirus. Tuberculosis (TB) was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of TB, including disseminated TB, also have been reported post-marketing. Most of these cases of TB occurred within the first 2 months after initiation of therapy with REMICADE and may reflect recrudescence of latent disease
In REMICADE clinical studies in patients with UC, infections treated with antimicrobials were reported in 27% of REMICADE-treated patients (average of 41 weeks of follow-up) and in 18% of placebo-treated patients (average 32 weeks of follow-up). The types of infections, including serious infections, reported in patients with UC were similar to those reported in other clinical studies.
The onset of serious infections may be preceded by constitutional symptoms such as fever, chills, weight loss, and fatigue. The majority of serious infections, however, may also be preceded by signs or symptoms localized to the site of the infection.
Approximately half of REMICADE-treated patients in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately one-fifth of REMICADE-treated patients compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.
In controlled trials, more REMICADE-treated patients developed malignancies than placebo-treated patients
In a randomized controlled clinical trial exploring the use of REMICADE in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with REMICADE at doses similar to those used in RA and CD. Of these REMICADE-treated patients, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 3.51 – 14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 – 9.10). The majority of the malignancies developed in the lung or head and neck
In a randomized, double-blind study evaluating REMICADE in moderate or severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of REMICADE 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg REMICADE dose. At 1 year, 8 patients in the 10 mg/kg REMICADE group had died compared with 4 deaths each in the 5 mg/kg REMICADE and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg REMICADE treatment groups, versus placebo. REMICADE has not been studied in patients with mild heart failure (NYHA Class I/II)
Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported in patients receiving REMICADE
In clinical trials in RA, CD, UC, AS, Ps, and PsA, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving REMICADE than in controls (Table 1), both when REMICADE was given as monotherapy and when it was used in combination with other immunosuppressive agents. 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 medications.
| Proportion of patients with elevated ALT | ||||||
|---|---|---|---|---|---|---|
| >1 to <3 × ULN | ≥3 × ULN | ≥5 × ULN | ||||
| Placebo | REMICADE | Placebo | REMICADE | Placebo | REMICADE | |
| Rheumatoid arthritisPlacebo 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 diseasePlacebo 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 colitisMedian 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 spondylitisMedian follow-up was 24 weeks for the placebo group and 102 weeks for the REMICADE group. | 15% | 51% | 0% | 10% | 0% | 4% |
| Psoriatic arthritisMedian follow-up was 39 weeks for the REMICADE group and 18 weeks for the placebo group. | 16% | 50% | 0% | 7% | 0% | 2% |
| Plaque psoriasisALT 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% | <1% | 8% | 0% | 3% |
During the placebo-controlled portion across the 3 clinical trials up to Week 16, the proportion of patients who experienced at least 1 serious adverse reaction (SAE; defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 0.5% in the 3 mg/kg REMICADE group, 1.9% in the placebo group, and 1.6% in the 5 mg/kg REMICADE group.
Among patients in the 2 Phase 3 studies, 12.4% of patients receiving REMICADE 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving REMICADE 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through 1 year of maintenance treatment experienced at least 1 SAE.
One death due to bacterial sepsis occurred 25 days after the second infusion of 5 mg/kg REMICADE. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving REMICADE 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 serious infection. In Study II, 1.0% and 1.3% of patients receiving REMICADE 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infection (requiring hospitalization) was abscess (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg REMICADE group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting REMICADE.
In the placebo-controlled portion of the Ps studies, 7 of 1123 patients who received REMICADE at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo.
In the Ps studies, 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility.
Safety data are available from 4779 REMICADE-treated adult patients, including 1304 with RA, 1106 with CD, 484 with UC, 202 with AS, 293 with PsA, 1373 with Ps and 17 with other conditions. [For information on other adverse reactions in pediatric patients,
| Placebo | REMICADE | |
|---|---|---|
| (n=350) | (n=1129) | |
| Average weeks of follow-up | 59 weeks | 66 weeks |
| Upper respiratory tract infection | 25% | 32% |
| Nausea | 20% | 21% |
| Headache | 14% | 18% |
| Sinusitis | 8% | 14% |
| Diarrhea | 12% | 12% |
| Abdominal pain | 8% | 12% |
| Pharyngitis | 8% | 12% |
| Coughing | 8% | 12% |
| Bronchitis | 9% | 10% |
| Rash | 5% | 10% |
| Dyspepsia | 7% | 10% |
| Fatigue | 7% | 9% |
| Urinary tract infection | 6% | 8% |
| Pain | 7% | 8% |
| Arthralgia | 7% | 8% |
| Pruritus | 2% | 7% |
| Fever | 4% | 7% |
| Hypertension | 5% | 7% |
| Moniliasis | 3% | 5% |
The most common serious adverse reactions observed in clinical trials were infections
- Body as a whole: allergic reaction, edema
- Blood: pancytopenia
- Cardiovascular: hypotension
- Gastrointestinal: constipation, intestinal obstruction
- Central and Peripheral Nervous: dizziness
- Heart Rate and Rhythm: bradycardia
- Liver and Biliary: hepatitis
- Metabolic and Nutritional: dehydration
- Platelet, Bleeding and Clotting: thrombocytopenia
- Neoplasms: lymphoma
- Red Blood Cell: anemia, hemolytic anemia
- Resistance Mechanism: cellulitis, sepsis, serum sickness, sarcoidosis
- Respiratory: lower respiratory tract infection (including pneumonia), pleurisy, pulmonary edema
- Skin and Appendages: increased sweating
- Vascular (Extracardiac): thrombophlebitis
- White Cell and Reticuloendothelial: leukopenia, lymphadenopathy
There were some differences in the adverse reactions observed in the pediatric patients receiving REMICADE compared to those observed in adults with CD. These differences are discussed in the following paragraphs.
The following adverse reactions were reported more commonly in 103 randomized pediatric CD patients administered 5 mg/kg REMICADE through 54 weeks than in 385 adult CD patients receiving a similar treatment regimen: anemia (11%), leukopenia (9%), flushing (9%), viral infection (8%), neutropenia (7%), bone fracture (7%), bacterial infection (6%), and respiratory tract allergic reaction (6%).
Infections were reported in 56% of randomized pediatric patients in Study Peds Crohn's and in 50% of adult patients in Study Crohn's I. In Study Peds Crohn's, infections were reported more frequently for patients who received every 8-week as opposed to every 12-week infusions (74% and 38%, respectively), while serious infections were reported for 3 patients in the every 8-week and 4 patients in the every 12-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. Pneumonia was reported for 3 patients, (2 in the every 8-week and 1 in the every 12-week maintenance treatment groups). Herpes zoster was reported for 2 patients in the every 8-week maintenance treatment group.
In Study Peds Crohn's, 18% of randomized patients experienced 1 or more infusion reactions, with no notable difference between treatment groups. Of the 112 patients in Study Peds Crohn's, there were no serious infusion reactions, and 2 patients had non-serious anaphylactoid reactions.
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in CD clinical trials; 4% had ALT elevations ≥3 × ULN, and 1% had elevations ≥5 × ULN. (Median follow-up was 53 weeks).
Overall, the adverse reactions reported in the pediatric UC trial and adult UC (Study UC I and Study UC II) studies were generally consistent. In a pediatric UC trial, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache.
Infections were reported in 31 (52%) of 60 treated patients in the pediatric UC trial and 22 (37%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in the pediatric UC trial was similar to that in the pediatric CD study (Study Peds Crohn's) but higher than the proportion in the adults' UC studies (Study UC I and Study UC II). The overall incidence of infections in the pediatric UC trial was 13/22 (59%) in the every 8 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.
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 17% (10/60) of pediatric patients in the pediatric UC trial; 7% (4/60) had ALT elevations ≥3 × ULN, and 2% (1/60) had elevations ≥5 × ULN (median follow-up was 49 weeks).
Overall, 8 of 60 (13%) treated patients experienced one or more infusion reactions, including 4 of 22 (18%) patients in the every 8-week treatment maintenance group. No serious infusion reactions were reported.
In the pediatric UC trial, 45 patients were in the 12 to 17 year age group and 15 in the 6 to 11 year age group. 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 (40% vs. 18%) and discontinuation due to adverse events (40% vs. 16%) 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 (60% vs. 49%), for serious infections, the proportions were similar in the two age groups (13% in the 6 to 11 year age group vs. 11% in the 12 to 17 year age group). Overall proportions of adverse reactions, including infusion reactions, were similar between the 6 to 11 and 12 to 17 year age groups (13%).
REMICADE is contraindicated in patients with a previous severe hypersensitivity reaction to infliximab or any of the inactive ingredients of REMICADE or any murine proteins [severe hypersensitivity reactions have included anaphylaxis, hypotension, and serum sickness]
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
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
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.
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.
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
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% (1/222) in the maintenance therapy arm. Patients enrolled in this trial did not receive any concomitant immunosuppressant therapy. In this study, the majority of serious infusion reactions occurred during the second infusion at Week 2. Symptoms included, but were not limited to, dyspnea, urticaria, facial edema, and hypotension. In all cases, REMICADE treatment was discontinued and/or other treatment instituted with complete resolution of signs and symptoms.
In Ps studies, approximately 1% of REMICADE-treated patients experienced a possible delayed hypersensitivity reaction, generally reported as serum sickness or a combination of arthralgia and/or myalgia with fever and/or rash. These reactions generally occurred within 2 weeks after repeat infusion.
In REMICADE clinical studies, treated infections were reported in 36% of REMICADE-treated patients (average of 51 weeks of follow-up) and in 25% of placebo-treated patients (average of 37 weeks of follow-up). The infections most frequently reported were respiratory tract infections (including sinusitis, pharyngitis, and bronchitis) and urinary tract infections. Among REMICADE-treated patients, serious infections included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial infection. In clinical trials, 7 opportunistic infections were reported; 2 cases each of coccidioidomycosis (1 case was fatal) and histoplasmosis (1 case was fatal), and 1 case each of pneumocystosis, nocardiosis and cytomegalovirus. Tuberculosis (TB) was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of TB, including disseminated TB, also have been reported post-marketing. Most of these cases of TB occurred within the first 2 months after initiation of therapy with REMICADE and may reflect recrudescence of latent disease
In REMICADE clinical studies in patients with UC, infections treated with antimicrobials were reported in 27% of REMICADE-treated patients (average of 41 weeks of follow-up) and in 18% of placebo-treated patients (average 32 weeks of follow-up). The types of infections, including serious infections, reported in patients with UC were similar to those reported in other clinical studies.
The onset of serious infections may be preceded by constitutional symptoms such as fever, chills, weight loss, and fatigue. The majority of serious infections, however, may also be preceded by signs or symptoms localized to the site of the infection.
Approximately half of REMICADE-treated patients in clinical trials who were antinuclear antibody (ANA) negative at baseline developed a positive ANA during the trial compared with approximately one-fifth of placebo-treated patients. Anti-dsDNA antibodies were newly detected in approximately one-fifth of REMICADE-treated patients compared with 0% of placebo-treated patients. Reports of lupus and lupus-like syndromes, however, remain uncommon.
In controlled trials, more REMICADE-treated patients developed malignancies than placebo-treated patients
In a randomized controlled clinical trial exploring the use of REMICADE in patients with moderate to severe COPD who were either current smokers or ex-smokers, 157 patients were treated with REMICADE at doses similar to those used in RA and CD. Of these REMICADE-treated patients, 9 developed a malignancy, including 1 lymphoma, for a rate of 7.67 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 3.51 – 14.56). There was 1 reported malignancy among 77 control patients for a rate of 1.63 cases per 100 patient-years of follow-up (median duration of follow-up 0.8 years; 95% CI 0.04 – 9.10). The majority of the malignancies developed in the lung or head and neck
In a randomized, double-blind study evaluating REMICADE in moderate or severe heart failure (NYHA Class III/IV; left ventricular ejection fraction ≤35%), 150 patients were randomized to receive treatment with 3 infusions of REMICADE 10 mg/kg, 5 mg/kg, or placebo, at 0, 2, and 6 weeks. Higher incidences of mortality and hospitalization due to worsening heart failure were observed in patients receiving the 10 mg/kg REMICADE dose. At 1 year, 8 patients in the 10 mg/kg REMICADE group had died compared with 4 deaths each in the 5 mg/kg REMICADE and the placebo groups. There were trends toward increased dyspnea, hypotension, angina, and dizziness in both the 10 mg/kg and 5 mg/kg REMICADE treatment groups, versus placebo. REMICADE has not been studied in patients with mild heart failure (NYHA Class I/II)
Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported in patients receiving REMICADE
In clinical trials in RA, CD, UC, AS, Ps, and PsA, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving REMICADE than in controls (Table 1), both when REMICADE was given as monotherapy and when it was used in combination with other immunosuppressive agents. 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 medications.
| Proportion of patients with elevated ALT | ||||||
|---|---|---|---|---|---|---|
| >1 to <3 × ULN | ≥3 × ULN | ≥5 × ULN | ||||
| Placebo | REMICADE | Placebo | REMICADE | Placebo | REMICADE | |
| Rheumatoid arthritisPlacebo 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 diseasePlacebo 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 colitisMedian 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 spondylitisMedian follow-up was 24 weeks for the placebo group and 102 weeks for the REMICADE group. | 15% | 51% | 0% | 10% | 0% | 4% |
| Psoriatic arthritisMedian follow-up was 39 weeks for the REMICADE group and 18 weeks for the placebo group. | 16% | 50% | 0% | 7% | 0% | 2% |
| Plaque psoriasisALT 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% | <1% | 8% | 0% | 3% |
During the placebo-controlled portion across the 3 clinical trials up to Week 16, the proportion of patients who experienced at least 1 serious adverse reaction (SAE; defined as resulting in death, life threatening, requires hospitalization, or persistent or significant disability/incapacity) was 0.5% in the 3 mg/kg REMICADE group, 1.9% in the placebo group, and 1.6% in the 5 mg/kg REMICADE group.
Among patients in the 2 Phase 3 studies, 12.4% of patients receiving REMICADE 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 SAE in Study I. In Study II, 4.1% and 4.7% of patients receiving REMICADE 3 mg/kg and 5 mg/kg every 8 weeks, respectively, through 1 year of maintenance treatment experienced at least 1 SAE.
One death due to bacterial sepsis occurred 25 days after the second infusion of 5 mg/kg REMICADE. Serious infections included sepsis, and abscesses. In Study I, 2.7% of patients receiving REMICADE 5 mg/kg every 8 weeks through 1 year of maintenance treatment experienced at least 1 serious infection. In Study II, 1.0% and 1.3% of patients receiving REMICADE 3 mg/kg and 5 mg/kg, respectively, through 1 year of treatment experienced at least 1 serious infection. The most common serious infection (requiring hospitalization) was abscess (skin, throat, and peri-rectal) reported by 5 (0.7%) patients in the 5 mg/kg REMICADE group. Two active cases of tuberculosis were reported: 6 weeks and 34 weeks after starting REMICADE.
In the placebo-controlled portion of the Ps studies, 7 of 1123 patients who received REMICADE at any dose were diagnosed with at least one NMSC compared to 0 of 334 patients who received placebo.
In the Ps studies, 1% (15/1373) of patients experienced serum sickness or a combination of arthralgia and/or myalgia with fever, and/or rash, usually early in the treatment course. Of these patients, 6 required hospitalization due to fever, severe myalgia, arthralgia, swollen joints, and immobility.
Safety data are available from 4779 REMICADE-treated adult patients, including 1304 with RA, 1106 with CD, 484 with UC, 202 with AS, 293 with PsA, 1373 with Ps and 17 with other conditions. [For information on other adverse reactions in pediatric patients,
| Placebo | REMICADE | |
|---|---|---|
| (n=350) | (n=1129) | |
| Average weeks of follow-up | 59 weeks | 66 weeks |
| Upper respiratory tract infection | 25% | 32% |
| Nausea | 20% | 21% |
| Headache | 14% | 18% |
| Sinusitis | 8% | 14% |
| Diarrhea | 12% | 12% |
| Abdominal pain | 8% | 12% |
| Pharyngitis | 8% | 12% |
| Coughing | 8% | 12% |
| Bronchitis | 9% | 10% |
| Rash | 5% | 10% |
| Dyspepsia | 7% | 10% |
| Fatigue | 7% | 9% |
| Urinary tract infection | 6% | 8% |
| Pain | 7% | 8% |
| Arthralgia | 7% | 8% |
| Pruritus | 2% | 7% |
| Fever | 4% | 7% |
| Hypertension | 5% | 7% |
| Moniliasis | 3% | 5% |
The most common serious adverse reactions observed in clinical trials were infections
- Body as a whole: allergic reaction, edema
- Blood: pancytopenia
- Cardiovascular: hypotension
- Gastrointestinal: constipation, intestinal obstruction
- Central and Peripheral Nervous: dizziness
- Heart Rate and Rhythm: bradycardia
- Liver and Biliary: hepatitis
- Metabolic and Nutritional: dehydration
- Platelet, Bleeding and Clotting: thrombocytopenia
- Neoplasms: lymphoma
- Red Blood Cell: anemia, hemolytic anemia
- Resistance Mechanism: cellulitis, sepsis, serum sickness, sarcoidosis
- Respiratory: lower respiratory tract infection (including pneumonia), pleurisy, pulmonary edema
- Skin and Appendages: increased sweating
- Vascular (Extracardiac): thrombophlebitis
- White Cell and Reticuloendothelial: leukopenia, lymphadenopathy
There were some differences in the adverse reactions observed in the pediatric patients receiving REMICADE compared to those observed in adults with CD. These differences are discussed in the following paragraphs.
The following adverse reactions were reported more commonly in 103 randomized pediatric CD patients administered 5 mg/kg REMICADE through 54 weeks than in 385 adult CD patients receiving a similar treatment regimen: anemia (11%), leukopenia (9%), flushing (9%), viral infection (8%), neutropenia (7%), bone fracture (7%), bacterial infection (6%), and respiratory tract allergic reaction (6%).
Infections were reported in 56% of randomized pediatric patients in Study Peds Crohn's and in 50% of adult patients in Study Crohn's I. In Study Peds Crohn's, infections were reported more frequently for patients who received every 8-week as opposed to every 12-week infusions (74% and 38%, respectively), while serious infections were reported for 3 patients in the every 8-week and 4 patients in the every 12-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. Pneumonia was reported for 3 patients, (2 in the every 8-week and 1 in the every 12-week maintenance treatment groups). Herpes zoster was reported for 2 patients in the every 8-week maintenance treatment group.
In Study Peds Crohn's, 18% of randomized patients experienced 1 or more infusion reactions, with no notable difference between treatment groups. Of the 112 patients in Study Peds Crohn's, there were no serious infusion reactions, and 2 patients had non-serious anaphylactoid reactions.
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in CD clinical trials; 4% had ALT elevations ≥3 × ULN, and 1% had elevations ≥5 × ULN. (Median follow-up was 53 weeks).
Overall, the adverse reactions reported in the pediatric UC trial and adult UC (Study UC I and Study UC II) studies were generally consistent. In a pediatric UC trial, the most common adverse reactions were upper respiratory tract infection, pharyngitis, abdominal pain, fever, and headache.
Infections were reported in 31 (52%) of 60 treated patients in the pediatric UC trial and 22 (37%) required oral or parenteral antimicrobial treatment. The proportion of patients with infections in the pediatric UC trial was similar to that in the pediatric CD study (Study Peds Crohn's) but higher than the proportion in the adults' UC studies (Study UC I and Study UC II). The overall incidence of infections in the pediatric UC trial was 13/22 (59%) in the every 8 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.
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 17% (10/60) of pediatric patients in the pediatric UC trial; 7% (4/60) had ALT elevations ≥3 × ULN, and 2% (1/60) had elevations ≥5 × ULN (median follow-up was 49 weeks).
Overall, 8 of 60 (13%) treated patients experienced one or more infusion reactions, including 4 of 22 (18%) patients in the every 8-week treatment maintenance group. No serious infusion reactions were reported.
In the pediatric UC trial, 45 patients were in the 12 to 17 year age group and 15 in the 6 to 11 year age group. 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 (40% vs. 18%) and discontinuation due to adverse events (40% vs. 16%) 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 (60% vs. 49%), for serious infections, the proportions were similar in the two age groups (13% in the 6 to 11 year age group vs. 11% in the 12 to 17 year age group). Overall proportions of adverse reactions, including infusion reactions, were similar between the 6 to 11 and 12 to 17 year age groups (13%).