These highlights do not include all the information needed to use REMICADE® safely and effectively. See full prescribing information for REMICADE.
Lyophilized Concentrate for Injection, for Intravenous Use
Initial U.S. Approval: 1998
- 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.
reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease.
Pediatric Crohn’s Disease (1.2):
reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
Ulcerative Colitis (1.3):
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.
Pediatric Ulcerative Colitis (1.4):
reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
Rheumatoid Arthritis (1.5) in combination with methotrexate:
reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active disease.
Ankylosing Spondylitis (1.6):
reducing signs and symptoms in patients with active disease.
Psoriatic Arthritis (1.7):
reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function.
Plaque Psoriasis (1.8):
- 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.
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 if they later lose their response.
Pediatric Crohn’s Disease (2.2)
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.
Ulcerative Colitis (2.3)
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.
Pediatric Ulcerative Colitis (2.4)
5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.
Rheumatoid Arthritis (2.5)
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 or treating as often as every 4 weeks.)
Ankylosing Spondylitis (2.6)
5 mg/kg at 0, 2 and 6 weeks, then every 6 weeks.
Psoriatic Arthritis (2.7) and Plaque Psoriasis (2.8)
- 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.
- 100 mg of lyophilized infliximab in a 20 mL vial for intravenous infusion. (3)
- REMICADE doses >5 mg/kg in moderate to severe heart failure. (4)
- Previous severe hypersensitivity reaction to REMICADE or known hypersensitivity to inactive components of REMICADE or to any murine proteins. (4)
- Serious infections – do not give REMICADE during an active infection. If an infection develops, monitor carefully and stop REMICADE if infection becomes serious. (5.1)
- Invasive fungal infections – for patients who develop a systemic illness on REMICADE, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic (5.1)
- Malignancies – the incidence of malignancies including lymphoma was greater in REMICADE treated patients than in controls. Due to the risk of HSTCL carefully assess the risk/benefit especially if the patient has Crohn’s disease or ulcerative colitis, is male, and is receiving azathioprine or 6-mercaptopurine treatment. (5.2)
- Hepatitis B virus reactivation – test for HBV infection before starting REMICADE. Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop REMICADE and begin anti-viral therapy. (5.3)
- Hepatotoxicity – rare severe hepatic reactions, some fatal or necessitating liver transplantation. Stop REMICADE in cases of jaundice and/or marked liver enzyme elevations. (5.4)
- Heart failure –new onset or worsening symptoms may occur. (4, 5.5)
- Cytopenias – advise patients to seek immediate medical attention if signs and symptoms develop, and consider stopping REMICADE. (5.6)
- Hypersensitivity – serious infusion reactions including anaphylaxis or serum sickness-like reactions may occur. (5.7)
- Demyelinating disease –exacerbation or new onset may occur. (5.8)
- Lupus-like syndrome – stop REMICADE if syndrome develops. (5.13)
- Live vaccines – should not be given with REMICADE. Bring pediatric patients up to date with all vaccinations prior to initiating REMICADE. (5.14)
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
- Use with anakinra or abatacept– increased risk of serious infections (7.1)
- Pediatric Use –REMICADE has not been studied in children with Crohn’s disease or ulcerative colitis <6 years of age. (8.4)
- 1.1 Crohn’s Disease
- 1.2 Pediatric Crohn’s Disease
- 1.3 Ulcerative Colitis
- 1.4 Pediatric Ulcerative Colitis
- 1.5 Rheumatoid Arthritis
- 1.6 Ankylosing Spondylitis
- 1.7 Psoriatic Arthritis
- 1.8 Plaque Psoriasis
- 2.1 Crohn’s Disease
- 2.2 Pediatric Crohn’s Disease
- 2.3 Ulcerative Colitis
- 2.4 Pediatric Ulcerative Colitis
- 2.5 Rheumatoid Arthritis
- 2.6 Ankylosing Spondylitis
- 2.7 Psoriatic Arthritis
- 2.8 Plaque Psoriasis
- 2.9 Monitoring to Assess Safety
- 2.10 Administration Instructions Regarding Infusion Reactions
- 2.11 General Considerations and Instructions for Preparation and Administration
- 5.1 Serious Infections
- 5.2 Malignancies
- 5.3 Hepatitis B Virus Reactivation
- 5.4 Hepatotoxicity
- 5.5 Patients with Heart Failure
- 5.6 Hematologic Reactions
- 5.7 Hypersensitivity
- 5.8 Neurologic Reactions
- 5.9 Use with Anakinra
- 5.10 Use with Abatacept
- 5.11 Concurrent Administration with other Biological Therapeutics
- 5.12 Switching Between Biological Disease-Modifying Antirheumatic Drugs (DMARDs)
- 5.13 Autoimmunity
- 5.14 Vaccinations
- 6.1 Clinical Trials Experience
- 6.2 Post-marketing Experience
- 7.1 Use with Anakinra or Abatacept
- 7.2 Use with Tocilizumab
- 7.3 Use with other Biological Therapeutics
- 7.4 Methotrexate (MTX) and Other Concomitant Medications
- 7.5 Immunosuppressants
- 7.6 Cytochrome P450 Substrates
- 7.7 Live Vaccines/Therapeutic Infectious Agents
- 8.1 Pregnancy
- 8.3 Nursing Mothers
- 8.4 Pediatric Use
- 8.5 Geriatric Use
- 12.1 Mechanism of Action
- 12.2 Pharmacodynamics
- 12.3 Pharmacokinetics
- 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
- 14.1 Crohn’s Disease
- 14.2 Pediatric Crohn’s Disease
- 14.3 Ulcerative Colitis
- 14.4 Pediatric Ulcerative Colitis
- 14.5 Rheumatoid Arthritis
- 14.6 Ankylosing Spondylitis
- 14.7 Psoriatic Arthritis
- 14.8 Plaque Psoriasis
- 17.1 Patient Counseling
FULL PRESCRIBING INFORMATION
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.
REMICADE is indicated for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease.
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy.
REMICADE is indicated for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy.
REMICADE, in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis.
REMICADE is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
REMICADE is indicated for reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis.
REMICADE is indicated for the 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. REMICADE should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warnings,Warnings and Precautions (5)].
The recommended dose 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 Crohn’s disease or fistulizing Crohn’s disease. For adult patients who respond and then lose their response, consideration may be given to treatment with 10 mg/kg. 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.
The recommended dose of REMICADE for pediatric patients 6 years and older with moderately to severely active Crohn’s disease 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.
The recommended dose 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 ulcerative colitis.
During infusion, mild to moderate infusion reactions may improve following slowing or suspension of the infusion, and upon resolution of the reaction, reinitiation at a lower infusion rate and/or therapeutic administration of antihistamines, acetaminophen, and/or corticosteroids. For patients that do not tolerate the infusion following these interventions, REMICADE should be discontinued.
During or following infusion, patients who have severe infusion-related hypersensitivity reactions should be discontinued from further REMICADE treatment. The management of severe infusion reactions should be dictated by the signs and symptoms of the reaction. Appropriate personnel and medication should be available to treat anaphylaxis if it occurs.
- Calculate the dose, total volume of reconstituted REMICADE solution required and the number of REMICADE vials needed. Each REMICADE vial contains 100 mg of the infliximab antibody.
- Reconstitute each REMICADE vial with 10 mL of Sterile Water for Injection, USP, 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. Avoid prolonged or vigorous agitation. DO NOT SHAKE. Foaming of the solution on reconstitution is not unusual. Allow the reconstituted solution to stand for 5 minutes. The solution 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 cake has not fully dissolved or if opaque particles, discoloration, or other foreign particles are present.
Dilute the total volume of the reconstituted REMICADE solution dose to
250 mLwith sterile 0.9% Sodium Chloride Injection, USP, by withdrawing a volume equal to the volume of reconstituted REMICADE from the 0.9% Sodium Chloride Injection, USP, 250 mLbottle or bag. Slowly add the total volume of reconstituted REMICADE solution to the 250 mL infusion bottle or bag. Gently mix. The resulting infusion concentration should range between 0.4 mg/mL and 4 mg/mL.
- The REMICADE infusion should begin within 3 hours of reconstitution and dilution. The infusion must be administered over a period of not less than 2 hours and must use an infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 1.2 µm or less). The vials do not contain antibacterial preservatives. Therefore, any unused portion of the infusion solution should not be stored 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.
- Parenteral drug products should be inspected visually before and after reconstitution for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particulates are observed, the solution should not be used.
100 mg vial: 100 mg lyophilized infliximab in a 20 mL vial for injection, for intravenous use.
REMICADE at doses >5 mg/kg should not be administered to patients with moderate to severe heart failure. In a randomized study evaluating REMICADE in patients with moderate to severe heart failure (New York Heart Association [NYHA] Functional Class III/IV), REMICADE treatment at 10 mg/kg was associated with an increased incidence of death and hospitalization due to worsening heart failure [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].
REMICADE should not be re-administered to patients who have experienced a severe hypersensitivity reaction to REMICADE. Additionally, REMICADE should not be administered to patients with known hypersensitivity to inactive components of the product or to any murine proteins.
Patients treated with REMICADE are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.
Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, or parasitic organisms including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis 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.
Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving REMICADE, including patients who have previously received treatment for latent or active tuberculosis. 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 blocking agents 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-Guerin (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.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with REMICADE, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with REMICADE.
REMICADE should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with REMICADE should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated.
Invasive Fungal Infections
For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.
In the controlled portions of clinical trials of all the TNF-blocking agents, 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 rheumatoid arthritis 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 rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 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 Crohn’s disease, rheumatoid arthritis or plaque psoriasis, 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-blocking therapy. Cases of acute and chronic leukemia have been reported with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF blocker therapy, patients with rheumatoid arthritis 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. All reported REMICADE cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. All of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with REMICADE at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to REMICADE or REMICADE in combination with these other immunosuppressants. When treating patients with inflammatory bowel disease, particularly in adolescents and young adults, consideration of whether to use REMICADE alone or in combination with other immunosuppressants 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)].
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocker therapy, including REMICADE [see Adverse Reactions (6.2)]. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
In the controlled portions of clinical trials of some TNF-blocking agents 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 rheumatoid arthritis, Crohn’s disease, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and plaque psoriasis, 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.
Psoriasis 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-blocking therapy 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.
Use of TNF blockers, including REMICADE, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients should be tested for HBV infection before initiating TNF blocker therapy, including REMICADE. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. Patients who are carriers of HBV and require treatment with TNF blockers should be closely monitored for clinical and laboratory signs of active HBV infection throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, TNF blockers should be stopped and antiviral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF blocker therapy in this situation and monitor patients closely.
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported rarely in postmarketing data in patients receiving REMICADE. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 year after initiation of REMICADE; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥5 times the upper limit of normal) develop, REMICADE should be discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving REMICADE without progression to severe hepatic injury [see Adverse Reactions (6.1)].
REMICADE has been associated with adverse outcomes in patients with heart failure, and should be used in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of REMICADE in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg REMICADE, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg. 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. If a decision is made to administer REMICADE to patients with heart failure, they should be closely monitored during therapy, and REMICADE should be discontinued if new or worsening symptoms of heart failure appear [see Contraindications (4) and Adverse Reactions (6.1)].
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving REMICADE. The causal relationship to REMICADE therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with REMICADE who have ongoing or a history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on REMICADE. Discontinuation of REMICADE therapy should be considered in patients who develop significant hematologic abnormalities.
REMICADE has been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include urticaria, dyspnea, and/or hypotension, have occurred during or within 2 hours of REMICADE infusion.
However, in some cases, serum sickness-like reactions have been observed in patients after initial REMICADE therapy (i.e., as early as after the second dose), and when REMICADE therapy was reinstituted following an extended period without REMICADE treatment. Symptoms associated with these reactions include fever, rash, headache, sore throat, myalgias, polyarthralgias, hand and facial edema and/or dysphagia. These reactions were associated with a marked increase in antibodies to infliximab, loss of detectable serum concentrations of infliximab, and possible loss of drug efficacy.
REMICADE should be discontinued for severe hypersensitivity reactions. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a reaction [see Adverse Reactions (6.1)].
In rheumatoid arthritis, Crohn’s disease and psoriasis clinical trials, re-administration of REMICADE after a period of no treatment resulted in a higher incidence of infusion reactions relative to regular maintenance treatment [see Adverse Reactions (6.1)]. In general, the benefit-risk of re-administration of REMICADE after a period of no-treatment, especially as a re-induction regimen given at weeks 0, 2 and 6, should be carefully considered. In the case where REMICADE maintenance therapy for psoriasis is interrupted, REMICADE should be reinitiated as a single dose followed by maintenance therapy.
REMICADE and other agents that inhibit TNF have been associated in rare cases with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of REMICADE in patients with these neurologic disorders and should consider discontinuation of REMICADE if these disorders develop.
Serious 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 reactions seen with the 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.
In clinical studies, concurrent administration of TNF-blocking agents and abatacept have been associated with an increased risk of infections including serious infections compared with TNF-blocking agents alone, without increased clinical benefit. Therefore, the combination of REMICADE and abatacept is not recommended [see Drug Interactions (7.1)].
There is insufficient information regarding the concomitant use of REMICADE with other biological therapeutics used to treat the same conditions as REMICADE. The concomitant use of REMICADE with these biologics is not recommended because of the possibility of an increased risk of infection [see Drug Interactions (7.3)].
Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.
Treatment with REMICADE may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with REMICADE, treatment should be discontinued [see Adverse Reactions (6.1)].
In 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. Caution is advised in the administration of live vaccines to infants born to female patients treated with REMICADE during pregnancy since REMICADE is known to cross the placenta and has been detected up to 6 months in the serum of infants born to female patients treated with REMICADE during pregnancy.
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.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not predict the rates observed in broader patient populations in clinical practice.
Adverse Reactions in Adults
The data described herein reflect exposure to REMICADE in 4779 adult patients (1304 patients with rheumatoid arthritis, 1106 patients with Crohn’s disease, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 484 with ulcerative colitis, 1373 with plaque psoriasis, and 17 patients with other conditions), including 2625 patients exposed beyond 30 weeks and 374 exposed beyond 1 year. [For information on adverse reactions in pediatric patients see Adverse Reactions (6.1)]. One of the most-common reasons for discontinuation of treatment was infusion-related reactions (e.g., dyspnea, flushing, headache and rash).
An infusion reaction was defined in clinical trials as any adverse event occurring during an infusion or within 1 hour after an infusion. In phase 3 clinical studies, 18% of REMICADE-treated patients experienced an infusion reaction compared to 5% of placebo-treated patients. Of infliximab-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 psoriasis through 1 year in psoriasis 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 psoriasis 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
Patients who became positive for antibodies to infliximab were more likely (approximately two- to three fold) to have an infusion reaction than were those who were negative. Use of concomitant immunosuppressant agents appeared to reduce the frequency of both antibodies to infliximab and infusion reactions [see Adverse Reactions (6.1) and Drug Interactions (7.3)].
Infusion reactions following re-administration
In a clinical trial of patients with moderate to severe psoriasis 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 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.
Delayed Reactions/Reactions Following Re-administration
In psoriasis 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 was reported in 14 patients, 4 of whom died due to miliary tuberculosis. Other cases of tuberculosis, including disseminated tuberculosis, also have been reported post-marketing. Most of these cases of tuberculosis occurred within the first 2 months after initiation of therapy with REMICADE and may reflect recrudescence of latent disease [see Warnings and Precautions (5.1)]. In the 1-year placebo-controlled studies RA I and RA II, 5.3% of patients receiving REMICADE every 8 weeks with MTX developed serious infections as compared to 3.4% of placebo patients receiving MTX. Of 924 patients receiving REMICADE, 1.7% developed pneumonia and 0.4% developed TB, when compared to 0.3% and 0.0% in the placebo arm respectively. In a shorter (22-week) placebo-controlled study of 1082 RA patients randomized to receive placebo, 3 mg/kg or 10 mg/kg REMICADE infusions at 0, 2, and 6 weeks, followed by every 8 weeks with MTX, serious infections were more frequent in the 10 mg/kg REMICADE group (5.3%) than the 3 mg/kg or placebo groups (1.7% in both). During the 54-week Crohn’s II Study, 15% of patients with fistulizing Crohn’s disease developed a new fistula-related abscess.
In REMICADE clinical studies in patients with ulcerative colitis, 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 ulcerative colitis 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 [see Warnings and Precautions (5.2)].
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 rheumatoid arthritis and Crohn’s disease. 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.
Patients with Heart Failure
In a randomized study evaluating REMICADE in moderate to 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) [see Contraindications (4) and Warnings and Precautions (5.5)].
Treatment with REMICADE can be associated with the development of antibodies to infliximab. The assay used to measure anti-infliximab antibodies in patient samples is subject to interference by serum infliximab, possibly resulting in an underestimation of the rate of patient antibody formation. The incidence of antibodies to infliximab in patients given a 3-dose induction regimen followed by maintenance dosing was approximately 10% as assessed through 1 to 2 years of REMICADE treatment. A higher incidence of antibodies to infliximab was observed in Crohn’s disease patients receiving REMICADE after drug-free intervals >16 weeks. In a study of psoriatic arthritis in which 191 patients received 5 mg/kg with or without MTX, antibodies to infliximab occurred in 15% of patients. The majority of antibody-positive patients had low titers. Patients who were antibody-positive were more likely to have higher rates of clearance, reduced efficacy and to experience an infusion reaction [see Adverse Reactions (6.1)] than were patients who were antibody negative. Antibody development was lower among rheumatoid arthritis and Crohn’s disease patients receiving immunosuppressant therapies such as 6-MP/AZA or MTX.
In the psoriasis Study II, which included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 36% of patients treated with 5 mg/kg every 8 weeks for 1 year, and in 51% of patients treated with 3 mg/kg every 8 weeks for 1 year. In the psoriasis Study III, which also included both the 5 mg/kg and 3 mg/kg doses, antibodies were observed in 20% of patients treated with 5 mg/kg induction (weeks 0, 2 and 6), and in 27% of patients treated with 3 mg/kg induction. Despite the increase in antibody formation, the infusion reaction rates in Studies I and II in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year and in Study III in patients treated with 5 mg/kg induction (14.1%-23.0%) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. The clinical significance of apparent increased immunogenicity on efficacy and infusion reactions in psoriasis patients as compared to patients with other diseases treated with REMICADE over the long term is not known.
The data reflect the percentage of patients whose test results were positive for antibodies to infliximab in an ELISA assay, and they are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors including sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to infliximab with the incidence of antibodies to other products may be misleading.
Severe liver injury, including acute liver failure and autoimmune hepatitis, has been reported rarely in patients receiving REMICADE [see Warnings and Precautions (5.4)]. Reactivation of hepatitis B virus has occurred in patients receiving TNF-blocking agents, including REMICADE, who are chronic carriers of this virus [see Warnings and Precautions (5.3)].
In clinical trials in rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, plaque psoriasis, and psoriatic arthritis, 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.
Adverse Reactions in Psoriasis Studies
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 psoriasis 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 psoriasis 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.
Other Adverse Reactions
Safety data are available from 4779 REMICADE-treated adult patients, including 1304 with rheumatoid arthritis, 1106 with Crohn’s disease, 484 with ulcerative colitis, 202 with ankylosing spondylitis, 293 with psoriatic arthritis, 1373 with plaque psoriasis and 17 with other conditions. [For information on other adverse reactions in pediatric patients, see Adverse Reactions (6.1)]. Adverse reactions reported in ≥5% of all patients with rheumatoid arthritis receiving 4 or more infusions are in Table 2. The types and frequencies of adverse reactions observed were similar in REMICADE-treated rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis and Crohn’s disease patients except for abdominal pain, which occurred in 26% of REMICADE-treated patients with Crohn’s disease. In the Crohn’s disease studies, there were insufficient numbers and duration of follow-up for patients who never received REMICADE to provide meaningful comparisons.
The most common serious adverse reactions observed in clinical trials were infections [see Adverse Reactions (6.1)]. Other serious, medically relevant adverse reactions ≥0.2% or clinically significant adverse reactions by body system were as follows:
Body as a whole: allergic reaction, edema
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
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
Adverse Reactions in Pediatric Patients
Pediatric Crohn’s Disease
There were some differences in the adverse reactions observed in the pediatric patients receiving REMICADE compared to those observed in adults with Crohn’s disease. These differences are discussed in the following paragraphs.
The following adverse reactions were reported more commonly in 103 randomized pediatric Crohn’s disease patients administered 5 mg/kg REMICADE through 54 weeks than in 385 adult Crohn’s disease 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.
In Study Peds Crohn’s, in which all patients received stable doses of 6-MP, AZA, or MTX, excluding inconclusive samples, 3 of 24 patients had antibodies to infliximab. Although 105 patients were tested for antibodies to infliximab, 81 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample.
Elevations of ALT up to 3 times the upper limit of normal (ULN) were seen in 18% of pediatric patients in Crohn’s disease clinical trials; 4% had ALT elevations ≥3 x ULN, and 1% had elevations ≥5 x ULN. (Median follow-up was 53 weeks.)
Pediatric Ulcerative Colitis
Overall, the adverse reactions reported in the pediatric ulcerative colitis trial and adult ulcerative colitis (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 Crohn’s disease study (Study Peds Crohn’s) but higher than the proportion in the adults’ ulcerative colitis 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.
In the pediatric UC trial, excluding inconclusive samples, 4 of 19 patients had antibodies to infliximab. Although 52 patients were tested, 33 patients were classified as inconclusive because they could not be ruled as negative due to assay interference by the presence of infliximab in the sample.
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 x ULN, and 2% (1/60) had elevations ≥5 x 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%).
The following adverse reactions, some with fatal outcome, have been reported during post-approval use of REMICADE: neutropenia [see Warnings and Precautions (5.6)], interstitial lung disease (including pulmonary fibrosis/interstitial pneumonitis and very rare rapidly progressive disease), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, pericardial effusion, systemic and cutaneous vasculitis, erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, peripheral demyelinating disorders (such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy), new onset and worsening psoriasis (all subtypes including pustular, primarily palmoplantar), transverse myelitis, and neuropathies (additional neurologic reactions have also been observed) [see Warnings and Precautions (5.8)], acute liver failure, jaundice, hepatitis, and cholestasis [see Warnings and Precautions (5.4)], serious infections [see Warnings and Precautions (5.1)] and malignancies including melanoma and Merkel cell carcinoma [see Warnings and Precautions (5.2)].
In post-marketing experience, cases of anaphylactic reactions, including laryngeal/pharyngeal edema and severe bronchospasm, and seizure have been associated with REMICADE administration.
Cases of myocardial ischemia/infarction and transient visual loss have also been rarely reported in association with REMICADE during or within 2 hours of infusion.
Adverse Reactions in Pediatric Patients
The following serious adverse reactions have been reported in the post-marketing experience in children: infections (some fatal) including opportunistic infections and tuberculosis, infusion reactions, and hypersensitivity reactions.
Serious adverse reactions in the post-marketing experience with REMICADE in the pediatric population have also included malignancies, including hepatosplenic T-cell lymphomas [see Boxed WARNINGS and Warnings and Precautions (5.2)], transient hepatic enzyme abnormalities, lupus-like syndromes, and the development of autoantibodies.
7.1 Use with Anakinra or Abatacept
The combination of REMICADE with other biological therapeutics used to treat the same conditions as REMICADE is not recommended [see Warnings and Precautions (5.11)].
It is recommended that live vaccines not be given concurrently with REMICADE [see Warnings and Precautions (5.14)].
It is recommended that therapeutic infectious agents not be given concurrently with REMICADE [see Warnings and Precautions (5.14)].
As with other IgG antibodies, REMICADE crosses the placenta and has been detected up to 6 months in the serum of infants born to female patients treated with REMICADE during pregnancy. Consequently, these infants may be at increased risk of infection, and caution is advised in the administration of live vaccines to these infants [see Warnings and Precautions (5.14)].
Pediatric Crohn’s Disease
REMICADE is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy [see Boxed Warnings, Warnings and Precautions (5), Indications and Usage (1.2), Dosage and Administration (2.2), Clinical Studies (14.2) and Adverse Reactions (6.1)].
REMICADE has been studied only in combination with conventional immunosuppressive therapy in pediatric Crohn’s disease. The longer term (greater than 1 year) safety and effectiveness of REMICADE in pediatric Crohn’s disease patients have not been established in clinical trials.
Pediatric Ulcerative Colitis
The safety and effectiveness of REMICADE for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients aged 6 years and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy are supported by evidence from adequate and well-controlled studies of REMICADE in adults. Additional safety and pharmacokinetic data were collected in 60 pediatric patients aged 6 years and older [see Clinical Pharmacology (12.3), Dosage and Administration (2.4), Adverse Reactions (6.1), and Clinical Studies, (14.4)]. The effectiveness of REMICADE in inducing and maintaining mucosal healing could not be established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at the Week 8 endoscopy, the induction phase was open-label and lacked a control group. Only 9 patients had an optional endoscopy at Week 54.
In the pediatric UC trial, approximately half of the patients were on concomitant immunomodulators (AZA, 6-MP, MTX) at study start. Due to the risk of HSTCL, a careful risk-benefit assessment should be made when REMICADE is used in combination with other immunosuppressants.
The longer term (greater than 1 year) safety and effectiveness of REMICADE in pediatric ulcerative colitis patients have not been established in clinical trials.
Juvenile Rheumatoid Arthritis (JRA)
The safety and efficacy of REMICADE in patients with juvenile rheumatoid arthritis (JRA) were evaluated in a multicenter, randomized, placebo-controlled, double-blind study for 14 weeks, followed by a double-blind, all-active treatment extension, for a maximum of 44 weeks. Patients with active JRA between the ages of 4 and 17 years who had been treated with MTX for at least 3 months were enrolled. Concurrent use of folic acid, oral corticosteroids (≤ 0.2 mg/kg/day of prednisone or equivalent), NSAIDs, and/or disease modifying antirheumatic drugs (DMARDs) was permitted.
Doses of 3 mg/kg REMICADE or placebo were administered intravenously at Weeks 0, 2 and 6. Patients randomized to placebo crossed-over to receive 6 mg/kg REMICADE at Weeks 14, 16, and 20, and then every 8 weeks through Week 44. Patients who completed the study continued to receive open-label treatment with REMICADE for up to 2 years in a companion extension study.
The study failed to establish the efficacy of REMICADE in the treatment of JRA. Key observations in the study included a high placebo response rate and a higher rate of immunogenicity than what has been observed in adults. Additionally, a higher rate of clearance of infliximab was observed than had been observed in adults [see Clinical Pharmacology (12.3)].
A total of 60 patients with JRA were treated with doses of 3 mg/kg and 57 patients were treated with doses of 6 mg/kg. The proportion of patients with infusion reactions who received 3 mg/kg REMICADE was 35% (21/60) over 52 weeks compared with 18% (10/57) in patients who received 6 mg/kg over 38 weeks. The most common infusion reactions reported were vomiting, fever, headache, and hypotension. In the 3 mg/kg REMICADE group, 4 patients had a serious infusion reaction and 3 patients reported a possible anaphylactic reaction (2 of which were among the serious infusion reactions). In the 6 mg/kg REMICADE group, 2 patients had a serious infusion reaction, 1 of whom had a possible anaphylactic reaction. Two of the 6 patients who experienced serious infusion reactions received REMICADE by rapid infusion (duration of less than 2 hours). Antibodies to infliximab developed in 38% (20/53) of patients who received 3 mg/kg REMICADE compared with 12% (6/49) of patients who received 6 mg/kg.
A total of 68% (41/60) of patients who received 3 mg/kg REMICADE in combination with MTX experienced an infection over 52 weeks compared with 65% (37/57) of patients who received 6 mg/kg REMICADE in combination with MTX over 38 weeks. The most commonly reported infections were upper respiratory tract infection and pharyngitis, and the most commonly reported serious infection was pneumonia. Other notable infections included primary varicella infection in 1 patient and herpes zoster in 1 patient.
REMICADE is supplied as a sterile, white, lyophilized powder for intravenous infusion. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the resulting pH is approximately 7.2. Each single-use vial contains 100 mg infliximab, 500 mg sucrose, 0.5 mg polysorbate 80, 2.2 mg monobasic sodium phosphate, monohydrate, and 6.1 mg dibasic sodium phosphate, dihydrate. No preservatives are present.
Following an initial dose of REMICADE, repeated infusions at 2 and 6 weeks resulted in predictable concentration-time profiles following each treatment. No systemic accumulation of infliximab occurred upon continued repeated treatment with 3 mg/kg or 10 mg/kg at 4- or 8-week intervals. Development of antibodies to infliximab increased infliximab clearance. At 8 weeks after a maintenance dose of 3 to 10 mg/kg of REMICADE, median infliximab serum concentrations ranged from approximately 0.5 to 6 mcg/mL; however, infliximab concentrations were not detectable (<0.1 mcg/mL) in patients who became positive for antibodies to infliximab. No major differences in clearance or volume of distribution were observed in patient subgroups defined by age, weight, or gender. It is not known if there are differences in clearance or volume of distribution in patients with marked impairment of hepatic or renal function.
Infliximab pharmacokinetic characteristics (including peak and trough concentrations and terminal half-life) were similar in pediatric (aged 6 to 17 years) and adult patients with Crohn’s disease or ulcerative colitis following the administration of 5 mg/kg infliximab.
Population pharmacokinetic analysis showed that in children with juvenile rheumatoid arthritis (JRA) with a body weight of up to 35 kg receiving 6 mg/kg REMICADE and children with JRA with body weight greater than 35 kg up to adult body weight receiving 3 mg/kg REMICADE, the steady state area under the concentration curve (AUCss) was similar to that observed in adults receiving 3 mg/kg of REMICADE.
Active Crohn’s Disease
The safety and efficacy of single and multiple doses of REMICADE were assessed in 2 randomized, double-blind, placebo-controlled clinical studies in 653 patients with moderate to severely active Crohn’s disease [Crohn’s Disease Activity Index (CDAI) ≥220 and ≤400] with an inadequate response to prior conventional therapies. Concomitant stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents were permitted and 92% of patients continued to receive at least one of these medications.
In the single-dose trial of 108 patients, 16% (4/25) of placebo patients achieved a clinical response (decrease in CDAI ≥70 points) at Week 4 vs. 81% (22/27) of patients receiving
In a multidose trial (ACCENT I [Study Crohn’s I]), 545 patients received 5 mg/kg at Week 0 and were then randomized to one of three treatment groups; the placebo maintenance group received placebo at Weeks 2 and 6, and then every 8 weeks; the 5 mg/kg maintenance group received
At Week 2, 57% (311/545) of patients were in clinical response. At Week 30, a significantly greater proportion of these patients in the 5 mg/kg and 10 mg/kg maintenance groups achieved clinical remission compared to patients in the placebo maintenance group (Table 3).
Additionally, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg REMICADE maintenance groups were in clinical remission and were able to discontinue corticosteroid use compared to patients in the placebo maintenance group at Week 54 (Table 3).
Patients in the REMICADE maintenance groups (5 mg/kg and 10 mg/kg) had a longer time to loss of response than patients in the placebo maintenance group (Figure 1). At Weeks 30 and 54, significant improvement from baseline was seen among the 5 mg/kg and 10 mg/kg REMICADE-treated groups compared to the placebo group in the disease-specific inflammatory bowel disease questionnaire (IBDQ), particularly the bowel and systemic components, and in the physical component summary score of the general health-related quality of life questionnaire SF-36.
Figure 1 Kaplan-Meier estimate of the proportion of patients who had not lost response through Week 54
In a subset of 78 patients who had mucosal ulceration at baseline and who participated in an endoscopic substudy, 13 of 43 patients in the REMICADE maintenance group had endoscopic evidence of mucosal healing compared to 1 of 28 patients in the placebo group at Week 10. Of the REMICADE-treated patients showing mucosal healing at Week 10, 9 of 12 patients also showed mucosal healing at Week 54.
Patients who achieved a response and subsequently lost response were eligible to receive REMICADE on an episodic basis at a dose that was 5 mg/kg higher than the dose to which they were randomized. The majority of such patients responded to the higher dose. Among patients who were not in response at Week 2, 59% (92/157) of REMICADE maintenance patients responded by Week 14 compared to 51% (39/77) of placebo maintenance patients. Among patients who did not respond by Week 14, additional therapy did not result in significantly more responses [see Dosage and Administration (2)].
Fistulizing Crohn’s Disease
The safety and efficacy of REMICADE were assessed in 2 randomized, double-blind, placebo-controlled studies in patients with fistulizing Crohn’s disease with fistula(s) that were of at least 3 months duration. Concurrent use of stable doses of corticosteroids, 5 aminosalicylates, antibiotics, MTX, 6 mercaptopurine (6-MP) and/or azathioprine (AZA) was permitted.
In the first trial, 94 patients received 3 doses of either placebo or REMICADE at Weeks 0, 2 and 6. Fistula response (≥50% reduction in number of enterocutaneous fistulas draining upon gentle compression on at least 2 consecutive visits without an increase in medication or surgery for Crohn’s disease) was seen in 68% (21/31) of patients in the 5 mg/kg REMICADE group (P=0.002) and 56% (18/32) of patients in the 10 mg/kg REMICADE group (P=0.021) vs. 26% (8/31) of patients in the placebo arm. The median time to onset of response and median duration of response in REMICADE-treated patients was 2 and 12 weeks, respectively. Closure of all fistulas was achieved in 52% of REMICADE-treated patients compared with 13% of placebo-treated patients (P<0.001).
In the second trial (ACCENT II [Study Crohn’s II]), patients who were enrolled had to have at least 1 draining enterocutaneous (perianal, abdominal) fistula. All patients received 5 mg/kg REMICADE at Weeks 0, 2 and 6. Patients were randomized to placebo or 5 mg/kg REMICADE maintenance at Week 14. Patients received maintenance doses at Week 14 and then every 8 weeks through Week 46. Patients who were in fistula response (fistula response was defined the same as in the first trial) at both Weeks 10 and 14 were randomized separately from those not in response. The primary endpoint was time from randomization to loss of response among those patients who were in fistula response.
Among the randomized patients (273 of the 296 initially enrolled), 87% had perianal fistulas and 14% had abdominal fistulas. Eight percent also had rectovaginal fistulas. Greater than 90% of the patients had received previous immunosuppressive and antibiotic therapy.
At Week 14, 65% (177/273) of patients were in fistula response. Patients randomized to REMICADE maintenance had a longer time to loss of fistula response compared to the placebo maintenance group (Figure 2). At Week 54, 38% (33/87) of REMICADE-treated patients had no draining fistulas compared with 22% (20/90) of placebo-treated patients (P=0.02). Compared to placebo maintenance, patients on REMICADE maintenance had a trend toward fewer hospitalizations.
Figure 2 Life table estimates of the proportion of patients who had not lost fistula response through Week 54
Patients who achieved a fistula response and subsequently lost response were eligible to receive REMICADE maintenance therapy at a dose that was 5 mg/kg higher than the dose to which they were randomized. Of the placebo maintenance patients, 66% (25/38) responded to 5 mg/kg REMICADE, and 57% (12/21) of REMICADE maintenance patients responded to 10 mg/kg.
Patients who had not achieved a response by Week 14 were unlikely to respond to additional doses of REMICADE.
Similar proportions of patients in either group developed new fistulas (17% overall) and similar numbers developed abscesses (15% overall).
All patients received induction dosing of 5 mg/kg REMICADE at Weeks 0, 2, and 6. At Week 10, 103 patients were randomized to a maintenance regimen of 5 mg/kg REMICADE given either every 8 weeks or every 12 weeks.
At Week 10, 88% of patients were in clinical response (defined as a decrease from baseline in the PCDAI score of ≥15 points and total PCDAI score of ≤30 points), and 59% were in clinical remission (defined as PCDAI score of ≤10 points).
The proportion of pediatric patients achieving clinical response at Week 10 compared favorably with the proportion of adults achieving a clinical response in Study Crohn’s I. The study definition of clinical response in Study Peds Crohn’s was based on the PCDAI score, whereas the CDAI score was used in the adult Study Crohn’s I.
At both Week 30 and Week 54, the proportion of patients in clinical response was greater in the every 8-week treatment group than in the every 12-week treatment group (73% vs. 47% at Week 30, and 64% vs. 33% at Week 54). At both Week 30 and Week 54, the proportion of patients in clinical remission was also greater in the every 8-week treatment group than in the every 12-week treatment group (60% vs. 35% at Week 30, and 56% vs. 24% at Week 54), (Table 4).
For patients in Study Peds Crohn’s receiving corticosteroids at baseline, the proportion of patients able to discontinue corticosteroids while in remission at Week 30 was 46% for the every 8-week maintenance group and 33% for the every 12-week maintenance group. At Week 54, the proportion of patients able to discontinue corticosteroids while in remission was 46% for the every 8-week maintenance group and 17% for the every 12-week maintenance group.
Patients in Study UC I had failed to respond or were intolerant to oral corticosteroids, 6-MP, or AZA. Patients in Study UC II had failed to respond or were intolerant to the above treatments and/or aminosalicylates. Similar proportions of patients in Studies UC I and UC II were receiving corticosteroids (61% and 51%, respectively), 6-MP/AZA (49% and 43%) and aminosalicylates (70% and 75%) at baseline. More patients in Study UC II than UC I were taking solely aminosalicylates for UC (26% vs. 11%, respectively). Clinical response was defined as a decrease from baseline in the Mayo score by ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1.
Clinical Response, Clinical Remission, and Mucosal Healing
In both Study UC I and Study UC II, greater percentages of patients in both REMICADE groups achieved clinical response, clinical remission and mucosal healing than in the placebo group. Each of these effects was maintained through the end of each trial (Week 54 in Study UC I, and Week 30 in Study UC II). In addition, a greater proportion of patients in REMICADE groups demonstrated sustained response and sustained remission than in the placebo groups (Table 5).
Of patients on corticosteroids at baseline, greater proportions of patients in the REMICADE treatment groups were in clinical remission and able to discontinue corticosteroids at Week 30 compared with the patients in the placebo treatment groups (22% in REMICADE treatment groups vs. 10% in placebo group in Study UC I; 23% in REMICADE treatment groups vs. 3% in placebo group in Study UC II). In Study UC I, this effect was maintained through Week 54 (21% in REMICADE treatment groups vs. 9% in placebo group). The REMICADE-associated response was generally similar in the 5 mg/kg and 10 mg/kg dose groups.
The improvement with REMICADE was consistent across all Mayo subscores through Week 54 (Study UC I shown in Table 6; Study UC II through Week 30 was similar).
All patients received induction dosing of 5 mg/kg REMICADE at Weeks 0, 2, and 6. Patients who did not respond to REMICADE at Week 8 received no further REMICADE and returned for safety follow-up. At Week 8, 45 patients were randomized to a maintenance regimen of 5 mg/kg REMICADE given either every 8 weeks through Week 46 or every 12 weeks through Week 42. Patients were allowed to change to a higher dose and/or more frequent administration schedule if they experienced loss of response.
Clinical response at Week 8 was defined as a decrease from baseline in the Mayo score by ≥ 30% and ≥ 3 points, including a decrease in the rectal bleeding subscore by ≥ 1 points or achievement of a rectal bleeding subscore of 0 or 1.
Clinical remission at Week 8 was measured by the Mayo score, defined as a Mayo score of ≥ 2 points with no individual subscore >1. Clinical remission was also assessed at Week 8 and Week 54 using the Pediatric Ulcerative Colitis Activity Index (PUCAI)6 score and was defined by a PUCAI score of <10 points.
Endoscopies were performed at baseline and at Week 8. A Mayo endoscopy subscore of 0 indicated normal or inactive disease and a subscore of 1 indicated mild disease (erythema, decreased vascular pattern, or mild friability).
Of the 60 patients treated, 44 were in clinical response at Week 8. Of 32 patients taking concomitant immunomodulators at baseline, 23 achieved clinical response at Week 8, compared to 21 of 28 of those not taking concomitant immunomodulators at baseline. At Week 8, 24 of 60 patients were in clinical remission as measured by the Mayo score and 17 of 51 patients were in remission as measured by the PUCAI score.
At Week 54, 8 of 21 patients in the every 8-week maintenance group and 4 of 22 patients in the every 12-week maintenance group achieved remission as measured by the PUCAI score.
During maintenance phase, 23 of 45 randomized patients (9 in the every 8-week group and 14 in the every 12-week group) required an increase in their dose and/or increase in frequency of REMICADE administration due to loss of response. Nine of the 23 patients who required a change in dose had achieved remission at Week 54. Seven of those patients received the 10 mg/kg every 8-week dosing.
Study RA I was a placebo-controlled study of 428 patients with active rheumatoid arthritis despite treatment with MTX. Patients enrolled had a median age of 54 years, median disease duration of 8.4 years, median swollen and tender joint count of 20 and 31 respectively, and were on a median dose of 15 mg/wk of MTX. Patients received either placebo + MTX or one of 4 doses/schedules of REMICADE + MTX: 3 mg/kg or 10 mg/kg of REMICADE by IV infusion at Weeks 0, 2 and 6 followed by additional infusions every 4 or 8 weeks in combination with MTX.
Study RA II was a placebo-controlled study of 3 active treatment arms in 1004 MTX naive patients of 3 or fewer years’ duration active rheumatoid arthritis. Patients enrolled had a median age of 51 years with a median disease duration of 0.6 years, median swollen and tender joint count of 19 and 31, respectively, and >80% of patients had baseline joint erosions. At randomization, all patients received MTX (optimized to 20 mg/wk by Week 8) and either placebo, 3 mg/kg or 6 mg/kg REMICADE at Weeks 0, 2, and 6 and every 8 weeks thereafter.
Data on use of REMICADE without concurrent MTX are limited [see Adverse Reactions (6.1)].
In Study RA I, all doses/schedules of REMICADE + MTX resulted in improvement in signs and symptoms as measured by the American College of Rheumatology response criteria (ACR 20) with a higher percentage of patients achieving an ACR 20, 50 and 70 compared to placebo + MTX (Table 7). This improvement was observed at Week 2 and maintained through Week 102. Greater effects on each component of the ACR 20 were observed in all patients treated with REMICADE + MTX compared to placebo + MTX (Table 8). More patients treated with REMICADE reached a major clinical response than placebo-treated patients (Table 7).
In Study RA II, after 54 weeks of treatment, both doses of REMICADE + MTX resulted in statistically significantly greater response in signs and symptoms compared to MTX alone as measured by the proportion of patients achieving ACR 20, 50 and 70 responses (Table 7). More patients treated with REMICADE reached a major clinical response than placebo-treated patients (Table 7).
Structural damage in both hands and feet was assessed radiographically at Week 54 by the change from baseline in the van der Heijde-modified Sharp (vdH-S) score, a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing in hands/wrists and feet.3
In Study RA I, approximately 80% of patients had paired X-ray data at 54 weeks and approximately 70% at 102 weeks. The inhibition of progression of structural damage was observed at 54 weeks (Table 9) and maintained through 102 weeks.
In Study RA II, >90% of patients had at least 2 evaluable X-rays. Inhibition of progression of structural damage was observed at Weeks 30 and 54 (Table 9) in the REMICADE + MTX groups compared to MTX alone. Patients treated with REMICADE + MTX demonstrated less progression of structural damage compared to MTX alone, whether baseline acute-phase reactants (ESR and CRP) were normal or elevated: patients with elevated baseline acute-phase reactants treated with MTX alone demonstrated a mean progression in
Physical function response
Physical function and disability were assessed using the Health Assessment Questionnaire (HAQ-DI) and the general health-related quality of life questionnaire SF-36.
In Study RA I, all doses/schedules of REMICADE + MTX showed significantly greater improvement from baseline in HAQ-DI and SF-36 physical component summary score averaged over time through Week 54 compared to placebo + MTX, and no worsening in the SF-36 mental component summary score. The median (interquartile range) improvement from baseline to Week 54 in HAQ-DI was 0.1 ( -0.1, 0.5) for the placebo + MTX group and 0.4 (0.1, 0.9) for REMICADE + MTX (p<0.001). Both HAQ-DI and SF-36 effects were maintained through Week 102. Approximately 80% of patients in all doses/schedules of REMICADE + MTX remained in the trial through 102 weeks.
In Study RA II, both REMICADE treatment groups showed greater improvement in HAQ-DI from baseline averaged over time through Week 54 compared to MTX alone; 0.7 for REMICADE + MTX vs. 0.6 for MTX alone (P≤0.001). No worsening in the SF-36 mental component summary score was observed.
At 24 weeks, improvement in the signs and symptoms of ankylosing spondylitis, as measured by the proportion of patients achieving a 20% improvement in ASAS response criteria (ASAS 20), was seen in 60% of patients in the REMICADE-treated group vs. 18% of patients in the placebo group (p<0.001). Improvement was observed at Week 2 and maintained through Week 24 (Figure 3 and Table 10).
Figure 3 Proportion of patients achieving ASAS 20 response
At 24 weeks, the proportions of patients achieving a 50% and a 70% improvement in the signs and symptoms of ankylosing spondylitis, as measured by ASAS response criteria (ASAS 50 and ASAS 70, respectively), were 44% and 28%, respectively, for patients receiving REMICADE, compared to 9% and 4%, respectively, for patients receiving placebo (P<0.001, REMICADE vs. placebo). A low level of disease activity (defined as a value <20 [on a scale of 0-100 mm] in each of the 4 ASAS response parameters) was achieved in 22% of REMICADE-treated patients vs. 1% in placebo-treated patients (P<0.001).
The median improvement from baseline in the general health-related quality-of-life questionnaire SF-36 physical component summary score at Week 24 was 10.2 for the REMICADE group vs. 0.8 for the placebo group (P<0.001). There was no change in the SF-36 mental component summary score in either the REMICADE group or the placebo group.
Results of this study were similar to those seen in a multicenter double-blind, placebo-controlled study of 70 patients with ankylosing spondylitis.
Treatment with REMICADE resulted in improvement in signs and symptoms, as assessed by the ACR criteria, with 58% of REMICADE-treated patients achieving ACR 20 at Week 14, compared with 11% of placebo-treated patients (P< 0.001). The response was similar regardless of concomitant use of methotrexate. Improvement was observed as early as Week 2. At 6 months, the ACR 20/50/70 responses were achieved by 54%, 41%, and 27%, respectively, of patients receiving REMICADE compared to 16%, 4%, and 2%, respectively, of patients receiving placebo. Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and spondylitis with peripheral arthritis subtypes.
Compared to placebo, treatment with REMICADE resulted in improvements in the components of the ACR response criteria, as well as in dactylitis and enthesopathy (Table 11). The clinical response was maintained through Week 54. Similar ACR responses were observed in an earlier randomized, placebo-controlled study of 104 psoriatic arthritis patients, and the responses were maintained through 98 weeks in an open-label extension phase.
Improvement in Psoriasis Area and Severity Index (PASI) in psoriatic arthritis patients with baseline body surface area (BSA) ≥3% (n=87 placebo, n=83 REMICADE) was achieved at Week 14, regardless of concomitant methotrexate use, with 64% of REMICADE-treated patients achieving at least 75% improvement from baseline vs. 2% of placebo-treated patients; improvement was observed in some patients as early as Week 2. At 6 months, the PASI 75 and PASI 90 responses were achieved by 60% and 39%, respectively, of patients receiving REMICADE compared to 1% and 0%, respectively, of patients receiving placebo. The PASI response was generally maintained through Week 54. [See also Clinical Studies (14.8)].
Structural damage in both hands and feet was assessed radiographically by the change from baseline in the van der Heijde-Sharp (vdH-S) score, modified by the addition of hand DIP joints. The total modified vdH-S score is a composite score of structural damage that measures the number and size of joint erosions and the degree of joint space narrowing (JSN) in the hands and feet. At Week 24, REMICADE-treated patients had less radiographic progression than placebo-treated patients (mean change of -0.70 vs. 0.82, P<0.001). REMICADE-treated patients also had less progression in their erosion scores (-0.56 vs 0.51) and JSN scores (-0.14 vs 0.31). The patients in the REMICADE group demonstrated continued inhibition of structural damage at Week 54. Most patients showed little or no change in the vdH-S score during this 12-month study (median change of 0 in both patients who initially received REMICADE or placebo). More patients in the placebo group (12%) had readily apparent radiographic progression compared with the REMICADE group (3%).
Physical function status was assessed using the HAQ Disability Index (HAQ-DI) and the SF-36 Health Survey. REMICADE-treated patients demonstrated significant improvement in physical function as assessed by HAQ-DI (median percent improvement in HAQ-DI score from baseline to Week 14 and 24 of 43% for REMICADE-treated patients vs 0% for placebo-treated patients).
During the placebo-controlled portion of the trial (24 weeks), 54% of REMICADE-treated patients achieved a clinically meaningful improvement in HAQ-DI (≥0.3 unit decrease) compared to 22% of placebo-treated patients. REMICADE-treated patients also demonstrated greater improvement in the SF-36 physical and mental component summary scores than placebo-treated patients. The responses were maintained for up to 2 years in an open-label extension study.
Study I (EXPRESS) evaluated 378 patients who received placebo or REMICADE at a dose of
Study II (EXPRESS II) evaluated 835 patients who received placebo or REMICADE at doses of
Study III (SPIRIT) evaluated 249 patients who had previously received either psoralen plus ultraviolet A treatment (PUVA) or other systemic therapy for their psoriasis. These patients were randomized to receive either placebo or REMICADE at doses of 3 mg/kg or 5 mg/kg at Weeks 0, 2, and 6. At Week 26, patients with a sPGA score of moderate or worse (greater than or equal to 3 on a scale of 0 to 5) received an additional dose of the randomized treatment. Across all treatment groups, the median baseline PASI score was 19, and the baseline sPGA score ranged from moderate (62% of patients) to marked (22%) to severe (3%). In addition, 75% of patients had a BSA >20%. Of the enrolled patients, 114 (46%) received the Week 26 additional dose.
In Studies I, II and III, the primary endpoint was the proportion of patients who achieved a reduction in score of at least 75% from baseline at Week 10 by the PASI (PASI 75). In Study I and Study III, another evaluated outcome included the proportion of patients who achieved a score of “cleared” or “minimal” by the sPGA. The sPGA is a 6-category scale ranging from
Study II also evaluated the proportion of patients who achieved a score of “clear” or “excellent” by the relative Physician’s Global Assessment (rPGA). The rPGA is a 6-category scale ranging from “6 = worse” to “1 = clear” that was assessed relative to baseline. Overall lesions were graded with consideration to the percent of body involvement as well as overall induration, scaling, and erythema. Treatment success, defined as “clear” or “excellent,” consisted of some residual pinkness or pigmentation to marked improvement (nearly normal skin texture; some erythema may be present). The results of these studies are presented in Table 12.
In Study I, in the subgroup of patients with more extensive psoriasis who had previously received phototherapy, 85% of patients on 5 mg/kg REMICADE achieved a PASI 75 at Week 10 compared with 4% of patients on placebo.
In Study II, in the subgroup of patients with more extensive psoriasis who had previously received phototherapy, 72% and 77% of patients on 3 mg/kg and 5 mg/kg REMICADE achieved a PASI 75 at Week 10 respectively compared with 1% on placebo. In Study II, among patients with more extensive psoriasis who had failed or were intolerant to phototherapy, 70% and 78% of patients on 3 mg/kg and 5 mg/kg REMICADE achieved a PASI 75 at Week 10 respectively, compared with 2% on placebo.
Maintenance of response was studied in a subset of 292 and 297 REMICADE-treated patients in the 3 mg/kg and 5 mg/kg groups; respectively, in Study II. Stratified by PASI response at Week 10 and investigational site, patients in the active treatment groups were re-randomized to either a scheduled or as needed maintenance (PRN) therapy, beginning on Week 14.
The groups that received a maintenance dose every 8 weeks appear to have a greater percentage of patients maintaining a PASI 75 through week 50 as compared to patients who received the as-needed or PRN doses, and the best response was maintained with the 5 mg/kg every 8-week dose. These results are shown in Figure 4. At Week 46, when REMICADE serum concentrations were at trough level, in the every 8-week dose group, 54% of patients in the 5 mg/kg group compared to 36% in the 3 mg/kg group achieved PASI 75. The lower percentage of PASI 75 responders in the 3 mg/kg every 8-week dose group compared to the
Figure 4 Proportion of patients achieving ≥ 75% improvement in PASI from baseline through Week 50; patients randomized at Week 14
Efficacy and safety of REMICADE treatment beyond 50 weeks have not been evaluated in patients with plaque psoriasis.
- American Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med 2000;161:S221-S247.
- See latest Centers for Disease Control guidelines and recommendations for tuberculosis testing in immunocompromised patients.
- van der Heijde DM, van Leeuwen MA, van Riel PL, et al. Biannual radiographic assessments of hands and feet in a three-year prospective follow-up of patients with early rheumatoid arthritis. Arthritis Rheum. 1992;35(1):26-34.
- van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27(4):361-368.
- Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med. 1987;317(26):1625-1629.
- Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: A prospective multicenter study. Gastroenterology. 2007;133:423–432.
Each REMICADE 20 mL vial is individually packaged in a carton. REMICADE is supplied in an accumulator carton containing 10 vials.
NDC 57894-030-01 100 mg vial
Each single dose vial contains 100 mg of infliximab for final reconstitution volume of 10 mL.
Storage and Stability
REMICADE must be refrigerated at 2ºC to 8ºC (36ºF to 46ºF). Do not use REMICADE beyond the expiration date (Exp) located on the carton and the vial. This product contains no preservative.
See FDA-Approved Patient Labeling (Medication Guide)
Patients or their caregivers should be advised of the potential benefits and risks of REMICADE. Physicians should instruct their patients to read the Medication Guide before starting REMICADE therapy and to reread it each time they receive an infusion. It is important that the patient's overall health be assessed at each treatment visit and that any questions resulting from the patient's or their caregiver's reading of the Medication Guide be discussed.
Janssen Biotech, Inc.
Horsham, PA 19044
U.S. License No. 1864
©Janssen Biotech, Inc. 2013
Read the Medication Guide that comes with REMICADE before you receive the first treatment, and before each time you get a treatment of REMICADE. This Medication Guide does not take the place of talking with your doctor about your medical condition or treatment.
What is the most important information I should know about REMICADE?
REMICADE may cause serious side effects, including:
1.Risk of infection
REMICADE is a medicine that affects your immune system. REMICADE can lower the ability of your immune system to fight infections. Serious infections have happened in patients receiving REMICADE. These infections include tuberculosis (TB) and infections caused by viruses, fungi or bacteria that have spread throughout the body. Some patients have died from these infections.
- Your doctor should test you for TB before starting REMICADE.
- Your doctor should monitor you closely for signs and symptoms of TB during treatment with REMICADE.
Before starting REMICADE, tell your doctor if you:
- think you have an infection. You should not start taking REMICADE if you have any kind of infection.
- are being treated for an infection
- have signs of an infection, such as a fever, cough, flu-like symptoms
- have any open cuts or sores on your body
- get a lot of infections or have infections that keep coming back
- have diabetes or an immune system problem. People with these conditions have a higher chance for infections.
- Have TB, or have been in close contact with someone with TB
- live or have lived in certain parts of the country (such as the Ohio and Mississippi River valleys) where there is an increased risk for getting certain kinds of fungal infections (histoplasmosis, coccidioidomycosis, or blastomycosis). These infections may develop or become more severe if you take REMICADE. If you do not know if you have lived in an area where histoplasmosis, coccidioidomycosis, or blastomycosis is common, ask your doctor.
- have or have had hepatitis B
- use the medicines KINERET (anakinra), ORENCIA (abatacept), ACTEMRA (tocilizumab), or other medicines called biologics used to treat the same conditions as REMICADE.
After starting REMICADE, if you have an infection, any sign of an infection including a fever, cough, flu-like symptoms, or have open cuts or sores on your body, call your doctor right away. REMICADE can make you more likely to get infections or make any infection that you have worse.
2.Risk of Cancer
- There have been cases of unusual cancers in children and teenage patients using TNF-blocking agents.
- For children and adults taking TNF-blocker medicines, including REMICADE, the chances of getting lymphoma or other cancers may increase.
- Some patients with Crohn's disease or ulcerative colitis have developed Hepatosplenic T-cell Lymphoma, a rare type of cancer. Most of the patients were teenage or young adult males. This type of cancer results in death. All of these patients had received medicines known as azathioprine or 6-mercaptopurine together with REMICADE.
- People who have been treated for rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis for a long time may be more likely to develop lymphoma. This is especially true for people with very active disease.
- Some people treated with REMICADE have developed certain kinds of skin cancer. If any changes in the appearance of your skin or growths on your skin occur during or after your treatment with REMICADE, tell your doctor.
- Patients with COPD (a specific type of lung disease) may have an increased risk for getting cancer while being treated with REMICADE.
- Tell your doctor if you have ever had any type of cancer. Discuss with your doctor any need to adjust medicines you may be taking.
See the section "What are the possible side effects of REMICADE?" below for more information.
What is REMICADE?
REMICADE is a prescription medicine that is approved for patients with:
- Rheumatoid Arthritis - adults with moderately to severely active rheumatoid arthritis, along with the medicine methotrexate
- Crohn's Disease - children 6 years and older and adults with Crohn's disease who have not responded well to other medicines
- Ankylosing Spondylitis
- Psoriatic Arthritis
- Plaque Psoriasis - adult patients with plaque psoriasis that is chronic (doesn't go away) severe, extensive, and/or disabling.
- Ulcerative Colitis - children 6 years and older and adults with moderately to severely active ulcerative colitis who have not responded well to other medicines.
REMICADE blocks the action of a protein in your body called tumor necrosis factor-alpha (TNF-alpha). TNF-alpha is made by your body's immune system. People with certain diseases have too much TNF-alpha that can cause the immune system to attack normal healthy parts of the body. REMICADE can block the damage caused by too much TNF-alpha.
Who should not receive REMICADE?
You should not receive REMICADE if you have:
- heart failure, unless your doctor has examined you and decided that you are able to take REMICADE. Talk to your doctor about your heart failure.
- had an allergic reaction to REMICADE, or any of the other ingredients in REMICADE. See the end of this Medication Guide for a complete list of ingredients in REMICADE.
What should I tell my doctor before starting treatment with REMICADE?
Your doctor will assess your health before each treatment.
Tell your doctor about all of your medical conditions, including if you:
- have an infection (see "What is the most important information I should know about REMICADE?").
- have other liver problems including liver failure.
- have heart failure or other heart conditions. If you have heart failure, it may get worse while you take REMICADE.
- have or have had any type of cancer.
- have had phototherapy (treatment with ultraviolet light or sunlight along with a medicine to make your skin sensitive to light) for psoriasis. You may have a higher chance of getting skin cancer while receiving REMICADE.
- have COPD (Chronic Obstructive Pulmonary Disease), a specific type of lung disease. Patients with COPD may have an increased risk of getting cancer while taking REMICADE.
have or have had a condition that affects your nervous system such as
- multiple sclerosis, or Guillain-Barré syndrome, or
- if you experience any numbness or tingling, or
- if you have had a seizure.
- have recently received or are scheduled to receive a vaccine. Adults and children taking REMICADE should not receive live vaccines or treatment with a weakened bacteria (such as BCG for bladder cancer). Children should have all of their vaccines brought up to date before starting treatment with REMICADE.
- are pregnant or planning to become pregnant. It is not known if REMICADE harms your unborn baby. REMICADE should be given to a pregnant woman only if clearly needed. Talk to your doctor about stopping REMICADE if you are pregnant or planning to become pregnant.
- are breast-feeding or planning to breast-feed. It is not known whether REMICADE passes into your breast milk. Talk to your doctor about the best way to feed your baby while taking REMICADE. You should not breast-feed while taking REMICADE.
- If you have a baby and you were using REMICADE during your pregnancy, it is important to tell your baby's doctor and other health care professionals about your REMICADE use so they can decide when your baby should receives any vaccine. Certain vaccinations may cause infections.
- If you received REMICADE while you were pregnant, your baby may be at higher risk for getting an infection for at least six months after the last dose of REMICADE you received during your pregnancy.
How should I receive REMICADE?
- You will be given REMICADE through a needle placed in a vein (IV or intravenous infusion) in your arm.
- Your doctor may decide to give you medicine before starting the REMICADE infusion to prevent or lessen side effects.
- Only a healthcare professional should prepare the medicine and administer it to you.
- REMICADE will be given to you over a period of about 2 hours.
- If you have side effects from REMICADE, the infusion may need to be adjusted or stopped. In addition, your healthcare professional may decide to treat your symptoms.
- A healthcare professional will monitor you during the REMICADE infusion and for a period of time afterward for side effects. Your doctor may do certain tests while you are taking REMICADE to monitor you for side effects and to see how well you respond to the treatment.
- Your doctor will determine the right dose of REMICADE for you and how often you should receive it. Make sure to discuss with your doctor when you will receive infusions and to come in for all your infusions and follow-up appointments.
What should I avoid while receiving REMICADE?
Do not take REMICADE together with medications such as KINERET (anakinra), ORENCIA (abatacept), ACTEMRA (tocilizumab), or other medicines called biologics that are used to treat the same conditions as REMICADE.
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. These include any other medicines to treat Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis or psoriasis.
Know the medicines you take. Keep a list of your medicines and show them to your doctor and pharmacist when you get a new medicine.
What are the possible side effects of REMICADE?
REMICADE can cause serious side effects, including:
See "What is the most important information I should know about REMICADE?".
- Some patients, especially those 65 years and older have had serious infections while receiving REMICADE. These serious infections include TB and infections caused by viruses, fungi, or bacteria that have spread throughout the body. Some patients die from these infections. If you get an infection while receiving treatment with REMICADE your doctor will treat your infection and may need to stop your REMICADE treatment.
Tell your doctor right away if you have any of the following signs of an infection while taking or after taking REMICADE:
- a fever
- feel very tired
- have a cough
- have flu-like symptoms
- warm, red, or painful skin
- Your doctor will examine you for TB and perform a test to see if you have TB. If your doctor feels that you are at risk for TB, you may be treated with medicine for TB before you begin treatment with REMICADE and during treatment with REMICADE.
- Even if your TB test is negative, your doctor should carefully monitor you for TB infections while you are taking REMICADE. Patients who had a negative TB skin test before receiving REMICADE have developed active TB.
If you are a chronic carrier of the hepatitis B virus, the virus can become active while you are being treated with REMICADE. In some cases, patients have died as a result of hepatitis B virus being reactivated. Your doctor should do a blood test for hepatitis B virus before you start treatment with REMICADE and occasionally while you are being treated. Tell your doctor if you have any of the following symptoms:
- feel unwell
- poor appetite
- tiredness (fatigue)
- fever, skin rash and/or joint pain
If you have a heart problem called congestive heart failure, your doctor should check you closely while you are taking REMICADE. Your congestive heart failure may get worse while you are taking REMICADE. Be sure to tell your doctor of any new or worse symptoms including:
- shortness of breath
- swelling of ankles or feet
- sudden weight gain
Treatment with REMICADE may need to be stopped if you get new or worse congestive heart failure.
In rare cases, some patients taking REMICADE have developed serious liver problems. Tell your doctor if you have
- jaundice (skin and eyes turning yellow)
- dark brown-colored urine
- pain on the right side of your stomach area (right-sided abdominal pain)
- extreme tiredness (severe fatigue)
In some patients taking REMICADE, the body may not make enough of the blood cells that help fight infections or help stop bleeding. Tell your doctor if you
- have a fever that does not go away
- bruise or bleed very easily
- look very pale
Nervous System Disorders
In rare cases, patients taking REMICADE have developed problems with their nervous system. Tell your doctor if you have
- changes in your vision
- weakness in your arms and/or legs
- numbness or tingling in any part of your body
Some patients have had allergic reactions to REMICADE. Some of these reactions were severe. These reactions can happen while you are getting your REMICADE treatment or shortly afterward. Your doctor may need to stop or pause your treatment with REMICADE and may give you medicines to treat the allergic reaction. Signs of an allergic reaction can include:
- hives (red, raised, itchy patches of skin)
- difficulty breathing
- chest pain
- high or low blood pressure
Some patients treated with REMICADE have had delayed allergic reactions. The delayed reactions occurred 3 to 12 days after receiving treatment with REMICADE. Tell your doctor right away if you have any of these signs of delayed allergic reaction to REMICADE:
- sore throat
- muscle or joint pain
- swelling of the face and hands
- difficulty swallowing
Some patients have developed symptoms that are like the symptoms of Lupus. If you develop any of the following symptoms, your doctor may decide to stop your treatment with REMICADE.
- chest discomfort or pain that does not go away
- shortness of breath
- joint pain
- rash on the cheeks or arms that gets worse in the sun
Some people using REMICADE had new psoriasis or worsening of psoriasis they already had. Tell your doctor if you develop red scaly patches or raised bumps on the skin that are filled with pus. Your doctor may decide to stop your treatment with REMICADE.
The most common side effects of REMICADE include:
- respiratory infections, such as sinus infections and sore throat
- stomach pain
Infusion reactions can happen up to 2 hours after your infusion of REMICADE. Symptoms of infusion reactions may include:
- chest pain
- low blood pressure or high blood pressure
- shortness of breath
Children who took REMICADE in studies for Crohn's disease showed some differences in side effects compared with adults who took REMICADE for Crohn's disease. The side effects that happened more in children were: anemia (low red blood cells), leukopenia (low white blood cells), flushing (redness or blushing), viral infections, neutropenia (low neutrophils, the white blood cells that fight infection), bone fracture, bacterial infection and allergic reactions of the breathing tract. Among patients who took REMICADE for ulcerative colitis in clinical studies, more children had infections as compared with adults.
Tell your doctor about any side effect that bothers you or does not go away.
These are not all of the side effects with REMICADE. Ask your doctor or pharmacist for more information.
General information about REMICADE
Medicines are sometimes prescribed for purposes that are not mentioned in Medication Guides or patient information sheets. Do not use REMICADE for a condition for which it was not prescribed.
This information sheet summarizes the most important information about REMICADE. You can ask your doctor or pharmacist for information about REMICADE that is written for health professionals.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
For more information go to www.remicade.com , or call 1-800-JANSSEN (1-800-526-7736).
What are the ingredients in REMICADE?
The active ingredient is Infliximab.
The inactive ingredients in REMICADE include: sucrose, polysorbate 80, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate dihydrate. No preservatives are present.