RISK OF INFECTIONS
(See Boxed WARNINGS)
Serious infections, including sepsis and pneumonia, have been reported in patients receiving TNF-blocking agents. Some of these infections have been fatal. Although some of the serious infections in patients treated with REMICADE have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infections, some patients who were hospitalized or had a fatal outcome from infection were treated with REMICADE alone.
REMICADE should not be given to patients with a clinically important, active infection. Caution should be exercised when considering the use of REMICADE in patients with a chronic infection or a history of recurrent infection. Patients should be monitored for signs and symptoms of infection while on or after treatment with REMICADE. New infections should be closely monitored. If a patient develops a serious infection, REMICADE therapy should be discontinued (see ADVERSE REACTIONS: Infections).
Cases of tuberculosis, histoplasmosis, coccidioidomycosis, listeriosis, pneumocystosis, other bacterial, mycobacterial and fungal infections have been observed in patients receiving REMICADE. Patients should be evaluated for tuberculosis risk factors and be tested for latent tuberculosis infection. Treatment of latent tuberculosis infections should be initiated prior to therapy with REMICADE. When tuberculin skin testing is performed for latent tuberculosis infection an induration size of 5 mm or greater should be considered positive, even if vaccinated previously with Bacille Calmette-Guerin (BCG).
Patients receiving REMICADE should be monitored closely for signs and symptoms of active tuberculosis, particularly since tests for latent tuberculosis infection may be falsely negative. The possibility of undetected latent tuberculosis should be considered, especially in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or had close contact with a person with active tuberculosis. All patients treated with REMICADE should have a thorough history taken prior to initiating therapy. Some patients who have previously received treatment for latent or active tuberculosis have developed active tuberculosis while being treated with REMICADE. Anti-tuberculosis therapy should 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. Anti-tuberculosis therapy prior to initiating REMICADE should also be considered in patients who have several or highly significant risk factors for tuberculosis infection 14 and have a negative test for latent tuberculosis. The decision to initiate anti-tuberculosis therapy in these patients should only be made following consultation with a physician with expertise in the treatment of tuberculosis and taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy.
For patients who have resided in regions where histoplasmosis or coccidioidomycosis is endemic, the benefits and risks of REMICADE treatment should be carefully considered before initiation of REMICADE therapy.
Serious infections were seen in clinical studies with concurrent use of anakinra and another TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse events seen with combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of REMICADE and anakinra is not recommended.
HEPATOSPLENIC T-CELL LYMPHOMAS
(See Boxed WARNINGS)
Rare postmarketing cases of hepatosplenic T-cell lymphomas have been reported in adolescent and young adult patients with Crohn's disease treated with REMICADE. All of these reports have occurred in patients on concomitant treatment with azathioprine or 6-mercaptopurine. The clinical course of this disease is very aggressive with a fatal outcome in most patients within 2 years of diagnosis. 15 The causal relationship of hepatosplenic T-cell lymphoma to REMICADE therapy remains unclear.
Hepatitis B Virus Reactivation
Use of TNF blockers, including REMICADE has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers, including REMICADE, for patients identified as carriers of HBV. 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 two weeks to more than a 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) develops, 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, Hepatotoxicity).
Patients with Heart Failure
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 and ADVERSE REACTIONS, Patients with Heart Failure.)
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 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 (see also CONTRAINDICATIONS). 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: Infusion-related Reactions).
REMICADE and other agents that inhibit TNF have been associated in rare cases with optic neuritis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis, and CNS manifestation of systemic vasculitis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of REMICADE in patients with pre-existing or recent onset of demyelinating or seizure disorders. Discontinuation of REMICADE should be considered in patients who develop significant central nervous system adverse reactions.
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 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 3-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 4-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.
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, Malignancies). 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: Adverse Reactions in Psoriasis Studies).
The potential role of TNF-blocking therapy in the development of malignancies is not known (see ADVERSE REACTIONS, Malignancies). 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.
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, Autoantibodies/Lupus-like Syndrome).
No data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines in patients receiving anti-TNF therapy. It is recommended that live vaccines not be given concurrently.
It is recommended that all pediatric Crohn's disease patients be brought up to date with all vaccinations prior to initiating REMICADE therapy. The interval between vaccination and initiation of REMICADE therapy should be in accordance with current vaccination guidelines.
Information for Patients
Patients developing signs and symptoms of infection should seek medical evaluation immediately.
Patients or their caregivers should be provided the REMICADE Medication Guide and provided an opportunity to read it and ask questions prior to each treatment infusion session. Because caution should be exercised in administering REMICADE to patients with clinically important active infections, it is important that the patient's overall health be assessed at each treatment visit and any questions resulting from the patient's or caregiver's reading of the Medication Guide be discussed.
Concurrent administration of etanercept (another TNFα-blocking agent) and anakinra (an interleukin-1 receptor antagonist) has been associated with an increased risk of serious infections, and increased risk of neutropenia and no additional benefit compared to these medicinal products alone. Other TNFα-blocking agents (including REMICADE) used in combination with anakinra may also result in similar toxicities (see WARNINGS, RISK OF INFECTIONS).
Specific drug interaction studies, including interactions with MTX, have not been conducted. The majority of patients in rheumatoid arthritis or Crohn's disease clinical studies received one or more concomitant medications. In rheumatoid arthritis, concomitant medications besides MTX were nonsteroidal anti-inflammatory agents, folic acid, corticosteroids and/or narcotics. Concomitant Crohn's disease medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA and aminosalicylates. In psoriatic arthritis clinical trials, concomitant medications included MTX in approximately half of the patients as well as nonsteroidal anti-inflammatory agents, folic acid and corticosteroids.
Patients with Crohn's disease who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants (see ADVERSE REACTIONS, Immunogenicity and Infusion-related Reactions). Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of Crohn's disease including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates.
Carcinogenesis, Mutagenesis and Impairment of Fertility
A repeat dose toxicity study was conducted with mice given cV1q anti-mouse TNFα to evaluate tumorigenicity. CV1q is an analogous antibody that inhibits the function of TNFα in mice. Animals were assigned to 1 of 3 dose groups: control, 10 mg/kg or 40 mg/kg cV1q given weekly for 6 months. The weekly doses of 10 mg/kg and 40 mg/kg are 2 and 8 times, respectively, the human dose of 5 mg/kg for Crohn's disease. Results indicated that cV1q did not cause tumorigenicity in mice. No clastogenic or mutagenic effects of infliximab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. Chromosomal aberrations were not observed in an assay performed using human lymphocytes. The significance of these findings for human risk is unknown. It is not known whether infliximab can impair fertility in humans. No impairment of fertility was observed in a fertility and general reproduction toxicity study with the analogous mouse antibody used in the 6-month chronic toxicity study.
Pregnancy Category B
Since infliximab does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with REMICADE. No evidence of maternal toxicity, embryotoxicity or teratogenicity was observed in a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα. Doses of 10 to 15 mg/kg in pharmacodynamic animal models with the anti-TNF analogous antibody produced maximal pharmacologic effectiveness. Doses up to 40 mg/kg were shown to produce no adverse effects in animal reproduction studies. It is not known whether REMICADE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. REMICADE should be given to a pregnant woman only if clearly needed.
It is not known whether REMICADE is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from REMICADE, women should not breast-feed their infants while taking REMICADE. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
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, INDICATIONS AND USAGE, PRECAUTIONS-Vaccinations, DOSAGE AND ADMINISTRATION, CLINICAL STUDIES-Active Crohn's Disease in Pediatric Patients and ADVERSE REACTIONS - Adverse Reactions in Pediatric Crohn's Disease).
REMICADE has not been studied in children with Crohn's disease < 6 years of age. The longer term (greater than one year) safety and effectiveness of REMICADE in pediatric Crohn's disease patients have not been established in clinical trials.
Safety and effectiveness of REMICADE in pediatric patients with ulcerative colitis and plaque psoriasis have not been established.
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 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, Pharmacokinetics).
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, one 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.
In rheumatoid arthritis and plaque psoriasis clinical trials, no overall differences were observed in effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis, aged 65 or older who received REMICADE, compared to younger patients although the incidence of serious adverse events in patients aged 65 or older was higher in both REMICADE and control groups compared to younger patients. In Crohn's disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis studies, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly (see ADVERSE REACTIONS, Infections).