WARNINGS
RISK OF INFECTIONS
(See boxed WARNING) SERIOUS INFECTIONS, INCLUDING SEPSIS HAVE BEEN REPORTED IN PATIENTS RECEIVING TNF-BLOCKING AGENTS. SOME OF THESE INFECTIONS HAVE BEEN FATAL. MANY OF THE SERIOUS INFECTIONS IN PATIENTS TREATED WITH REMICADE HAVE OCCURRED IN PATIENTS ON CONCOMITANT IMMUNOSUPPRESSIVE THERAPY THAT, IN ADDITION TO THEIR CROHN'S DISEASE OR RHEUMATOID ARTHRITIS, COULD PREDISPOSE THEM TO INFECTIONS. 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 HISTOPLASMOSIS, COCCIDIOIDOMYCOSIS, LISTERIOSIS, PNEUMOCYSTOSIS, TUBERCULOSIS, OTHER BACTERIAL, MYCOBACTERIAL AND FUNGAL INFECTIONS HAVE BEEN OBSERVED IN PATIENTS RECEIVING REMICADE. 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 TNF(alpha)-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 TNF(alpha)-BLOCKING AGENTS. THEREFORE, THE COMBINATION OF REMICADE AND ANAKINRA IS NOT RECOMMENDED.
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.)
HEMATOLOGIC EVENTS
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. Hypersensitivity
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 Crohn's disease patients 3 to 12 days after 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 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, Infusion-related Reactions).
NEUROLOGIC EVENTS
Infliximab 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. Prescribers should exercise caution in considering the use of REMICADE in patients with pre-existing or recent onset of central nervous system demyelinating or seizure disorders. Discontinuation of REMICADE should be considered in patients who develop significant central nervous system adverse reactions.
PRECAUTIONS
AUTOIMMUNITY
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).
MALIGNANCY
Patients with long duration of Crohn's disease or rheumatoid arthritis and chronic exposure to immunosuppressant therapies are more prone to develop lymphomas (see ADVERSE REACTIONS, Malignancies/Lymphoproliferative Disease). The impact of treatment with REMICADE on these phenomena is unknown.
VACCINATIONS
No data are available on the response to vaccination 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.
INFORMATION FOR PATIENTS
Patients should be provided the REMICADE Patient Information Sheet and provided an opportunity to read it 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 reading of the Patient Information Sheet be discussed.
DRUG INTERACTIONS
Concurrent administration of etanercept (another TNF(alpha)-blocking agent) and anakinra (an interleukin-1 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 TNF(alpha)-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. 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 TNF(alpha) to evaluate tumorigenicity. CV1q is an analogous antibody that inhibits the function of TNF(alpha) 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 TNF(alpha) 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 TNF(alpha). 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.
NURSING MOTHERS
It is not known whether infliximab 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, 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.
PEDIATRIC USE
Safety and effectiveness of REMICADE in patients with juvenile rheumatoid arthritis and in pediatric patients with Crohn's disease have not been established.
GERIATRIC USE
In the ATTRACT study, no overall differences were observed in effectiveness or safety in 72 patients aged 65 or older compared to younger patients. In Crohn's disease 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).
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