Please see the Serious Warnings and Precautions Box at the beginning of Part I: Health Professional Information.
Risk of Infections
Serious infections due to bacterial (including sepsis and pneumonia), invasive fungal, viral, and other opportunistic pathogens, 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 infliximab for injection have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infections.
INFLECTRA® should not be given to patients with a clinically important active infection, including tuberculosis. Caution should be exercised when considering the use of INFLECTRA®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 INFLECTRA®. New infections should be closely monitored. If a patient develops a serious infection, INFLECTRA® therapy should be discontinued (see ADVERSE REACTIONS, Infections).
Cases of histoplasmosis, coccidioidomycosis, blastomycosis, listeriosis, pneumocystosis, and tuberculosis have been observed in patients receiving infliximab for injection. For patients who have resided in or travelled to regions where histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of INFLECTRA® treatment should be carefully considered before initiation or continuation of INFLECTRA® therapy.
Invasive Fungal Infections
In patients treated with INFLECTRA®, an invasive fungal infection such as aspergillosis, candidiasis, pneumocystosis, histoplasmosis, coccidioidomycosis or blastomycosis should be suspected if they develop a serious systemic illness. Invasive fungal infections may present as disseminated rather than localized disease, and antigen and antibody testing may be negative in some patients with active infection. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. The decision to administer empiric antifungal therapy 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.
Cases of active tuberculosis have occurred in patients treated with infliximab for injection during and after treatment for latent tuberculosis. Patients receiving INFLECTRA® should be monitored closely for signs and symptoms of active tuberculosis during and after treatment, including patients who tested negative for latent tuberculosis infection. 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 INFLECTRA® 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 infliximab for injection. Anti-tuberculosis therapy should be considered prior to initiation of INFLECTRA® 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 INFLECTRA® should also be considered in patients who have several or highly significant risk factors for tuberculosis infection 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.
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, including infliximab for injection. Patients have frequently presented with disseminated rather than localized disease.
Concurrent Administration of TNF-alpha Inhibitor and Anakinra
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 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 INFLECTRA® and anakinra is not recommended.
Concurrent Administration of INFLECTRA® with Abatacept
In clinical studies, concurrent administration of TNF-blocking agents and abatacept has been associated with an increased risk of infections including serious infections compared with TNF- blocking agents alone, without increased clinical benefit. Because of the nature of the adverse events seen with the combination of TNF-blocking agents and abatacept therapy, the combination of INFLECTRA® and abatacept is not recommended.
Concurrent Administration with other Biological Therapeutics
There is insufficient information regarding the concomitant use of INFLECTRA® with other biological therapeutics used to treat the same conditions as INFLECTRA®. The concomitant use of INFLECTRA® with these biologics is not recommended because of the possibility of an increased risk of infection.
Switching between Biological Therapeutics
When switching from one biologic to another, patients should continue to be monitored, since overlapping biological activity may further increase the risk of infection.
Carcinogenesis and Mutagenesis
Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤18 years of age), including infliximab for injection. Approximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF-blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous post-marketing reports.
Lymphomas have been observed in patients treated with TNF-blocking agents, including infliximab for injection. In clinical trials, patients treated with infliximab for injection had a higher incidence of lymphoma than the expected rate in the general population. Patients with rheumatoid arthritis and Crohn’s disease, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) for the development of lymphoma than the general population, even in the absence of TNF-blocking therapy. The role of TNF-blockers in the development of malignancy is not known.
Hepatosplenic T-cell lymphoma
Post-marketing cases of hepatosplenic T-cell lymphoma have been reported in patients treated with TNF-blockers including infliximab for injection. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Almost all patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with or immediately prior to a TNF-blocker. The vast majority of infliximab for injection cases have occurred in patients with Crohn’s disease or ulcerative colitis and most were reported in adolescent or young adult males. Cases of hepatosplenic T-cell lymphoma have also occurred in Crohn’s disease and ulcerative colitis patients receiving azathioprine or 6-mercaptopurine who were not treated with infliximab for injection. Before initiating or continuing INFLECTRA® therapy in a patient who is receiving an immunosuppressant such as azathioprine or 6-mercaptopurine, carefully assess the need for continuing the immunosuppressant therapy in light of the potential risks of concomitant treatment. The causal relationship of hepatosplenic T-cell lymphoma to infliximab for injection therapy remains unclear.
Cases of acute and chronic leukemia have been reported with post-marketing 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.
In the controlled portions of clinical trials of some TNF-blocking agents, including infliximab for injection, more malignancies (excluding lymphoma and non-melanoma skin cancer [NMSC]) have been observed in patients receiving those TNF-blockers compared with control patients (see ADVERSE REACTIONS, Malignancies/Lymphoproliferative Disease). The rate of non-lymphoma malignancies among infliximab for injection-treated patients was similar to that expected in the general population whereas the rate among control patients was lower than expected.
In an exploratory clinical trial evaluating the use of infliximab for injection in patients with moderate to severe chronic obstructive pulmonary disease (COPD), more malignancies were reported in infliximab for injection-treated patients compared with control patients. All patients had a history of heavy smoking.
A population-based retrospective cohort study using data from Swedish national health registries found an increased incidence of cervical cancer in women with rheumatoid arthritis treated with infliximab for injection compared to biologics-naïve patients or the general population, including those over 60 years of age. A causal relationship between infliximab for injection and cervical cancer cannot be excluded. Periodic screening should continue in women treated with INFLECTRA®, including those over 60 years of age.
Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF-blocker therapy, including infliximab for injection (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions). Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
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 infliximab for injection, NMSCs were more common in patients with previous phototherapy (see ADVERSE REACTIONS, Malignancies/ Lymphoproliferative Disease).
The potential role of TNF-blocking therapy in the development of malignancies is not known. Caution should be exercised when considering TNF-blocking therapy for patients with a history of malignancy or when considering continuing treatment in patients who develop a malignancy (see ADVERSE REACTIONS, Malignancies/Lymphoproliferative Disease).
Long-term studies in animals have not been performed to evaluate the carcinogenic potential. No clastogenic or mutagenic effects of infliximab for injection 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. Tumourigenicity studies in mice deficient in TNFα demonstrated no increase in tumours when challenged with known tumour initiators and/or promoters.
Doses greater than 5 mg/kg should not be administered to patients with congestive heart failure (CHF). INFLECTRA® should be used with caution in patients with mild heart failure (NYHA Class I/II). Patients should be closely monitored, and INFLECTRA® must not be continued in patients who develop new or worsening symptoms of heart failure (see CONTRAINDICATIONS and ADVERSE REACTIONS, Congestive Heart Failure).
The results of a randomized study evaluating the use of infliximab for injection in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab for injection, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg.
There have been reports of pancytopenia, leukopenia, neutropenia, and thrombocytopenia in patients receiving TNF-blockers, including infliximab for injection. Caution should be exercised in patients treated with INFLECTRA® who have a current or past history of significant cytopenias. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g. persistent fever, bruising, bleeding, pallor). Discontinuation of INFLECTRA® therapy should be considered in patients with confirmed significant hematologic abnormalities.
Cases of jaundice and non-infectious hepatitis, some with features of autoimmune hepatitis, have been observed in the post-marketing experience with infliximab for injection. Isolated cases of liver failure resulting in liver transplantation or death have occurred. A causal relationship between infliximab for injection and these events has not been established. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or ALT elevations ≥5 times the upper limit of normal develop, INFLECTRA® should be discontinued immediately, and a thorough investigation of the abnormality should be undertaken. As also observed with the use of other immunosuppressive drugs, reactivation of hepatitis B has occurred very rarely in patients receiving infliximab for injection who are chronic carriers of this virus (i.e., surface antigen positive). Patients should be tested for hepatitis B virus (HBV) infection before initiating treatment with immunosuppressants, including INFLECTRA®. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended. Chronic carriers of hepatitis B should be appropriately evaluated prior to the initiation of INFLECTRA® therapy and monitored closely during treatment and for several months following discontinuation of therapy.
To minimize the incidence of hypersensitivity reactions, including infusion reactions and serum sickness-like reactions, INFLECTRA® should be administered as regular maintenance therapy after an induction regimen at weeks 0, 2 and 6 (see DOSAGE AND ADMINISTRATION).
Infliximab for injection has been associated with hypersensitivity reactions that vary in their time of onset. Hypersensitivity reactions, which include urticaria, dyspnea, and/or bronchospasm, laryngeal edema and hypotension, have occurred during or within 2 hours of infliximab for injection infusion. However, in some cases, serum sickness-like reactions have been observed in Crohn’s disease and rheumatoid arthritis patients 3 to 12 days after infliximab for injection therapy was reinstituted following an extended period without infliximab for injection 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. INFLECTRA® 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).
During clinical trials, infliximab for injection was sometimes readministered within 14 weeks following the last infusion. After a drug free interval of 15 weeks to 2 years, the risk of delayed hypersensitivity following readministration has not been accurately determined (see ADVERSE REACTIONS, Infusion-related Reactions, Delayed Hypersensitivity/Reactions following readministration of infliximab for injection).
Infusion reactions following readministration of infliximab for injection
In a rheumatoid arthritis clinical trial where subjects were receiving low dose methotrexate and in a psoriasis clinical trial, a 3-dose induction of infliximabfor injection after a period of no treatment resulted in a higher incidence of serious and severe infusion reactions during the reinduction regimen than had been observed in rheumatoid arthritis, psoriasis and Crohn’s disease trials in which a period of no drug treatment was followed by regular maintenance therapy without reinduction. Most of these reactions occurred during the second reinduction infusion at Week 2. The serious infusion reactions included anaphylaxis, urticaria, facial edema, chills and itching. Retreatment with a reinduction regimen after a period of no treatment is not recommended (see ADVERSE REACTIONS, Infusion-related Reactions, Infusion Reactions following readministration of infliximab for injection).
The INFLECTRA patient assistance program (PfizerFlexTM) facilitates the administration of INFLECTRA®. The INFLECTRA patient assistance program (PfizerFlexTM) clinics are staffed by qualified healthcare professionals specially trained in the administration of INFLECTRA® infusions and are available across Canada. Information about the INFLECTRA patient assistance program (PfizerFlexTM) can be obtained by calling 1-855-935-3539.
Treatment with infliximab for injection may result in the formation of autoantibodies and in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with infliximab for injection, treatment should be discontinued (see ADVERSE REACTIONS, Autoantibodies/Lupus-like Syndrome).
Treatment with infliximab for injection can be associated with the development of antibodies to infliximab (see WARNINGS AND PRECAUTIONS, Hypersensitivity Reactions). Approximately 10% of patients were antibody positive. The majority of antibody positive patients had low titers.
In a Phase III study of Crohn’s disease (SONIC) in patients who were immunomodulator-naïve, antibodies occurred at Week 30 in 14% of patients receiving infliximab for injection monotherapy and in 1% of patients receiving infliximab for injection in combination with azathioprine (AZA). Through Week 50, anti-infliximab antibodies occurred in 19% and 2.5% of patients, respectively. In the 20 patients on infliximab for injection monotherapy who were positive for anti-infliximab antibodies at some point during the study through Week 50, 10 patients had an infusion reaction, one of which was serious. None of the 3 patients on infliximab for injection in combination with AZA who were positive for anti-infliximab antibodies had an infusion reaction.
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, Infusion-related Reactions) than were patients who were antibody negative. Antibody development was lower among adult rheumatoid arthritis, Crohn’s disease, and psoriatic arthritis patients receiving immunosuppressant therapies such as 6-mercaptopurine (6-MP), azathioprine (AZA), or methotrexate (MTX), although among patients with juvenile rheumatoid arthritis antibody development occurred in a high percentage of patients receiving 3 mg/kg infliximab for injection with concomitant MTX (see Adverse Reactions in Pediatric Patients, Juvenile Rheumatoid Arthritis).
With repeated dosing of infliximab for injection, serum concentrations of infliximab were higher in rheumatoid arthritis patients who received concomitant MTX. In the 2 Phase 3 studies of psoriasis (EXPRESS and EXPRESS II), infliximab for injection was administered as induction followed by maintenance and without concomitant immunosuppressive therapy. In these studies, antibodies occurred in approximately 26.5% to 35.8% of patients who received 5 mg/kg every 8 week maintenance for 1 year and at higher rates (up to 1.4-fold) with other dose regimens (3 mg/kg q8 week, 3 mg/kg dosed as needed, and 5 mg/kg dosed as needed). Despite the increase in the rate of antibody formation, the infusion reaction rates in the 2 psoriasis Phase 3 studies (EXPRESS and EXPRESS II) in patients treated with 5 mg/kg induction followed by every 8 week maintenance for 1 year (14.1% and 23.0%, respectively) and serious infusion reaction rates (<1%) were similar to those observed in other study populations. In the Phase 3 study of psoriatic arthritis (IMPACT 2), where patients received 5 mg/kg with and without MTX, antibodies to infliximab occurred in 15.4% of patients.
Immunogenicity tests are generally product-specific. Comparison of antibody rates to those from other products, or comparison of the incidence of antibodies between different tests without cross-validation is not appropriate.
It is recommended that all patients, if possible, be brought up to date with all vaccinations in agreement with current vaccination guidelines prior to initiating INFLECTRA® therapy.
Live Vaccines/Therapeutic Infectious Agents
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 can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with INFLECTRA® is not recommended.
Fatal outcome due to disseminated Bacille Calmette-Guérin (BCG) infection has been reported in an infant who received BCG vaccine after in utero exposure to infliximab for injection. At least a six month waiting period following birth is recommended before the administration of live vaccines to infants exposed in utero to infliximab for injection (see WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).
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 INFLECTRA®.
In a subset of patients from the ASPIRE study, a similar proportion of patients in each treatment group mounted an effective two-fold increase in titers to a polyvalent pneumococcal vaccine indicating that infliximab for injection did not interfere with T-cell independent humoral immune responses.
Infliximab for injection and other agents that inhibit TNF have been associated with 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 INFLECTRA® in patients with these neurological disorders, and should consider discontinuation of INFLECTRA® if these disorders develop.
Physicians should alert patients to the presence of the Patient Package Insert, provide this information to them, and ensure full understanding of the content.
There is limited safety experience of infliximab for injection in patients who have undergone surgical procedures, including arthroplasty. The long half-life of infliximab should be taken in to consideration if a surgical procedure is planned. A patient who requires surgery while on INFLECTRA® should be closely monitored for infections, and appropriate actions should be taken.
It is not known whether infliximab for injection can impair fertility in humans. No impairment of fertility was observed in a fertility and general reproduction toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNFα.
Driving and Operating Machinery
INFLECTRA® may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of INFLECTRA®.
Since infliximab for injection does not cross-react with TNFα in species other than humans and chimpanzees, animal reproduction studies have not been conducted with infliximab for injection. 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 INFLECTRA® can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. INFLECTRA® should be given to a pregnant woman only if clearly needed.
As with other IgG antibodies, infliximab crosses the placenta. Infliximab for injection has been detected in the serum of infants up to 6 months following birth. After in utero exposure to infliximab for injection, infants may be at increased risk of infection, including disseminated infection that can become fatal (see WARNINGS AND PRECAUTIONS, Live Vaccines/Therapeutic Infectious Agents and Non-Live Vaccines).
Women of childbearing potential must use adequate contraception to prevent pregnancy and continue to do so for at least 6 months after the last INFLECTRA® treatment.
It is not known whether infliximab for injection is excreted in human milk or absorbed systemically after ingestion. Because immunoglobulins are excreted in human milk, and because of the potential for adverse reactions in nursing infants from infliximab for injection, breast feeding is not recommended during treatment and for 6 months after the last dose of INFLECTRA®. 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.
Pediatrics (6-17 years of age)
INFLECTRA® is indicated for reducing signs and symptoms and for 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. INFLECTRA® is also indicated for reducing signs and symptoms, inducing and maintaining clinical remission and inducing mucosal healing in pediatric patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy (i.e., aminosalicylate and/or corticosteroid and/or an immunosuppressant). In general, the adverse events in pediatric patients with Crohn’s disease or ulcerative colitis who received infliximab for injection were similar to those seen in adult patients with Crohn’s disease or ulcerative colitis respectively. It should be noted that in REACH, all patients were required to be on a stable dose of either 6-MP, AZA, or MTX (See INDICATIONS, Pediatrics; ADVERSE REACTIONS, Adverse Reactions in Pediatric Patients, Crohn’s Disease; Adverse Reactions in Pediatric Patients, Ulcerative Colitis, DOSAGE AND ADMINISTRATION, and CLINICAL TRIALS - REFERENCE BIOLOGIC DRUG. For additional pediatric information, also see WARNINGS AND PRECAUTIONS, Immunogenicity, Live Vaccines/Therapeutic Infectious Agents and Non-Live Vaccines, and ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Special Populations).
The safety and efficacy of infliximab for injection has not been established in pediatric patients with Crohn’s disease <9 years of age or with ulcerative colitis <6 years of age. The safety and efficacy of infliximab for injection in pediatric patients with plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis have not been established.
Geriatrics (65 years of age or older)
In rheumatoid arthritis clinical trials (ATTRACT) and in plaque psoriasis studies, no overall differences were observed in the effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis, aged 65 or older compared to younger patients although the incidence of serious adverse events in patients aged 65 or older was higher in both infliximab for injection and control groups compared to younger patients. Mean duration of infliximab for injection treatment in this population (154) was approximately 50 weeks. 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 responded differently from patients aged 18 to 64. There is a greater incidence of infections in the elderly population in general. The incidence of serious infections in infliximab for injection-treated patients 65 years and older was greater than in those under 65 years of age; therefore caution should be used in treating the elderly (see ADVERSE REACTIONS, Infections).