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Infections: Bacterial (including sepsis and pneumonia), mycobacterial (tuberculosis), invasive fungal and opportunistic infections, including fatalities, have been reported in patients receiving TNF-blocking agents, including SIMPONI. Patients have frequently presented with disseminated rather than localized disease. Some of these serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infections.
For patients who have resided in or traveled to regions where invasive fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis are endemic, the benefits and risks of SIMPONI treatment should be carefully considered before initiation or continuation of SIMPONI therapy. In at-risk patients treated with SIMPONI, an invasive fungal infection should be suspected if they develop a serious systemic illness. 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, if feasible, 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.
SIMPONI should not be given to patients with a clinically important, active infection. Caution should be exercised when considering the use of SIMPONI in patients with a chronic infection or a history of recurrent infection. Patients should be advised of and avoid exposure to potential risk factors for infection as appropriate.
Tuberculosis: Patients should be evaluated for tuberculosis risk factors (including close contact with a person with active tuberculosis) and tested for latent tuberculosis infections prior to treatment with SIMPONI. Treatment of latent tuberculosis infections should be initiated prior to therapy with SIMPONI.
Anti-tuberculosis therapy should be considered prior to initiation of SIMPONI in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed.
Tests for latent tuberculosis may yield false negative results, especially in patients who are immunocompromised or severely ill. Prior to initiating SIMPONI, treatment for latent TB should be considered in patients who have significant risk factors for TB despite 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.
In patients receiving SIMPONI, tuberculosis has frequently presented as disseminated or extrapulmonary disease. Cases of active tuberculosis have occurred in patients treated with SIMPONI during and after treatment for latent tuberculosis. Patients receiving SIMPONI should be monitored closely for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis, patients who are on treatment for latent tuberculosis, or patients who were previously treated for tuberculosis infection.
Malignancies: 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 malignancy.
Pediatric malignancy: Postmarketing cases of malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) who received TNF-blocking agents (initiation of therapy ≤ 18 years of age) to treat Juvenile Idiopathic Arthritis (JIA), Crohn's disease or other conditions. Approximately half of the reports were lymphomas. The other cases represented a variety of different malignancies and included malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants, such as methotrexate, azathioprine or 6-mercaptopurine. The role of TNF blockers in the development of malignancies in children and adolescents remains unclear.
Lymphoma: In the controlled portions of clinical trials of all the TNF-blocking agents including SIMPONI, more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with control patients. During the SIMPONI Phase 2 and Phase 3 clinical trials in RA, PsA and AS, the incidence of lymphoma in SIMPONI-treated patients was higher than expected in the general population. Patients with rheumatoid arthritis and other chronic inflammatory diseases, particularly patients with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF-blocking therapy.
Rare postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with other TNF-blocking agents (see Adverse Reactions). This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Nearly all of these cases have occurred in patients with Crohn's disease or ulcerative colitis. The majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine (AZA) or 6-mercaptopurine (6–MP) concomitantly with a TNF-blocker at or prior to diagnosis. The potential risk with the combination of AZA or 6-MP and SIMPONI should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma in patients treated with TNF-blockers cannot be excluded.
Leukemia: Cases of acute and chronic leukemia have been reported with TNF-blocker use, including SIMPONI 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.
Malignancies other than lymphoma: In the controlled portions of the SIMPONI Phase 2 and Phase 3 clinical trials in RA, PsA, AS, and UC, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar between the SIMPONI and the control groups.
In an exploratory clinical trial evaluating the use of SIMPONI in patients with severe persistent asthma, more patients treated with SIMPONI reported malignancies compared with control patients (see Adverse Reactions). The significance of this finding is unknown.
Colon dysplasia/carcinoma: It is not known if SIMPONI treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at increased risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations. In patients with newly diagnosed dysplasia treated with SIMPONI, the risks and benefits to the individual patient must be carefully reviewed and consideration should be given to whether therapy should be continued.
Skin cancers: Melanoma and Merkel cell carcinoma have been reported in patients treated with TNF blocking agents, including SIMPONI (see Adverse Reactions). Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Hepatitis B virus reactivation: As observed with the use of other immunosuppressive drugs, the use of TNF blocking-agents, including SIMPONI, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of the virus (i.e., surface antigen positive). Patients should be tested for HBV infection before initiating treatment with immunosuppressants, including SIMPONI. 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 and monitored prior to the initiation of, during treatment with, and for several months following discontinuation of SIMPONI.
Congestive Heart Failure (CHF): Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers, including SIMPONI. Some cases had a fatal outcome. SIMPONI has not been studied in patients with CHF. SIMPONI should be used with caution in patients with heart failure. If a decision is made to administer SIMPONI to patients with heart failure, they should be closely monitored during therapy, and SIMPONI should be discontinued if new or worsening symptoms of heart failure appear.
Demyelinating disorders: Use of TNF blocking agents have been associated with cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis (MS) and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of TNF-blockers, including SIMPONI, in patients with central or peripheral nervous system demyelinating disorders. Discontinuation of SIMPONI should be considered if these disorders develop.
Autoimmune processes: Treatment with TNF blockers, including SIMPONI, may result in the formation of antinuclear antibodies (ANA) and, rarely, in the development of a lupus-like syndrome (see Adverse Reactions). If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with SIMPONI, treatment should be discontinued.
Concurrent administration of SIMPONI with anakinra: Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNF-blocking agent, etanercept, with no added clinical benefit. Because of the nature of the adverse events seen with this combination therapy, similar toxicities may also result from the combination of anakinra and other TNF-blocking agents. Therefore, the combination of SIMPONI and anakinra is not recommended.
Concurrent administration of SMPONI with abatacept: 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. Because of the nature of the adverse events seen with the combination of TNF-blocking agents and abatacept therapy, the combination of SIMPONI and abatacept is not recommended.
Concurrent administration with other biological therapeutics: There is insufficient information regarding the concomitant use of SIMPONI with other biological therapeutics used to treat the same conditions as SIMPONI. The concomitant use of SIMPONI 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.
Hematologic reactions: There have been reports of pancytopenia, leukopenia, neutropenia, agranulocytosis, and thrombocytopenia in patients receiving TNF blockers, including SIMPONI. Caution should be exercised in patients treated with SIMPONI who have a current or past history of significant cytopenias.
Live vaccines/therapeutic infectious agents: Patients treated with SIMPONI may receive concurrent vaccinations, except for live vaccines. 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.
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 SIMPONI.
Non-live vaccines: Psoriatic arthritis patients treated with SIMPONI in one Phase 3 PsA study were able to mount effective B-cell immune responses to pneumococcal polysaccharide vaccine. Similar numbers of psoriatic arthritis patients receiving SIMPONI and not receiving SIMPONI had at least a 2-fold increase in antibody titers. The proportions of patients with response to pneumococcal vaccine were lower among SIMPONI and control-treated patients receiving MTX compared with patients not receiving MTX. Overall, the data indicate that SIMPONI does not suppress the humoral immune response to this vaccine.
Allergic reactions: Latex sensitivity: The needle cover on the pre-filled syringe as well as the pre-filled syringe in the autoinjector contains dry natural rubber (a derivative of latex), which may cause allergic reactions in individuals sensitive to latex.
Hypersensitivity reactions: In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following SIMPONI administration. Some of these reactions occurred after the first administration of SIMPONI. If an anaphylactic or other serious allergic reaction occurs, administration of SIMPONI should be discontinued immediately and appropriate therapy instituted.
Special populations: Geriatric use: In the Phase 3 SC studies in RA, PsA, and AS and the Phase 3 IV studies in RA, no overall differences in AEs, SAEs, and serious infections in patients age 65 or older who received SIMPONI were observed compared with younger patients. In the Phase 3 IV Studies in AS, there were insufficient numbers of patients aged 65 years and over to determine whether they respond differently from patients aged 18 to 65 years old. In UC, 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. There were no patients aged 65 and over in the nr-Axial SpA study.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed.
