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Patients treated with SIMPONI ARIA 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. The concomitant use of a TNF-blocker and abatacept or anakinra was associated with a higher risk of serious infections; therefore, the concomitant use of SIMPONI ARIA and these biologic products is not recommended [see Use with Abatacept, Use with Anakinra and DRUG INTERACTIONS].
Treatment with SIMPONI ARIA 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. Consider the risks and benefits of treatment prior to initiating SIMPONI ARIA 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.
Closely monitor patients for the development of signs and symptoms of infection during and after treatment with SIMPONI ARIA. Discontinue SIMPONI ARIA if a patient develops a serious infection, an opportunistic infection, or sepsis. For patients who develop a new infection during treatment with SIMPONI ARIA, perform a prompt and complete diagnostic workup appropriate for an immunocompromised patient and initiate appropriate antimicrobial therapy and closely monitor them.
Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving TNF-blockers, including patients who have previously received treatment for latent or active tuberculosis. Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating SIMPONI ARIA and periodically during therapy.
Treatment of latent tuberculosis infection prior to therapy with TNF-blockers has been shown to reduce the risk of tuberculosis reactivation during therapy. Prior to initiating SIMPONI ARIA, assess if treatment for latent tuberculosis is needed. An induration of 5 mm or greater is a positive tuberculin skin test, even for patients previously vaccinated with Bacille Calmette-Guerin (BCG).
Consider anti-tuberculosis therapy prior to initiation of SIMPONI ARIA 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.
Cases of active tuberculosis have occurred in patients treated with the subcutaneous formulation of golimumab during and after treatment for latent tuberculosis. Monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy, patients who are on treatment for latent tuberculosis, or patients who were previously treated for tuberculosis infection.
Consider tuberculosis in the differential diagnosis in patients who develop a new infection during SIMPONI ARIA 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.
Invasive Fungal Infections
If patients develop a serious systemic illness and they reside or travel in regions where mycoses are endemic, consider invasive fungal infection in the differential diagnosis. Consider appropriate empiric antifungal therapy and take into account both the risk for severe fungal infection and the risks of antifungal therapy while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. To aid in the management of such patients, consider consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections.
Hepatitis B Virus Reactivation
The use of TNF-blockers, of which SIMPONI ARIA is a member, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic hepatitis B carriers (i.e., surface antigen positive). In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients who received concomitant immunosuppressants.
All patients should be tested for HBV infection before initiating TNF-blocker therapy. For patients who test positive for hepatitis B surface antigen, consultation with a physician with expertise in the treatment of hepatitis B is recommended before initiating TNF-blocker therapy. The risks and benefits of treatment should be considered prior to prescribing TNF-blockers, including SIMPONI ARIA, to patients who are carriers of HBV. Adequate data are not available on whether anti-viral therapy can reduce the risk of HBV reactivation in HBV carriers who are treated with TNF-blockers. 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-blockers after HBV reactivation has been controlled is not known. Therefore, prescribers should exercise caution when considering resumption of TNF-blockers in this situation and monitor patients closely.
Malignancies In Pediatric Patients
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), of which SIMPONI ARIA is a member. Approximately half the 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 postmarketing reports. Use of SIMPONI ARIA in patients under 18 years of age has not been established.
Malignancies In Adult Patients
The risks and benefits of TNF-blocker treatment including SIMPONI ARIA should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF-blocker in patients who develop a malignancy.
In the controlled portions of clinical trials of TNF-blockers including the subcutaneous formulation of golimumab more cases of lymphoma have been observed among patients receiving anti-TNF treatment compared with patients in the control groups. Patients with RA 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. 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.
Melanoma has been reported in patients treated with TNF-blocking agents, including the subcutaneous formulation of golimumab. Merkel cell carcinoma has been reported in patients treated with TNF-blocking agents. Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
In controlled trials of other TNF-blockers in patients at higher risk for malignancies (e.g., patients with COPD, patients with Wegener's granulomatosis treated with concomitant cyclophosphamide) a greater portion of malignancies occurred in the TNF-blocker group compared to the controlled group. In an exploratory clinical trial evaluating the use of the subcutaneous formulation of golimumab in patients with severe persistent asthma, more patients treated with golimumab reported malignancies compared with control patients. The significance of this finding is unknown.
During the controlled portion of the Phase 3 trial in RA for SIMPONI ARIA, the incidence of malignancies other than lymphoma and NMSC per 100-patient-years of follow-up was 0.56 (95% CI: 0.01, 3.11) in the SIMPONI ARIA group compared with an incidence of 0 (95% CI: 0.00, 3.79) in the placebo group.
Congestive Heart Failure
Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF-blockers, including SIMPONI ARIA. In several exploratory trials of other TNF-blockers in the treatment of CHF, there were greater proportions of TNF-blocker treated patients who had CHF exacerbations requiring hospitalization or increased mortality. SIMPONI ARIA has not been studied in patients with a history of CHF and SIMPONI ARIA should be used with caution in patients with CHF. If a decision is made to administer SIMPONI ARIA to RA patients with CHF, these patients should be closely monitored during therapy, and SIMPONI ARIA should be discontinued if new or worsening symptoms of CHF appear.
Use of TNF-blockers, of which SIMPONI ARIA is a member, has been associated with rare cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS) and peripheral demyelinating disorders, including Guillain-Barré syndrome. Cases of central demyelination, MS, optic neuritis, and peripheral demyelinating polyneuropathy have rarely been reported in patients treated with the subcutaneous formulation of golimumab. Prescribers should exercise caution in considering the use of TNF-blockers, including SIMPONI ARIA, in patients with central or peripheral nervous system demyelinating disorders. Discontinuation of SIMPONI ARIA should be considered if these disorders develop.
Use With Abatacept
In controlled trials, the concurrent administration of another TNF-blocker and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; and the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of TNF-blockers including SIMPONI ARIA and abatacept is not recommended [see DRUG INTERACTIONS].
Use With Anakinra
Concurrent administration of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater portion of serious infections and neutropenia and no additional benefits compared with the TNF-blocker alone. Therefore, the combination of anakinra with TNF-blockers, including SIMPONI ARIA, is not recommended [see DRUG INTERACTIONS].
Switching Between Biological Disease Modifying Antirheumatic Drugs (DMARDs)
Care should be taken when switching from one biologic product to another biologic product since overlapping biological activity may further increase the risk of infection.
There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anemia, and thrombocytopenia in patients receiving TNF-blockers. In clinical studies, cases of pancytopenia, leukopenia, neutropenia, and thrombocytopenia have also occurred in SIMPONI ARIA-treated patients. Caution should be exercised when using TNF-blockers, including SIMPONI ARIA, in patients who have or have had significant cytopenias.
Vaccinations/Therapeutic Infectious Agents
Patients treated with SIMPONI ARIA may receive vaccinations, except for live vaccines. In patients receiving anti-TNF therapy, limited data are available on the response to live vaccination, or on the secondary transmission of infection by live vaccines. Use of live vaccines could result in clinical infections, including disseminated infections.
Therapeutic Infectious Agents
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 ARIA.
In post-marketing experience, serious systemic hypersensitivity reactions (including anaphylactic reaction) have been reported following administration of the subcutaneous formulation of golimumab. Some of these reactions occurred after the first administration of golimumab. If an anaphylactic or other serious allergic reaction occurs, administration of SIMPONI ARIA should be discontinued immediately and appropriate therapy instituted.
Serious infections observed in SIMPONI ARIA-treated patients included sepsis, pneumonia, cellulitis, abscess, opportunistic infections, tuberculosis (TB), and invasive fungal infections. Cases of TB included pulmonary and extrapulmonary TB. The majority of the TB cases occurred in countries with a high incidence rate of TB. [see WARNINGS AND PRECAUTIONS]
In the controlled phase of Trial 1 through Week 24, infections were observed in 27% of SIMPONI ARIA-treated patients compared with 24% of control-treated patients, and serious infections were observed in 0.9% of SIMPONI ARIA-treated patients and 0.0% of control-treated patients. Through Week 24, the incidence of serious infections per 100 patient-years of follow-up was 2.2 (95% CI 0.61, 5.71) for the SIMPONI ARIA group, and 0 (0.00, 3.79) for the placebo group. In the controlled and uncontrolled portions of Trial 1, 958 total patient-years of follow-up with a median follow-up of approximately 92 weeks, the incidence per 100 patient-years of all serious infections was 4.07 (CI: 2.90, 5.57) in patients receiving SIMPONI ARIA [see WARNINGS AND PRECAUTIONS. In the controlled and uncontrolled portions of Trial 1, in SIMPONI ARIA treated patients, the incidence of active TB per 100 patient-years was 0.31 (95% CI: 0.06; 0.92) and the incidence of other opportunistic infections per 100 patient-years was 0.42 (95% CI: 0.11, 1.07).
One case of malignancy other than lymphoma and NMSC with SIMPONI ARIA was reported through Week 24 during the controlled phase of Trial 1. In the controlled and uncontrolled portions through approximately 92 weeks, the incidence of malignancies per 100 patient-years, other than lymphoma and NMSC, in SIMPONI ARIA-treated patients was 0.31 (CI: 0.06, 0.92) and the incidence of NMSC was 0.1 (95% CI: 0.00, 0.58).
Other Medical Conditions
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Long-term animal studies of golimumab have not been conducted to evaluate its carcinogenic potential. Mutagenicity studies have not been conducted with golimumab. A fertility study conducted in mice using an analogous anti-mouse TNFα antibody administered by the intravenous route at doses up to 40 mg/kg once per week showed no impairment of fertility.
Use In Specific Populations
Pregnancy Category B
There are no adequate and well-controlled studies of SIMPONI ARIA in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, it is not known whether SIMPONI ARIA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SIMPONI ARIA should be used during pregnancy only if clearly needed.
An embryofetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated subcutaneously with golimumab during the first trimester with doses up to 50 mg/kg twice weekly (200 times greater than the maximum recommended human dose-MHRD) and has revealed no evidence of harm to maternal animals or fetuses. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. In this study, in utero exposure to golimumab produced no developmental defects to the fetus.
A pre- and post-natal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation at doses up to 50 mg/kg twice weekly (33 times and 12 times greater than the maximal steady state human blood levels for maternal animals and neonates, respectively) and has revealed no evidence of harm to maternal animals or neonates. Golimumab was present in the neonatal serum from the time of birth and for up to six months postpartum. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants.
IgG antibodies are known to cross the placenta during pregnancy and have been detected in the serum of infants born to patients treated with these antibodies. Since SIMPONI ARIA is an IgG antibody, infants born to women treated with SIMPONI ARIA during their pregnancy may be at increased risk of infection for up to 6 months. Administration of live vaccines to infants exposed to SIMPONI ARIA in utero is not recommended for 6 months following the mother's last SIMPONI ARIA infusion during pregnancy [see WARNINGS AND PRECAUTIONS].
It is not known whether SIMPONI ARIA 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 SIMPONI ARIA, 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.
In the pre- and post-natal development study in cynomolgus monkeys in which golimumab was administered subcutaneously during pregnancy and lactation, golimumab was detected in the breast milk at concentrations that were approximately 400-fold lower than the maternal serum concentrations.
Safety and effectiveness of SIMPONI ARIA in pediatric patients less than 18 years of age have not been established. Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with other TNF-blocking agents [see WARNINGS AND PRECAUTIONS].
In Trial 1 in RA, the number of patients ages 65 or older was too small to make comparisons with younger SIMPONI ARIA-treated patients. Because there is a higher incidence of infections in the geriatric population in general, caution should be used in treating geriatric patients with SIMPONI ARIA.
Last reviewed on RxList: 2/14/2014
This monograph has been modified to include the generic and brand name in many instances.
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