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The three SIMPONI I.V. RA, PsA and AS trials included 539 control-treated patients and 740 SIMPONI I.V.-treated patients.
Through Week 54 of the UC trials, 16% of patients who received SIMPONI reported one or more serious adverse events (SAEs). The most common SAEs were ulcerative colitis (7.6%), anaemia (0.6%) and appendicitis (0.3%). The proportion of subjects with SAEs was higher in the SIMPONI 100 mg maintenance group compared with golimumab 50 mg maintenance group and placebo groups (16% vs. 8% and 8%, respectively).
Upper respiratory tract infection and nasopharyngitis were the most common adverse reactions reported in the combined Phase 3 SC RA, PsA and AS trials through Week 16, occurring in 7% and 6% of SIMPONI-treated patients as compared with 6% and 5% of control-treated patients, respectively. Nasopharyngitis was the most common adverse reaction reported in the controlled Phase 2/3 UC trials through Week 6 occurring in 2.5% of SIMPONI-treated patients as compared with 2.9% of control-treated patients.
In the Phase 3 trial in nr-Ax SpA, no new ADRs were identified and the frequency/incidence of ADRs was comparable to that observed in patients with RA, PsA, AS and UC.
Clinical Trial Adverse Drug Reactions: Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
RA, AS and PsA: Table 22 summarizes the adverse drug reactions that occurred at a rate equal to or higher than 1% in SIMPONI groups and at a frequency higher than the placebo group during the placebo-controlled period of the Phase 3 SIMPONI studies in RA, AS and PsA, respectively. (See Table 22.)
Click on icon to see table/diagram/imageUlcerative Colitis (UC): Table 23 summarizes the adverse drug reactions that occurred at a rate equal to or higher than 1% in SIMPONI groups and at a frequency higher than the placebo group during the placebo-controlled period of the Phase 3 studies in UC. (See Table 23.)
Click on icon to see table/diagram/imageOther Clinical Trial Adverse Drug Reactions: Adverse drug reactions that do not appear in Tables 22 and 23 and that occurred ≥1% in golimumab-treated patients beyond the placebo control period included the following events listed as follows: Blood and lymphatic system disorders: leukopenia (including neutropenia).
Infections and Infestations: lower respiratory tract infection (pneumonia).
Deaths: During the placebo-controlled Phase 2 and Phase 3 SIMPONI trials in RA, PsA, AS and severe, persistent asthma, there was 1 (0.13%) death among 753 patients in the placebo group and 5 deaths (0.25%) among 2,024 patients in the combined SIMPONI group. The most common cause of death among SIMPONI-treated patients (2/5, 40%) was sepsis. In the controlled and uncontrolled Phase 2 and 3 RA, PsA and AS studies through approximately 3 years, there were 21 deaths among 2,363 patients treated with at least one dose of SIMPONI over an exposure period of 5,714 patient-years (0.37 per 100 patient-years), and one death among placebo patients over an exposure period of 344 patient-years (0.29 per 100 patient-years). The most common known cause of death among SIMPONI-treated patients through approximately 3 years (3 out of 21 patients, 14%) was lung cancer.
Among 1233 UC patients treated with at least one dose of SIMPONI over an exposure period of 1080 patient-years, 4 deaths occurred through Week 54 (0.37 per 100 patient-years). Causes of death were: sepsis (2 subjects), tuberculosis (1 subject), and congestive heart failure (1 subject). No deaths occurred among placebo patients (n=407).
Among 599 UC patients treated with at least one dose of SIMPONI during the study extension (Weeks 54 - 228), 7 deaths were reported (0.44 per 100 patient-years). The most common cause of death was cancer (colorectal (2 subjects) and gall bladder). Among 96 UC patients treated with placebo one patient died (0.95 per 100 patient-years).
Injection Site Reactions: In the controlled period of the pivotal trials, 5.1% (123/2392) of golimumab-treated patients had injection site reactions compared with 2.0% (19/969) in control-treated patients. The majority of the injection site reactions were mild and moderate and the most frequent manifestation was injection site erythema.
In the controlled and uncontrolled Phase 3 RA, PsA and AS trials through approximately 3 years, 12.4% of SIMPONI-treated patients (8.6% in the 50 mg dose group) had injection site reactions. In the controlled pivotal trials in RA, PsA, AS, severe persistent asthma, and Phase 2/3 trials in UC, no patients treated with golimumab developed anaphylactic reactions deemed to be related to golimumab.
Malignancies (see Warnings and Precautions): Lymphoma: The incidence of lymphoma in golimumab-treated patients during the pivotal trials was higher than expected in the general population. In the controlled and uncontrolled portions of these clinical trials with a median follow-up of up to 3 years, a greater incidence of lymphoma was observed in patients receiving golimumab 100 mg compared with patients receiving golimumab 50 mg. These results may be confounded by the small number of events, designs of the Phase 3 studies, and different durations of follow-up across treatment groups. The majority of lymphomas occurred in RA Study 2, which enrolled patients previously exposed to anti-TNF agents who had longer disease duration and more refractory disease. 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.
Malignancies other than lymphoma: In the controlled periods of pivotal trials, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar between the golimumab and the control group. Through approximately 4 years of follow-up, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar to the general population. The most frequently observed malignancies in SIMPONI-treated patients during the Phase 3 trials in RA, PsA, and AS were basal cell carcinoma (19/2226, 0.9%), breast cancer (11/2226, 0.5%) and lung cancer (7/2226, 0.3%).
In an exploratory clinical trial involving patients with severe persistent asthma, more patients treated with SIMPONI had malignancies compared with control patients. The significance of this finding in the asthma population is unknown.
The potential role of TNF-blocking therapy in the development of malignancies is unknown.
Demyelinating Disorders (see Precautions): In the controlled and uncontrolled periods of the pivotal trials with a median follow-up of up to 3 years, a greater incidence of demyelination was observed in patients receiving golimumab 100 mg compared with patients receiving golimumab 50 mg. These results may be confounded by the small number of events, designs of the pivotal trials, and different durations of follow-up across treatment groups.
Hepatic: In the controlled period of RA and PsA pivotal trials, mild ALT elevations (>1 and <3 x ULN) occurred in similar proportions of golimumab-treated and control patients (22.1% to 27.4% of patients); in the AS study, more golimumab-treated patients (25.6%) than control patients (3.9%) had mild ALT elevations. With a median follow-up of approximately 5 years, the incidence of mild ALT elevations was similar in SIMPONI-treated and control patients. In the AS pivotal trial, the incidence of mild ALT elevations was higher in golimumab-treated patients than in control patients. In the controlled period of UC pivotal trials of golimumab induction, mild ALT elevations (>1 and <3 x ULN) occurred in 8.0% and 6.9% of golimumab-treated and control patients, respectively. In the controlled and uncontrolled periods of the UC pivotal trials with a mean follow-up of approximately 2 years, the proportion of patients with mild ALT elevations was 24.7% in patients receiving golimumab and 13.0% in patients receiving placebo.
In the controlled period of RA and AS pivotal trials, ALT elevations ≥5 x ULN were uncommon and seen in more SIMPONI-treated patients (0.4% to 0.9%) than control patients (0.0%). This trend was not observed in the PsA population. In the controlled and uncontrolled periods of RA, PsA and AS pivotal trials with a median follow-up of 5 years, ALT elevations ≥5 x ULN were observed in 2.0% (34/1740 patients; 0.81 events per 100 patient-years) across the RA studies, 0.8% (3/394 patients; 0.91 events per 100 patient-years) for the PsA study and 1.4% (8/564 patients; 0.61 events per 100 patient-years) for the AS studies for the golimumab-treated patients. The majority of these elevations were asymptomatic.
In the controlled periods of the pivotal UC trials of golimumab induction, ALT elevations ≥5 x ULN occurred in 0.3% and 1.0% of golimumab-treated patients and placebo-treated patients, respectively. In the controlled and uncontrolled periods of the Phase 2/3 studies in UC with a mean follow-up of approximately 1 year, the incidence of ALT elevations ≥3 x ULN was 2% in patients receiving SIMPONI and 0.7% in patients receiving placebo. The incidence of ALT elevations ≥5 x ULN was 0.8% in patients receiving SIMPONI and 1.2% in patients receiving placebo.
In the controlled Phase 3 trials in RA, PsA and AS through Week 16, the proportions of patients with hepatobiliary adverse events were 0.9% (SIMPONI 50 mg), 0.7% (SIMPONI 100 mg) and 0.6% (placebo). At Week 24, the proportions of patients with hepatobiliary adverse events were 0.9% (SIMPONI 50 mg), 1.3% (SIMPONI 100 mg) and 0.6% (placebo). In controlled and uncontrolled periods of the Phase 3 studies in RA, PsA and AS through approximately 3 years, 3.5% of SIMPONI-treated patients had hepatobiliary adverse events.
Infections (see Warnings and Precautions): In the controlled period of pivotal trials, upper respiratory tract infection was the most common adverse reaction reported in 12.6% of golimumab-treated patients (incidence per patient-year: 0.61; 95% confidence interval; CI: 0.55, 0.67) as compared with 10.7% of control patients (incidence per patient-year: 0.53; 95% CI: 0.44, 0.63). In controlled and uncontrolled portions of the studies with a median follow-up of approximately 4 years, upper respiratory tract infections were observed in 46.2% (1693/3666; 0.35 events per patient-year) for golimumab-treated patients.
In the controlled period of pivotal trials, infections were observed in 22.8% of golimumab-treated patients (incidence per patient-year: 1.30; 95% CI: 1.22, 1.40) compared with 19.9% of control patients (incidence per patient-year: 1.23; 95% CI: 1.09, 1.38). In the controlled and uncontrolled portions of the studies with a median follow-up of approximately 4 years, infections were observed in 65.5% (2438/3666; 0.81 events per patient-year) for golimumab-treated patients. In the controlled Phase 2/3 trials through Week 6 of SIMPONI induction in UC, infections were observed in 11.9% of SIMPONI-treated patients compared with 11.3% of control patients. Through Week 54 of UC trials, the incidence per patient-year of infections was 39% [0.86 events (95% CI: 0.78, 0.94)] in patients receiving SIMPONI induction and 100 mg maintenance, 44% [1.0 events (95% CI: 0.85, 1.18)] in patients receiving SIMPONI induction and 50 mg maintenance, and 35% [0.95 events (95% CI: 0.78, 1.15)] in patients receiving SIMPONI induction and placebo maintenance.
Serious infections observed in golimumab-treated patients included sepsis, pneumonia, cellulitis, abscess, opportunistic infections and tuberculosis. In the controlled period of RA, PsA, and AS trials, serious infections were observed in 1.4% of golimumab-treated patients and 1.3% of control-treated patients. The incidence of serious infections per patient-year of follow-up in the controlled period of RA, PsA and AS trials was 0.07 (95% CI: 0.05, 0.11) for the golimumab 100 mg group, 0.03 (95% CI: 0.01, 0.07) for the golimumab 50 mg group, and 0.04 (95% CI: 0.02, 0.08) for the placebo group. In the controlled period of UC trials of golimumab induction, serious infections were observed in 0.8% of golimumab-treated patients compared with 1.5% of control-treated patients. In the controlled and uncontrolled portions of the pivotal trials with a median follow-up of up to 3 years, there was a greater incidence of serious infections, including opportunistic infections and TB in patients receiving golimumab 100 mg compared with patients receiving golimumab 50 mg. The incidence per patient-year of all serious infections was 0.04 (95% CI: 0.04, 0.05) in patients receiving golimumab 100 mg and 0.03 (95% CI: 0.02, 0.03) in patients receiving golimumab 50 mg. These results may be confounded by the designs of the Phase 3 studies and different durations of follow-up across treatment groups.
Through Week 54 of UC trials, the incidence per patient-year of serious infections was 3.3% [0.04 events (95% CI: 0.02, 0.06)] in patients receiving SIMPONI induction and 100 mg maintenance, 3.2% [0.05 events (95% CI: 0.02, 0.11)] in patients receiving SIMPONI induction and 50 maintenance, and 2.5% [0.06 events (95% CI: 0.02, 0.12)] in patients receiving SIMPONI induction and placebo maintenance. Infectious agents include bacterial, mycobacterial, invasive fungal, and other opportunistic infectious agents (see Warnings and Precautions). Among 1233 UC patients treated with at least one dose of SIMPONI, 4 cases of TB and 3 cases of opportunistic infections were reported through Week 54. All opportunistic infections and 3 of 4 TB occurred in patients receiving SIMPONI at the 100 mg maintenance dose. Among 599 UC patients treated with at least one dose of SIMPONI during the study extension (Weeks 54 - 228), 4 cases of TB and 3 cases of opportunistic infections were reported in patients receiving SIMPONI at the 100 mg maintenance dose.
Serious infections observed in SIMPONI-treated patients included sepsis, pneumonia, cellulitis, abscess, opportunistic infections, tuberculosis, invasive fungal infections, and hepatitis B infection. Cases of tuberculosis included pulmonary and extrapulmonary tuberculosis. The overwhelming majority of the tuberculosis cases occurred in countries with a high incidence rate of tuberculosis. No cases of tuberculosis have been reported in 1153 patients treated with SIMPONI in the United States and Canada in the Phase 2 RA and Phase 3 RA, PsA, AS and IV RA trials with 2544 patient-years of follow-up.
Immune: Autoantibodies: Use of TNF-blocking agents has been associated with the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome.
In the controlled and uncontrolled periods of the pivotal trials through 1 year of follow-up, 3.5% of golimumab-treated patients and 2.3% of control patients were newly ANA-positive (at titers of 1:160 or greater). The frequency of anti-dsDNA antibodies at 1 year of follow-up in patients anti-dsDNA negative at baseline was 1.1%.
In Phase 2/3 trials in UC through approximately 1 year of follow-up, 3.5% of patients who received SIMPONI induction and 100 mg during the maintenance portion of the UC studies, 4.8% of patients who received SIMPONI induction and 50 mg during the maintenance portion of the UC studies, and 3.5% of patients who received SIMPONI induction and placebo during the maintenance portion of the UC studies were newly ANA-positive (at titers of 1:160 or greater). The frequency of anti-dsDNA antibodies at 1 year of follow-up in patients who were anti-dsDNA negative at baseline was 3 (0.5%) in patients receiving SIMPONI induction and 100 mg during maintenance, 1 (0.7%) in patients receiving SIMPONI induction and 50 mg during maintenance and 0 (0%) in patients who received SIMPONI induction and placebo during maintenance.
Immunogenicity: Following SC administration in patients with RA, PsA or AS, antibodies to SIMPONI, nearly all neutralizing in vitro, were detected by the enzyme immunoassay (EIA) method in 5% of SIMPONI-treated patients through Week 52. Similar rates were shown across rheumatologic indications. Treatment with concomitant MTX resulted in a lower proportion of patients with antibodies to SIMPONI than patients receiving SIMPONI without MTX (approximately 3% versus 8%, respectively).
Following SC administration in patients with nr-Ax SpA, antibodies to SIMPONI, all neutralizing in vitro, were detected in 4% of SIMPONI-treated patients through Week 16 by the EIA method.
Following SC administration in UC patients, antibodies to SIMPONI were detected by the EIA method in 34 (2.7%) of SIMPONI-treated patients through Week 54. 21 (68%) of antibody-positive patients had neutralizing antibodies in vitro. The proportion of patients achieving clinical response was 22% (2/9) in antibody-positive patients compared with 51% (148/290) antibody-negative patients. Median serum golimumab concentrations were lower in antibody-positive subjects compared with levels in antibody-negative subjects. The model-predicted mean clearance (CL) value for golimumab was 24.3% higher in antibody-positive patients compared with antibody-negative patients. Treatment with concomitant immunomodulators (azathioprine, 6-mercaptopurine and MTX) resulted in a lower proportion of patients with antibodies to SIMPONI than patients receiving SIMPONI without immunomodulators (1.3% versus 3.4%, respectively).
The small number of patients positive for antibodies to golimumab detected by the EIA method limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures.
The previously mentioned data reflect the percentage of patients whose test results were considered positive for antibodies to golimumab in an EIA assay.
A drug-tolerant EIA method was subsequently developed for the detection of antibodies to golimumab. This method is approximately 16-fold more sensitive than the original EIA method with less interference from golimumab in serum. Due to the higher sensitivity and the improved drug tolerance, a higher incidence of antibodies to golimumab was expected to be detected with the drug-tolerant EIA method compared to the original EIA method.
Less Common Clinical Trial Adverse Drug Reactions (<1%): Adverse drug reactions that occurred at rates less than 1% during the SIMPONI clinical trials included the following events listed by system organ class: Blood and lymphatic disorders: thrombocytopenia, pancytopenia.
Cardiac disorders: congestive heart failure (new onset or worsening).
Infections and infestations: sepsis including septic shock, tuberculosis, histoplasmosis, coccidioidomycosis, pneumocystosis, opportunistic infections (invasive fungal infections, bacterial, atypical mycobacterial and protozoal), arthritis bacterial, pyelonephritis, bursitis infective, and hepatitis B reactivation (see Infections: Opportunistic Infections under Precautions).
Musculoskeletal and connective tissue disorders: lupus-like syndrome.
Neoplasm benign and malignant: Lymphoma, pediatric malignancy, leukemia.
Nervous system disorders: demyelinating disorders (central and peripheral).
Respiratory, thoracic and mediastinal disorders: Interstitial lung disease.
Skin and subcutaneous tissue disorders: psoriasis: new onset or worsening, palmar/plantar, and pustular, vasculitis (cutaneous).
Vascular disorders: vasculitis (systemic).
Post-Market Adverse Drug Reactions: Adverse reactions have been reported from worldwide post-marketing use of SIMPONI. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to SIMPONI exposure.
General Disorders and Administration Site Conditions: Infusion-related reaction.
Immune system disorders: serious systemic hypersensitivity reactions (including anaphylactic reaction), sarcoidosis.
Neoplasm benign and malignant: melanoma, Merkel cell carcinoma, Hepatosplenic T-cell lymphoma (HSTCL)*.
Skin and subcutaneous tissue disorders: bullous skin reactions, skin exfoliation, lichenoid reactions.
* observed with other TNF-blocking agents.
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