Simponi

Each mL of SIMPONI contains 100 mg of golimumab, 0.87 mg L-histidine and L-histidine hydrochloride, 41.0 mg sorbitol, 0.15 mg polysorbate 80, and water for injection. SIMPONI is available in one strength: 50 mg of golimumab in 0.5 mL.
Each 50 mg single-use autoinjector contains 50 mg golimumab per 0.5 mL in an autoinjector.
SIMPONI is supplied as a single-use sterile solution in a Type 1 glass syringe with a fixed stainless steel needle. The syringe is contained in a single-use autoinjector. The syringe is stoppered with a coated stopper and the needle is covered with a needle shield to prevent leakage of the solution through the needle and to protect the needle during handling prior to administration. The fixed needle is a 5-bevel, 27G, half-inch stainless steel needle. The needle shields are manufactured using a dry natural rubber containing latex (see Immune: Allergic Reactions: Hypersensitivity Reactions: Latex Sensitivity under Precautions). SIMPONI does not contain preservatives.
SIMPONI (golimumab) is a human IgG1κ monoclonal antibody that exhibits multiple glycoforms with predicted molecular masses ranging from 149,802 daltons to 151,064 daltons. SIMPONI (golimumab) is produced by a recombinant cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses. Golimumab forms high affinity, stable complexes with both the soluble and transmembrane bioactive forms of human TNF, which prevents the binding of TNF to its receptors. Golimumab does not bind or neutralize human lymphotoxin. Golimumab inhibits TNF-induced activation of human endothelial cells and human diploid fibroblasts, and significantly reduces clinical symptoms and joint degradation in a human TNF transgenic mouse model of arthritis.
Summary Product Information: See Table 1.

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Pharmacology: Mechanism of Action: Golimumab is a human monoclonal antibody that forms high affinity, stable complexes with both the soluble and transmembrane bioactive forms of human TNF, which prevents the binding of TNF to its receptors. No binding to other TNF super-family ligands was observed; in particular, golimumab does not bind or neutralize human lymphotoxin. TNFα is synthesized primarily by activated monocytes, macrophages and T-cells as a transmembrane protein that self-associates to form the bioactive homotrimer and is rapidly released from the cell surface by proteolysis. The binding of TNF to either the p55 or p75 TNF receptors leads to the clustering of the receptor cytoplasmic domains and initiates signaling. TNF has been identified as a key sentinel cytokine that is produced in response to various stimuli and subsequently promotes the inflammatory response through activation of the caspase-dependent apoptosis pathway and the transcription factors nuclear factor (NF)-κB and activator protein-1 (AP-1). TNF also modulates the immune response through its role in the organization of immune cells in germinal centres. Elevated expression of TNF has been linked to chronic inflammatory diseases such as rheumatoid arthritis, as well as spondyloarthropathies such as psoriatic arthritis and ankylosing spondylitis, and is an important mediator of the articular inflammation and structural damage that are characteristic of these diseases.
Pharmacodynamics: Nonclinical: The binding of human TNF by golimumab was shown to neutralize TNF-induced cell-surface expression of the adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 by human endothelial cells. TNF-induced secretion of interleukin (IL)-6, IL-8 and granulocyte-macrophage colony stimulating factor (GM-CSF) by human endothelial cells was also inhibited by golimumab. Consistent with other human IgG1 antibodies, golimumab is capable of binding to Fc receptors and activating complement.
However, no golimumab-mediated cell lysis was seen with lipopolysaccharide (LPS)-stimulated human monocytes upon addition of complement or effector cells. In addition, no golimumab-induced apoptosis was detected with LPS-stimulated human peripheral blood mononuclear cells. The effect of golimumab in vivo was tested in a human TNF transgenic mouse model of experimental arthritis. Golimumab treatment produced a statistically significant delay in the onset of clinical symptoms compared with untreated mice, as well as a significant reduction in joint pathology.
Clinical: SIMPONI was effective in modulating select markers of inflammation and bone metabolism across indications. Improvement in C-reactive protein (CRP) levels were observed relative to placebo groups and treatment with SIMPONI resulted in significant reductions from baseline in serum levels of IL-6, ICAM-1, matrix metalloproteinase-3 (MMP-3) and vascular endothelial growth factor (VEGF) compared to control treatment. In addition, levels of TNFα were significantly reduced in RA and AS patients and levels of IL-8 were reduced in PsA patients.
These changes were observed at the first assessment (Week 4) after the initial SIMPONI administration and were generally sustained through Weeks 14 and/or 24. SIMPONI with or without methotrexate (MTX) resulted in significant changes in serum levels of select markers of bone metabolism [increases in osteocalcin and procollagen type I N-terminal propeptide (PINP) and decreases in deoxy-pyridinoline (DPD) levels] at Week 4. All of these biomarker changes are consistent with an improvement in the disease processes with reduced inflammation, increased bone growth and decreased bone resorption.
Clinical Trials: Rheumatoid Arthritis: Study demographics and trial design: The efficacy and safety of SIMPONI were evaluated in three multicentre, randomized, double-blind, placebo-controlled studies in over 1,500 patients ≥18 years of age with moderately to severely active RA diagnosed according to American College of Rheumatology (ACR) criteria for at least 3 months prior to screening (Table 2). Patients had at least 4 swollen and 4 tender joints. SIMPONI was administered subcutaneously at doses of 50 mg or 100 mg, with or without MTX, every 4 weeks. (See Table 2.)

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RA Study 1 (GO-FORWARD): Active Rheumatoid Arthritis Despite MTX: Study RA-1 (GO-FORWARD) evaluated 444 patients who had active RA despite a stable dose of at least 15 mg/week of MTX and who had not been previously treated with an anti-TNF agent. Patients were randomized to receive placebo + MTX (n=133), SIMPONI 50 mg + MTX (n=89), SIMPONI 100 mg + MTX (n=89) or SIMPONI 100 mg monotherapy + placebo (n=133). The co-primary endpoints were the percent of patients achieving ACR 20 response at Week 14 and improvement from baseline in HAQ at Week 24. Major secondary endpoints included change from baseline in van der Heijde-modified Sharp (vdH-S) score at Week 24, DAS28 (using CRP) response at Week 14, ACR 20 response at Week 24, and improvement from baseline in HAQ at Week 14. All patients receiving placebo + MTX received SIMPONI 50 mg + MTX after Week 24, but the trial remained blinded until all patients had completed 52 weeks of treatment. At Week 52, patients entered the long-term extension phase and patients receiving SIMPONI 50 mg could have the dose increased to 100 mg at the discretion of the investigator. Through Week 252, the time point for the last scheduled study agent administration, 131 (29.5%) treated subjects discontinued study agent. Efficacy data were collected and analyzed through Week 256. Through Week 252, the time point for the last scheduled study agent administration, 29 (32.6%) treated subjects initially randomized to receive golimumab 50 mg, continually received the authorized dose of golimumab 50 mg once a month.
RA Study 2 (GO-AFTER): Active Rheumatoid Arthritis, previously treated with anti-TNFα agent(s): Study RA-2 (GO-AFTER) evaluated 445 patients who were previously treated with one or more of the anti-TNF agents adalimumab, etanercept, or infliximab, without serious adverse reaction. Reasons for discontinuation of prior anti-TNF therapies included lack of efficacy (59%), intolerance (17%), and/or reasons other than safety or efficacy (39%). Patients were randomized to receive placebo (n=150), SIMPONI 50 mg (n=147), and SIMPONI 100 mg (n=148). Patients were allowed to continue concomitant DMARD therapy with MTX, sulfasalazine (SSZ), and/or hydroxychloroquine (HCQ) during the study. The use of other DMARDs including cytotoxic agents or other biologics was prohibited. The primary endpoint was the percent of patients achieving ACR 20 response at Week 14. Major secondary endpoints included ACR 50 response at Week 14, DAS28 (using CRP) response at Week 14, ACR 20 response at Week 24 and improvement from baseline in HAQ score at Week 24. Through Week 252, the time point for the last scheduled study agent administration, 276 (60.1%) treated subjects discontinued study agent. Efficacy data were collected and analyzed through Week 256. Through Week 252, the time point for the last scheduled study agent administration, 21 (14.3%) treated subjects initially randomized to receive golimumab 50 mg continually received the authorized dose of golimumab 50 mg once a month.
RA Study 3 (GO-BEFORE): Active Rheumatoid Arthritis, MTX Naïve: Study RA-3 (GO-BEFORE) evaluated 637 patients with active RA who were MTX-naïve and had not previously been treated with an anti-TNF agent. Patients were randomized to receive placebo + MTX (n=160), SIMPONI 50 mg + MTX (n=159), SIMPONI 100 mg + MTX (n=159) or SIMPONI 100 mg monotherapy + placebo (n=159). For patients receiving active MTX, MTX was administered at a dose of 10 mg/week beginning at Week 0 and increased to 20 mg/week by Week 8. The co-primary endpoints were the percent of patients achieving ACR 50 response at Week 24, and the change from baseline in vdH-S score at Week 52. Major secondary endpoints included the change from baseline in HAQ at Week 52, ACR 20 response at Week 24, the change from baseline in vdH-S score at Week 52 in subjects with abnormal CRP at baseline, and the percent of patients with abnormal CRP at baseline achieving an ACR 50 response at Week 24. At Week 52, patients entered the long-term extension phase in which patients receiving placebo + MTX who had at least 1 tender or swollen joint were switched to SIMPONI 50 mg + MTX. Patients receiving SIMPONI 50 mg could have the dose increased to 100 mg at the discretion of the investigator. Through Week 252, the time point for the last scheduled study agent administration, 215 (33.9%) treated subjects discontinued study agent.
Efficacy data were collected and analyzed through Week 256. Through Week 252, 62 (39%) treated subjects initially randomized to receive golimumab 50 mg, continually received the authorized dose of golimumab 50 mg once a month.
Study results: Reduction in Signs and Symptoms: In general, no clinically meaningful differences across efficacy measures were apparent between the SIMPONI 50 mg and 100 mg dosing regimens in each of the Phase 3 RA studies. Patients in the long-term extension may have their dose modified at the discretion of the study physician.
RA Study 1 (GO-FORWARD): Treatment with SIMPONI in patients with active RA despite MTX resulted in improvement in signs and symptoms as demonstrated by the percent of patients achieving an ACR 20 response at Week 14. A significantly greater percent of patients achieved an ACR 20 response in the SIMPONI 50 mg + MTX group than in the placebo + MTX group (p≤0.001) at Weeks 14 and 24. The percent of patients achieving ACR 50 and ACR 70 responses was also greater in the SIMPONI 50 mg + MTX group than in the placebo + MTX group at Weeks 14 and 24 (Table 3). (See Table 3.)
When ACR 20 responses over time were considered, improvement was observed at the first assessment (Week 4) after the first SIMPONI 50 mg + MTX administration, and was maintained through Week 24 (Figure 1). (See Figure 1.)

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The percentages of patients achieving a DAS28 response were 72% and 73% for patients treated with SIMPONI 50 mg + MTX at Week 14 and at Week 24, respectively, compared to 50% and 42% in those who received placebo + MTX. Remission (defined as DAS28 <2.6) was achieved by 27% of patients treated with SIMPONI 50 mg + MTX and 7% of those who received placebo + MTX at Week 24.

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Among 89 patients randomized to SIMPONI 50 mg + MTX, 70 patients were still on SIMPONI 50 mg + MTX treatment at Week 52. Among those, 64 (91%) and 43 (61%) out of 70 patients achieved DAS28 response and DAS28 remission, respectively. Forty-eight patients were still on SIMPONI 50 mg + MTX treatment at Week 104. Among those, 40 (83%), 33 (69%) and 24 (50%) out of 48 patients achieved ACR 20, 50 and 70 responses, respectively.
During the long-term extension study, of those patients initially randomized to receive SIMPONI 50 mg, 29 patients received only SIMPONI 50 mg + MTX treatment through Week 252. Among those, 26 (89.7%) showed an ACR 20 response at the last efficacy assessment (Week 256).
SIMPONI 50 mg + MTX treatment also resulted in significantly greater improvement for each ACR component compared with treatment with placebo + MTX (Table 4). (See Table 4.)

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RA Study 2 (GO-AFTER): Treatment with SIMPONI 50 mg in patients with active RA, previously treated with anti-TNF agent(s), resulted in significant improvement in signs and symptoms as demonstrated by ACR 20, 50 and 70 responses at Week 14 and 24 (Table 5).
When ACR 20 responses over time were considered, improvement was observed at the first assessment (Week 4) after the first SIMPONI 50 mg + DMARDs (MTX, SSZ and/or HCQ) administration, and was maintained through Week 24. (See Table 5.)

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During the long-term extension study, of those patients initially randomized to receive SIMPONI 50 mg, 21 patients had received only SIMPONI 50 mg treatment through Week 252. Among those, 12 (57.1%) had an ACR 20 response at the last efficacy assessment (Week 256).
Table 6 shows the percent of patients achieving an ACR 20 response by reported reason for discontinuation of one or more prior anti-TNF therapies. (See Table 6.)

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SIMPONI 50 mg treatment also resulted in significantly greater improvement for each ACR component compared with treatment with placebo. Swollen joint count for the SIMPONI 50 mg and placebo group improved by 44% and 20%, respectively at Week 14 and 33% and 1%, respectively at Week 24. Improvement in tender joint count was 34% compared with 6% at Week 14, and 29% compared with -7% at Week 24, for the SIMPONI 50 mg and placebo groups, respectively. Patients' and physicians' assessments and HAQ score were also significantly improved for SIMPONI 50 mg compared with placebo at Week 14 and 24. For SIMPONI 50 mg, there was a 37% improvement in CRP compared with 0% improvement for placebo at Week 14, and 15% compared with 0% at Week 24.
The percent of patients achieving a DAS28 (using CRP) response was significantly greater for those patients treated with SIMPONI 50 mg compared with those who received placebo at Week 14 (56% compared with 27%; p<0.001) and at Week 24 (45% compared with 21%; p<0.001).
RA Study 3 (GO-BEFORE): This study evaluated patients with active RA who were MTX naïve and had not previously been treated with an anti-TNF agent. The co-primary endpoint was the percent of patients achieving an ACR 50 response at Week 24. The percent of randomized patients achieving an ACR 50 response with SIMPONI + MTX compared to MTX plus placebo was not statistically significant (38.4 vs. 29.4%, p=0.053). The percentage of patients achieving an ACR 20 response at Week 24 (major secondary endpoint) was 62% for the SIMPONI 50 mg + MTX group compared with 49% for the placebo + MTX group.
At Week 52, 60% and 42% of patients who received SIMPONI 50 mg + MTX achieved ACR 20 and 50 responses, respectively, compared to 52% and 36% of patients who received MTX alone.
At Week 52, 15% of patients in the SIMPONI 50 mg + MTX group achieved a major clinical response, defined as maintenance of an ACR 70 response over a continuous 6-month period, compared with 7% of patients in the placebo + MTX group.
During the long-term extension study, of those patients initially randomized to receive SIMPONI 50 mg, 62 patients had received only SIMPONI 50 mg + MTX treatment through Week 252. Among those, 45 (72.6%) had an ACR 50 response at the last efficacy assessment (Week 256).
Radiographic Response: RA Study 3 (GO-BEFORE): In study GO-BEFORE, the change from baseline in the vdH-S score (a composite score of structural damage that radiographically measures the number and size of joint erosions and the degree of joint space narrowing in hands/wrists and feet) was used to assess the degree of structural damage. Key radiographic results for the SIMPONI 50 mg dose group at Week 52 are presented in Table 7. (See Table 7.)

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At Week 52, 74% of patients in the SIMPONI 50 mg + MTX group had no progression of structural damage as defined by a change from baseline in total vdH-S Score ≤0, compared to 58% in those with MTX plus placebo.
Improvement in Physical Function and Health-Related Quality of Life: RA Study 1 (GO-FORWARD): Patients treated with SIMPONI 50 mg showed significantly greater (p<0.001) improvement in the Disability Index of the Health Assessment Questionnaire (HAQ) score compared with placebo at Week 14 (mean ± SD 0.42 ± 0.50 vs. 0.16 ± 0.49) and Week 24 (mean ± SD 0.47 ± 0.55 vs. 0.13 ± 0.58). Among 89 subjects randomized to SIMPONI 50 mg + MTX, 48 were still on this treatment at Week 104. The mean (± SD) improvement in HAQ score from baseline was 0.67 ± 0.64 in patients receiving SIMPONI 50 mg + MTX. At Week 24, 47 (53.4%) patients treated with SIMPONI 50 mg + MTX had an improvement in HAQ of ≥0.3 units, compared to 43 (33.9%) of patients treated with placebo + MTX. At Week 104, 40 out of 47 (85%) SIMPONI 50 mg + MTX-treated patients maintained ≥0.3 units improvement in HAQ.
Patients treated with SIMPONI 50 mg showed significantly greater improvement (p<0.001) from baseline in SF-36 physical component summary (PCS) score compared to placebo at Week 14 (mean change ± SD 8.0 ± 7.2 vs. 2.4 ± 7.8, respectively) and at Week 24 (mean change ± SD 8.3 ± 8.3 vs. 2.5 ± 8.1). At Week 104, the mean (± SD) improvement in SF-36 PCS score from baseline was 11.0 ± 9.7 in patients treated with SIMPONI 50 mg + MTX (n=48).
Patients treated with SIMPONI 50 mg showed significantly greater improvement (p<0.001) from baseline in the FACIT-F scores compared to placebo at Week 14 (mean ± SD 7.58 ± 8.93 vs. 2.27 ± 9.24) and at Week 24 (mean ± SD 7.30 ± 8.65 vs. 2.16 ± 9.53).
RA Study 2 (GO-AFTER): The mean change from baseline in HAQ score at Week 24 was 0.23 ± 0.50 for the SIMPONI 50 mg group compared with 0.03 ± 0.50 for the placebo group (p<0.001).
The mean (± SD) change from baseline for the FACIT-F score at Week 14 was 6.02 ± 10.14 for the SIMPONI 50 mg group compared with 2.16 ± 9.74 for the placebo group (p=0.001).
Psoriatic Arthritis: Study Demographics and Trial Design: The safety and efficacy of SIMPONI were evaluated in a single PsA study (GO-REVEAL), a multicentre, randomized, double-blind, placebo-controlled (through Week 24) study assessing treatment with SIMPONI 50 mg or 100 mg administered as subcutaneous (SC) injections every 4 weeks in 405 adult patients with active PsA (Table 8). All patients randomized to placebo received SIMPONI 50 mg after Week 24, but the trial remained double-blind until all patients had completed 52 weeks of treatment. At Week 52, patients entered the long-term extension phase. Patients receiving SIMPONI 50 mg could have their dose increased to 100 mg at the discretion of the investigator. In addition, concomitant therapy with DMARDs (including MTX), corticosteroids, and NSAIDs could be added at the discretion of the investigator. Patients enrolled in this study were men and women with a diagnosis of PsA for at least 6 months with a psoriatic skin lesion of at least 2 cm in diameter and active disease with at least 3 swollen and 3 tender joints despite disease-modifying antirheumatic (DMARD) or nonsteroidal anti-inflammatory (NSAID) therapy. Patients with each subtype of psoriatic arthritis were enrolled, including polyarticular arthritis with no rheumatoid nodules (43%), asymmetric peripheral arthritis (30%), distal interphalangeal (DIP) joint arthritis (15%), spondylitis with peripheral arthritis (11%), and arthritis mutilans (1%).
Patients were randomly assigned to placebo (n=113), SIMPONI 50 mg (n=146), and SIMPONI 100 mg (n=146). The co-primary endpoints were percent of patients achieving ACR 20 response at Week 14 and change from baseline in total PsA modified vdH-S score at Week 24. Major secondary endpoints included percent of patients achieving ACR 20 response at Week 24, Psoriasis Area Severity Index (PASI) 75 response at Week 14 in a subset of patients with ≥3% Body Surface Area (BSA) psoriasis skin involvement at baseline, improvement from baseline in HAQ scores at Week 24, and change from baseline in the PCS score of the SF-36 at Week 14. Through Week 252, the time point for the last scheduled study agent administration, 126 (31.1%) randomized subjects discontinued study agent. Efficacy data were collected and analyzed through Week 256. Through Week 252, the time point for the last scheduled study agent administration, 43 (29.4%) treated subjects initially randomized to receive golimumab 50 mg, continually received the authorized dose of golimumab 50 mg once a month. (See Table 8.)

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Study results: Reduction in Signs and Symptoms: No clinically meaningful differences across efficacy measures were apparent between the SIMPONI 50 mg and 100 mg dosing regimens in the Phase 3 PsA study. By study design, patients in the long-term extension may have their dose modified at the discretion of the study physician.
Treatment with SIMPONI 50 mg resulted in significant improvement in signs and symptoms as demonstrated by percent of patients achieving ACR 20 response at Week 14 (p<0.001). Responses observed in the SIMPONI-treated groups were similar in patients receiving and not receiving concomitant MTX (Table 9). (See Table 9.)

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ACR 20 improvement was observed at the first assessment (Week 4) after the first SIMPONI administration, and was maintained through Week 24 (Figure 2). (See Figure 2.)

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The percent of patients achieving an ACR 50 response at Week 14 was 30% and 2%, and at Week 24 was 32% and 4% for the SIMPONI 50 mg and placebo groups, respectively (p<0.001). The percent of patients achieving an ACR 70 response was 12% and 1% at Week 14, and at Week 24 was 19% and 1% for the SIMPONI 50 mg and placebo groups, respectively (p<0.001). Of the 146 subjects randomized to SIMPONI 50 mg, 70 patients remained on this dose at Week 104. Of these 70 patients, 64 (91.4%), 46 (65.7%) and 31 (44.3%) patients achieved ACR 20, 50 and 70 responses, respectively. Of the 146 subjects randomized to SIMPONI 50 mg, 43 patients remained on the SIMPONI 50 mg dose through Week 252. Of these, 37 (86%) patients had an ACR 20 response at the last efficacy assessment (Week 256).
Responses observed in the SIMPONI 50 mg group were similar in patients receiving and not receiving concomitant MTX.
The percent of patients achieving Psoriatic Arthritis Response Criteria (PsARC) and DAS28 response (using CRP) was also significantly greater in the SIMPONI 50 mg group compared with placebo at Week 14 and 24 (p<0.001).
SIMPONI treatment also resulted in significantly greater improvement compared with placebo for each ACR component (p<0.001, Table 10). (See Table 10.)

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At Week 14 in patients with enthesitis at baseline, there was a significantly greater improvement from baseline in enthesitis score as measured by PsA-modified Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) with SIMPONI 50 mg compared with placebo (median 50% vs. 0%; p<0.001). Significant improvement was maintained through Week 24.
In patients with dactylitis at baseline, the improvement in dactylitis score was numerically greater in the SIMPONI 50 mg treatment group than in the placebo treatment group at both Week 14 and at Week 24 (median 76% vs. 0%, p=0.10; 100% vs. 42%, p=0.09 respectively).
Psoriasis Skin and Nail Response: Among patients with ≥3% BSA psoriasis skin involvement at baseline, a significantly greater percent of patients achieved PASI 75 response at Week 14 when treated with SIMPONI 50 mg compared with placebo. The percent of patients achieving a PASI 50 and 90 response in the SIMPONI 50 mg group at Week 14 was also greater than in placebo group (Table 11). The responses were maintained or increased through Week 24. Of the 109 subjects randomized to golimumab 50 mg and with ≥3% BSA psoriasis skin involvement at baseline, 48 patients were still on this treatment at Week 104. Of 48 patients, 33 (68.8%) achieved PASI 75 response at Week 104. (See Table 11.)

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Nail physician global assessment (PGA) and Nail Psoriasis Severity Index (NAPSI) analyses were performed on patients with fingernail involvement at baseline. Percent change from baseline in NAPSI and improvement in nail PGA were significantly greater in patients treated with SIMPONI 50 mg as compared with placebo at both Week 14 and at Week 24 (p≤0.015).
Radiographic Response: Structural damage in both hands and feet was assessed radiographically by the change from baseline in the van der Heijde-Sharp (vdH-S) score, modified for PsA by addition of hand distal interphalangeal (DIP) joints. Key radiographic results for the SIMPONI 50 mg dose at Week 24 are presented in Table 12. (See Table 12.)

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The number of patients in the individual PsA subtypes was too small to derive meaningful conclusions on the effect of SIMPONI in each of the PsA subtypes.
At Week 24, 81% (118/146) of patients in the SIMPONI 50 mg group had no progression of structural damage (as defined by a change from baseline in total vdH-S Score ≤0), compared to 66% in those receiving placebo. Of the 146 patients initially randomized to SIMPONI 50 mg, X-ray data were available for 101 and 66 patients who remained on this treatment at Weeks 52 and 104, respectively. Of these patients, 77% (78/101) and 76% (50/66) of patients showed no progression from baseline at Week 52 and Week 104, respectively.
Improvement in Physical Function and Health-Related Quality of Life: In the PsA Study, patients treated with SIMPONI 50 mg showed significantly greater (p<0.001) improvement in the HAQ score compared with placebo at Week 14 (mean ± SD 0.31 ± 0.50 vs. 0.04 ± 0.44) and Week 24 (mean ± SD 0.33 ± 0.55 vs. -0.01 ± 0.49).
At Week 24, the percent of patients who achieved clinically meaningful improvements in HAQ of ≥0.30 change from baseline was also significantly greater in those patients receiving SIMPONI 50 mg when compared with placebo (p<0.001). At Week 104, 69 of the 146 (47.3%) patients randomized to SIMPONI 50 mg were still on this dose. The mean (± SD) improvement in HAQ score from baseline in these 69 patients was 0.54 ± 0.55.
In the PsA study, patients treated with SIMPONI 50 mg showed significantly greater improvement (p<0.001) from baseline in the SF-36 physical component summary (PCS) score compared to placebo at Week 14 (mean change ± SD 6.5 ± 8.9 vs. 0.6 ± 7.7) and at Week 24 (mean change ± SD 7.4 ± 9.2 vs. 0.7 ± 8.7).
Patients treated with SIMPONI 50 mg showed significantly greater improvement from baseline (p<0.05) in SF-36 mental component summary (MCS) score compared to placebo at Week 14 (mean ± SD 2.8 ± 10.3 vs. 0.4 ± 11.4) and Week 24 (mean ± SD 3.4 ± 10.5 vs. -0.6 ± 12.1).
Ankylosing Spondylitis: Study Demographics and Trial Design: The safety and efficacy of SIMPONI were evaluated in an AS Study (GO-RAISE), a multicentre, randomized, double-blind, placebo-controlled (through Week 24) study assessing treatment with SIMPONI 50 mg or 100 mg administered as subcutaneous (SC) injections every 4 weeks in 356 adult patients with active AS (Table 13). Patients enrolled in this study were men and women who had symptoms of active disease (defined as a BASDAI ≥4 and a VAS for total back pain of ≥4, each on a scale of 0 to 10 cm) despite current or previous disease modifying antirheumatic drug (DMARD) or nonsteroidal anti-inflammatory drug (NSAID) therapy. Patients with complete ankylosis of the cervical and lumbar spine were excluded from study participation. Through Week 252, the time point for the last scheduled study agent administration, 101 (28.5%) randomized subjects discontinued study agent. Efficacy data were collected and analyzed through Week 256. Through Week 252, the time point for the last scheduled study agent administration, 68 (49.3%) treated subjects initially randomized to receive golimumab 50 mg, continually received the authorized dose of golimumab 50 mg once a month.
Patients were randomly assigned to placebo (n=78), SIMPONI 50 mg (n=138) and SIMPONI 100 mg (n=140). Placebo-controlled efficacy data were collected and analyzed through Week 24. The primary endpoint was Assessment in Ankylosing Spondylitis 20 (ASAS 20) response at Week 14. Major secondary endpoints included ASAS 20 response at Week 24, Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 14, and Bath Ankylosing Spondylitis Metrology Index (BASMI) at Week 14. (See Table 13.)

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Study results: Reduction in signs and symptoms: In general, no clinically meaningful differences across efficacy measures were apparent between the SIMPONI 50 mg and 100 mg dosing regimens in the Phase 3 AS study. During the long-term extension patients may have their dose modified at the discretion of the study physician.
At Week 14, ASAS 20/40 responses were achieved by 59% and 45% respectively, of patients receiving SIMPONI 50 mg compared with 22% and 15% respectively of patients receiving placebo (p<0.001, Table 14). Improvement in signs and symptoms as measured by ASAS 20 was observed at the first assessment (Week 4) after the first SIMPONI administration, and was maintained through Week 24 (Figure 3).
Among 68 patients who remained on the SIMPONI 50 mg dose through Week 252, 59 (86.8%) patients had an ASAS 20 response at the last efficacy assessment (Week 256). (See Figure 3 and Table 14.)

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Patients treated with SIMPONI 50 mg achieved significantly greater improvements in all ASAS 20 components compared with placebo (Table 15). (See Table 15.)

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Additional measures of efficacy such as ASAS partial remission, ASAS 5/6 response, and BASDAI 50, 70, and 90 were statistically significant at Weeks 14 and 24 for SIMPONI 50 mg compared with placebo (p<0.001).
Improvement in Physical Function: Median improvement in the Bath Ankylosing Spondylitis Functional Index (BASFI) at Week 14 was 1.4 in the SIMPONI 50 mg group, compared with worsening by 0.1 in the placebo group (p<0.001). The improvement in physical function was maintained at Week 24 in SIMPONI-treated patients.
Improvement in Range of Motion: No significant change in BASMI was observed at Weeks 14 or 24 in the SIMPONI 50 mg group compared with the placebo group. However, in the 50 mg SIMPONI group vs. placebo, significant median improvements from baseline were observed at Weeks 14 and 24 for lumbar flexion, lumbar side flexion at Week 24, and intermalleolar distance measurements at both Weeks 14 and Week 24 (p<0.05).
Improvement in Health-Related Quality of Life: In the AS study, patients treated with SIMPONI 50 mg showed significantly greater improvement from baseline (p<0.001) in SF-36 physical component summary (PCS) score compared to placebo at Week 14 (mean change ± SD 8.8 ± 9.6 vs. 3.0 ± 7.2) and was maintained through Week 24.
Improvement in Sleep: Patients treated with SIMPONI 50 mg showed significantly greater median improvement from baseline in sleep scores, as measured by the 20-point Jenkins Sleep Evaluation Questionnaire, compared with placebo at Week 14 (-3.0 vs. 0.0; p<0.001) and Week 24 (-3.0 vs. -1.0; p<0.001).
Non-radiographic Axial Spondyloarthritis: Study demographics and trial design: The safety and efficacy of SIMPONI 50 mg administered subcutaneously every 4 weeks were evaluated in a multi-center, randomized, double-blind, placebo-controlled (through Week 16) study (GO-AHEAD) in adult patients with severe active nr-Ax SpA (defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but that did not meet the modified New York criteria for AS). Subjects had a diagnosis of active Axial SpA of ≤5 years duration, and chronic back pain of ≥3 month duration. All eligible subjects were to be randomized in a 1:1 ratio to either the golimumab 50 mg treatment arm (N = 98) or the placebo treatment arm (N = 100). Subjects were stratified based on CRP level (limited to ≤60% of patients with CRP levels below the upper limit of normal at baseline) and evidence of sacroiliitis (active inflammation) on MRI (limited to ≤50% of patients with no MRI evidence of sacroiliitis at baseline). Subjects who successfully completed Part 1 (Weeks 0-16), were eligible to participate in Part 2 (Weeks 16-48) of the trial in which all patients received SIMPONI 50 mg administered subcutaneously every 4 weeks through Week 48. Efficacy assessments were performed through Week 52 and safety follow-up through Week 60. Approximately 93% (176/189) of patients who were receiving SIMPONI at the beginning of the open-label extension (Week 16) remained on treatment through the end of the study (Week 52).
Patients enrolled in this study had active disease, defined as a BASDAI ≥4 cm and a VAS for total back pain of ≥4 cm, each on a scale of 0 to 10 cm, and either experienced an inadequate response to NSAID therapy or were intolerant to NSAID therapy.
Patients who previously received TNF-α blockers or any biological agents were excluded from the study.
The primary endpoint was ASAS 20 response at Week 16. Major secondary endpoints included ASAS 40 response at Week 16, BASDAI 50 response at Week 16, ASAS partial remission at Week 16, and the change in the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI sacroiliac joints score from baseline to Week 16.
Baseline demographics and disease characteristics were generally comparable across both treatment groups. At baseline, the majority of patients (67%) had a diagnosis of nr-Ax SpA of less than 1 year duration. The mean BASDAI score at baseline was 6.5±1.5 cm. Approximately 81% of the total patient population at baseline received concomitant NSAID therapy. Approximately 41% of patients showed elevated CRP levels > upper limit of normal, 67% of subjects had evidence of sacroiliitis on MRI, and 80% showed evidence of elevated CRP levels > upper limit of normal and/or evidence of sacroiliitis on MRI. Most patients were male (57%), all (100%) were Caucasian, and the mean age was 31.2 (±7.2) years.
Analyses were performed on the All Treated population (AT, N=197). A subpopulation defined by elevated CRP above the upper limit of normal and/or evidence of sacroiliitis on MRI at baseline (n=158/197, 80.2%) was also evaluated.
Reduction in signs and symptoms: Treatment with SIMPONI 50 mg resulted in improvement in signs and symptoms as demonstrated by the proportion of subjects with an ASAS 20 response at Week 16 (Table 16). Figure 4 shows the proportion of subjects achieving ASAS 20 responses by visit. (See Figure 4 and Table 16.)

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The proportion of subjects achieving BASDAI 50 response at Week 16 in the golimumab 50 mg group (57.7%) was significantly greater (p<0.0001) than in the placebo group (30.0%).
The proportion of subjects achieving ASAS partial remission at Week 16 in the golimumab 50 mg group (33.0%) was significantly greater (p=0.0136) than in the placebo group (18.0%).
In the subpopulation of patients with elevated CRP (> the upper limit of normal) and/or evidence of sacroiliitis on MRI at baseline, comparable results to the AT population were observed in ASAS 20, ASAS 40, BASDAI 50 and ASAS partial remission.
Among subjects treated with golimumab 50 mg who remained on treatment through the end of the study (Week 52), improvements in ASAS 20, ASAS 40, BASDAI 50, and ASAS partial remission were comparable to those reported at Week 16.
Table 17 shows the percent improvement in the components of the ASAS response criteria for the SIMPONI 50 mg and placebo groups at Week 16. (See Table 17.)

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Spinal mobility was assessed by BASMI. The mean change from baseline in BASMI score at Week 16 in the golimumab 50 mg-treated group was -0.5 cm vs. -0.1 cm in the placebo-treated group.
The mean change from baseline in CRP at Week 16 was -0.99 mg/dL in the golimumab 50 mg group and was -0.35 mg/dL in the placebo group.
The mean change from baseline in the SPARCC (Spondyloarthritis Research Consortium of Canada) MRI SI joints score was -5.3 in the golimumab 50 mg group and was -0.9 in the placebo group at Week 16.
The change from baseline in the ASQoL score at Week 16 was -5.2 in the golimumab 50 mg group and -1.8 in the placebo group.
Ulcerative Colitis: Study demographics and trial design: The safety and efficacy of SIMPONI were evaluated in two multi-center, randomized, double-blind, placebo-controlled Phase 3 clinical studies in patients ≥18 years of age. (See Table 18.)

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UC Study 1 (PURSUIT-Induction): UC Study 1 was an induction study conducted in patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12; Endoscopy subscore ≥2) who had an inadequate response to or had failed to tolerate conventional therapies, or were corticosteroid dependent. The study was a combination Phase 2 (dose finding) and Phase 3 (dose confirming) study. In the dose finding portion of the study, patients were randomized to one of 4 treatment groups: 400 mg SIMPONI SC at Week 0 and 200 mg at Week 2 (400/200 mg), 200 mg SIMPONI SC at Week 0 and 100 mg at Week 2 (200/100 mg), 100 mg SIMPONI SC at Week 0 and 50 mg at Week 2 (100/50 mg), or placebo SC at Weeks 0 and 2. In the dose confirming portion of the study, efficacy was evaluated in 761 patients who were randomized to receive either 400 mg SIMPONI SC at Week 0 and 200 mg at Week 2, 200 mg SIMPONI SC at Week 0 and 100 mg at Week 2, or placebo SC at Weeks 0 and 2. Concomitant stable doses of oral aminosalicylates, corticosteroids, and/or immunomodulatory agents were permitted.
UC Study 2 (PURSUIT-Maintenance): UC Study 2 was a maintenance study that evaluated 456 patients who achieved clinical response with SIMPONI induction. Patients were randomized to receive SIMPONI 50 mg, SIMPONI 100 mg or placebo administered subcutaneously every 4 weeks. Concomitant stable doses of oral aminosalicylates and/or immunomodulatory agents were permitted. Corticosteroids were to be tapered at the start of the maintenance study. The efficacy of SIMPONI through Week 54 was assessed in this study. Patients who completed the maintenance study through Week 54 continued treatment through Week 216. Efficacy assessments were performed through the extension study.
Clinical Endpoints: The primary endpoint for UC Study 1 (PURSUIT-Induction) was clinical response at Week 6. The major secondary endpoints were clinical remission, mucosal healing (improvement of endoscopic appearance of the mucosa), and the improvement in the IBDQ score, all at Week 6. The primary endpoint for UC Study 2 (PURSUIT-Maintenance) was maintenance of clinical response through Week 54. Selected major secondary endpoints included clinical remission at both Week 30 and Week 54 and mucosal healing at both Week 30 and Week 54.
In both studies, clinical response and clinical remission were defined based on the Mayo score, which consists of four subscores: stool frequency, rectal bleeding, findings of endoscopy, and physician's global assessment. Each subscore is rated on a scale from 0 to 3, indicating normal (0) to severe (3) activity. The Mayo score is the sum of the 4 subscores. Clinical response was defined as a decrease from Week 0 of induction in the Mayo score of ≥30% and ≥3 points, accompanied by a decrease in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1. Clinical remission was defined as a Mayo score ≤2 points, with no individual subscore >1. Improvement of endoscopic appearance of the mucosa (study endpoint, mucosal healing) was defined as a Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability).
In UC Study 2, patients were assessed for UC disease activity by partial Mayo score every 4 weeks (loss of response was confirmed by endoscopy). A patient who maintained response was in a state of continuous clinical response at each evaluation through Week 54. Similarly, a patient had to be in remission at both Weeks 30 and 54 (without demonstrating a loss of response at any time point through Week 54) to achieve durable remission.
Health-related quality of life was assessed using the IBDQ, SF-36 and the EQ-5D. The IBDQ is a questionnaire specifically designed for patients with inflammatory bowel disease. The SF-36 is a general health status questionnaire that has been widely used in various diseases and conditions to assess patients' physical and mental well being. The EQ-5D is a standardized non-disease specific instrument for describing and valuing health-related quality of life.
Approximately 63% (358/570) of patients, who were receiving SIMPONI at the beginning of the study extension (Week 56), remained on treatment through the end of the study (last SIMPONI administration at Week 212).
Study results: The results for clinical endpoints during induction treatment are based on patients randomized during the dose confirming part of UC Study 1 (PURSUIT-Induction, n=504). The results for clinical endpoints during maintenance treatment are based on patients from UC Study 2 (PURSUIT-Maintenance) who achieved clinical response with SIMPONI from previous induction with golimumab (n=456).
Clinical Response, Clinical Remission, and Improvement of Endoscopic Appearance of the Mucosa: In UC Study 1, a significantly greater percentage of patients in the SIMPONI group achieved clinical response, clinical remission and endoscopic improvement of the mucosa when compared to placebo at Week 6.
The data from UC Study 2 demonstrate that the proportion of patients who maintained clinical response through Week 54 was significantly greater in the SIMPONI 100 mg group compared with the placebo group. Additionally, the proportion of patients in clinical response who achieved clinical remission and improvement of endoscopic appearance of the mucosa at both Weeks 30 and 54 were significantly greater in the SIMPONI 100 mg group compared with the placebo group. (See Table 19.)

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More SIMPONI-treated patients demonstrated sustained improvement of endoscopic appearance of the mucosa at both Week 30 and Week 54 in the 50 mg group (42%, nominal p<0.05) and 100 mg group (42%, p<0.005) compared with patients in the placebo group (27%).
Mayo Score: In UC Study 1 (PURSUIT-Induction), a greater reduction in the partial Mayo score was evident as early as Week 2 in the SIMPONI 200/100 mg group compared with the placebo group and this reduction was maintained through Week 6.
The reduced median partial Mayo score (at Week 0 of UC Study 2) was maintained in the SIMPONI 100 mg group through Week 52 and in the SIMPONI 50 mg group through Week 48; the median partial Mayo score in the placebo group increased after Week 8 and continued to increase over time to a value at Week 54 approaching the value prior to golimumab induction.
The proportion of subjects in UC Study 2 that maintained improvement in each Mayo subscore from Week 0 through Week 54 in UC Study 2 was greater in 100 mg group compared to the placebo group.
Among patients who entered the study extension, the proportion of subjects with inactive or mild disease activity as assessed by the Physician's global assessment subscore of the Mayo score was generally sustained through Week 216.
Health-related Quality of Life: In UC Study 1 (PURSUIT-Induction), the mean improvement from baseline in IBDQ score at Week 6 was significantly greater in the SIMPONI 200/100 mg group, 27.0 ± 33.72, compared with the placebo group, 14.8 ± 31.25; p<0.0001.
Pharmacokinetics: Following SC administration of SIMPONI to healthy subjects or patients with RA, the median time to reach maximum serum concentrations (T_max) ranged from 2 to 6 days. The systemic clearance of SIMPONI was estimated to be 6.9 ± 2.0 mL/day/kg, and mean volume of distribution 115 ± 19 mL/kg in healthy subjects; in patients with RA, the systemic clearance of SIMPONI was estimated to be 7.6 ± 2.0 mL/day/kg, and mean volume of distribution 151.1 ± 61 mL/kg. The volume of distribution for SIMPONI indicates that SIMPONI is distributed primarily in the circulatory system with limited extravascular distribution. Median terminal half-life values were estimated to be approximately 2 weeks in healthy subjects and patients with RA, PsA, AS, or UC. Following SC administration of SIMPONI in healthy subjects, the following PK parameters were obtained as shown in Table 20. (See Table 20.)

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Following a single SC dose in healthy subjects, dose-proportional pharmacokinetics were observed over a dose range of 50 mg to 400 mg with both C_max and area under the concentration-time curve (AUC) increased proportionally.
Following a single SC injection of 100 mg, the absorption of SIMPONI was similar in the upper arm, abdomen, and thigh, with a mean absolute bioavailability of 51%. Since SIMPONI exhibited approximately dose proportional PK following SC administration, the absolute bioavailability of the SIMPONI 50 mg or 200 mg dose is expected to be similar to the 100 mg dose.
When 50 mg SIMPONI was administered SC to patients with RA, PsA or AS every 4 weeks, serum concentrations reached steady-state by Week 12. With concomitant use of methotrexate, treatment with 50 mg SIMPONI every 4 weeks resulted in a median steady-state trough serum concentration of approximately 0.6 μg/mL in patients with active RA despite methotrexate therapy, and approximately 0.5 μg/mL in patients with active PsA and approximately 0.6 μg/mL in patients with AS. Patients with RA, PsA or AS who did not receive concomitant use of methotrexate had approximately 30% lower steady-state trough concentrations of SIMPONI than those who received SIMPONI with methotrexate. Concomitant use of methotrexate reduced the apparent clearance of SIMPONI by 36% after 6-month treatment with SIMPONI in patients with RA. However, population PK analysis indicated that concomitant use of nonsteroidal anti-inflammatory drugs, oral corticosteroids or sulfasalazine was not found to influence the apparent clearance of SIMPONI.
Steady-state mean trough serum golimumab concentrations in patients with nr-Ax SpA were comparable to those observed in patients with AS following subcutaneous administration of 50 mg golimumab every 4 week.
Following induction doses of 200 mg and 100 mg SIMPONI at Week 0 and 2 respectively, and maintenance doses of 100 mg SIMPONI every 4 weeks thereafter in patients with UC, serum golimumab concentrations reached steady-state approximately 14 weeks after the start of therapy. Treatment with 100 mg SIMPONI every 4 weeks during maintenance resulted in a mean steady-state trough serum concentration of approximately 1.8 ± 1.1 μg/mL.
Population pharmacokinetic analyses showed there was a trend toward higher apparent clearance of SIMPONI with increasing weight. As a result, patients with heavier weight tend to have lower steady-state trough concentrations of SIMPONI. However, across the RA, PsA, and AS populations, a treatment benefit from golimumab 50 mg was observed for all subgroups by weight quartiles with no meaningful differences in clinical efficacy among these subgroups. Treatment with the recommended dose regimens of SIMPONI in UC patients did not result in meaningful differences in clinical efficacy among the different weight subgroups, particularly among patients receiving the 100 mg maintenance dose. Therefore, there is no need to adjust the dosage of SIMPONI based on a patient's weight.
No gender-related pharmacokinetic differences were observed with SIMPONI after correction for patients' body weights. Pharmacokinetic parameters of SIMPONI were not influenced by age in adult patients. Patients with age ≥65 years had apparent clearance of SIMPONI similar to patients with age <65 years. No ethnicity-related pharmacokinetic differences were observed between Caucasians and Asians.
Patients who developed anti-SIMPONI antibodies generally had low trough steady-state serum concentrations of SIMPONI.
Special Populations and Conditions: Pediatrics: The safety and efficacy of SIMPONI have not been established in pediatric patients aged 17 years and younger.
Geriatrics: Pharmacokinetic parameters of SIMPONI were not influenced by age in adult patients. Patients with age ≥65 years had apparent clearance of SIMPONI similar to patients with age <65 years.
Gender: No gender-related pharmacokinetic differences were observed with SIMPONI after correction for patients' body weights.
Race: No ethnicity-related pharmacokinetic differences were observed between Caucasians and Asians.
Hepatic insufficiency: SIMPONI has not been studied in this patient population. No dose recommendation can be made.
Renal insufficiency: SIMPONI has not been studied in this patient population. No dose recommendation can be made.
Absorption: Following a single SC administration of SIMPONI to healthy subjects or patients with RA, the time to reach maximum serum concentrations (T_max) ranged from 2 to 6 days. A SC injection of 50 mg SIMPONI to healthy subjects produced a mean ± standard deviation maximum serum concentration (C_max) of 3.2 ± 1.4 μg/mL. Both C_max and area under the concentration-time curve (AUC) increased proportionally with doses over the range of 50 to 400 mg following a single SC administration.
Following a single SC injection of 100 mg in healthy subjects, the absorption of SIMPONI was similar in the upper arm, abdomen, and thigh, with a mean absolute bioavailability of 51%. Since SIMPONI exhibited approximately dose proportional PK following SC administration, the absolute bioavailability of a SIMPONI 50 mg or 200 mg dose is expected to be similar to the 100 mg dose.
Following a single IV administration of 2 mg/kg SIMPONI I.V., a mean C_max of 44.4 ± 11.3 μg/mL was observed in patients with RA.
Distribution: Following a single IV administration, the mean volume of distribution was estimated to be 115 ± 19 mL/kg in healthy subjects, and 151 ± 61 mL/kg in patients with RA. The volume of distribution for SIMPONI indicates that SIMPONI is distributed primarily in the circulatory system with limited extravascular distribution.
Metabolism: The exact metabolic pathway of SIMPONI is unknown.
Elimination: Following a single IV administration, the systemic clearance of SIMPONI was estimated to be 6.9 ± 2.0 mL/day/kg in healthy subjects and 7.6 ± 2.0 mL/day/kg in patients with RA.
Terminal half-life was consistent between IV and SC administration of SIMPONI. The terminal half-life was estimated to be 12 ± 3 days in healthy subjects and similar half-life was observed in patients with RA, PsA, AS, or UC.
After a 6-month treatment with SIMPONI by subcutaneous administration in patients with RA, concomitant use of methotrexate reduced the apparent clearance of SIMPONI by 36%; however, following IV administration, no appreciable effect of methotrexate on the clearance of SIMPONI was observed. Population PK analysis indicated that concomitant use of NSAIDs, oral corticosteroids or sulfasalazine did not influence the apparent clearance of SIMPONI following SC administration.
Population PK analyses showed that, following SC administration of SIMPONI, patients with higher C-reactive protein levels tended to have higher apparent clearance of SIMPONI. Patients with higher C-reactive protein levels were more likely to have lower trough serum concentrations of SIMPONI following SC administration of SIMPONI. In contrast, C-reactive protein level showed no effect on the clearance of SIMPONI following IV administrations of 2 mg/kg SIMPONI at Weeks 0, 4, and every 8 weeks thereafter.
Patients who developed anti-SIMPONI antibodies following SC or IV administration generally had low trough steady-state serum concentrations of SIMPONI.
Toxicology: Nonclinical toxicology studies include multiple-dose IV studies and single-dose and multiple-dose SC studies of up to 6 months duration, an embryo-fetal development study evaluating the maternal and fetal effects of golimumab treatment during pregnancy, and a prenatal and postnatal development study evaluating the maternal and neonatal effects of golimumab treatment during pregnancy and lactation. The developmental and reproductive toxicity of an analogous anti-mouse TNFα monoclonal antibody (mAb), cV1q, was also assessed and are included as additional supportive data for the development of golimumab. An in vitro human tissue cross-reactivity study was also conducted.
Results from nonclinical toxicology studies are summarized in Table 21. (See Table 21.)
Repeated Dose Toxicology Studies: Three repeated dose toxicity studies were conducted to support golimumab administration in patients. In the 6-month IV study, no abnormal findings considered golimumab-related were revealed at necropsy, except for a disseminated histoplasmosis infection found in one animal in the 25 mg/kg recovery group. This finding is not unexpected, as opportunistic infections are known risks of anti-TNF inhibitors and have been observed in human subjects treated with anti-TNF agents. In both the 6-month IV study and the 6-month SC study, there was a slight increase in the number of circulating lymphocytes. In the 6-month IV study there was a slight decrease in the humoral immune response to KLH. This reduction was not observed in the 6-month SC study where a different immunization protocol was used. The lymphocyte changes and slight reduction in immune response to KLH immunization are considered to be biological responses to TNFα inhibition and are not considered to be of toxicological significance.
Developmental and Reproductive Toxicity Studies: Golimumab administration to cynomolgus monkeys during pregnancy and lactation produced no adverse developmental effects, including no effects on the developing immune system. Fetuses were exposed to golimumab during gestation. In fetuses, golimumab acquired during gestation persisted in the infant serum for at least 6 months after birth. Golimumab was detected in the breast milk at concentrations that were approximately 350-fold lower than in the maternal serum concentrations.
In the mouse studies using cV1q, no toxicologically significant effects of anti-TNFα mAb treatment were detected on fertility, embryo-fetal, pre- and post-natal development and developmental immunotoxicity.
Genotoxicity: Genotoxicity studies have not been conducted with golimumab. Because of their large molecular size, mAbs are not expected to pass through the cellular and nuclear membranes and are not expected to gain access to or to interact with DNA or other chromosomal material.
Carcinogenicity: No carcinogenicity studies have been performed with golimumab.

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Rheumatoid Arthritis (RA): SIMPONI, in combination with methotrexate (MTX), is indicated for: Reducing signs and symptoms and improving physical function in adult patients with moderately to severely active rheumatoid arthritis; Inhibiting the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis who had not previously been treated with MTX.
Psoriatic Arthritis (PsA): SIMPONI is indicated for: Reducing signs and symptoms, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active psoriatic arthritis. SIMPONI can be used in combination with MTX in patients who do not respond adequately to MTX alone.
Ankylosing Spondylitis (AS): SIMPONI is indicated for: Reducing signs and symptoms in adult patients with active ankylosing spondylitis who have had an inadequate response to conventional therapies.
Non-radiographic Axial Spondyloarthritis (nr-Ax SpA): SIMPONI is indicated for: The treatment of adults with severe active non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) evidence who have had an inadequate response to, or are intolerant to nonsteroidal anti-inflammatory drugs (NSAIDs).
Ulcerative Colitis (UC): SIMPONI is indicated in adult patients with moderately to severely active disease who have had an inadequate response to, or have medical contraindications for, conventional therapy including corticosteroids, amino salicylates, azathioprine (AZA), or 6-mercaptopurine (6-MP), for: Inducing and maintaining clinical response (reduction in signs and symptoms); Inducing clinical remission; Achieving sustained clinical remission in induction responders; Improving endoscopic appearance of the mucosa during induction (see Pharmacology: Pharmacodynamics: Clinical Trials under Actions).
Geriatrics (≥65 years of age): See Use in the Elderly under Precautions; and Pharmacology: Pharmacokinetics: Special Populations and Conditions: Geriatrics under Actions.
Pediatrics (<18 years of age): The safety and efficacy of SIMPONI have not been established in pediatric patients aged 17 years and younger.

Dosing Considerations: SIMPONI is intended for use under the guidance and supervision of a physician. After an initial training in proper subcutaneous injection technique, an adult patient with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or ulcerative colitis may self-inject with SIMPONI if a physician determines that it is appropriate and with medical follow-up as necessary.
At the time of dosing, if multiple injections are required, the injections should be administered at different sites on the body.
Comprehensive instructions for the administration of SIMPONI are given in Instructions for Injecting SIMPONI Using a Single-Use SmartJect Autoinjector under Patient Counselling Information for preparation and giving an injection of SIMPONI. Patients should be instructed to inject the full amount of SIMPONI according to the directions provided in Patient Counselling Information.
Recommended Dose and Dosage Adjustment: SIMPONI is administered by subcutaneous injection.
Adult Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis and Non-Radiographic Axial Spondyloarthritis Patients: 50 mg of SIMPONI given as a subcutaneous injection once a month, on the same date each month.
For all the previously mentioned indications, available data from clinical trials suggest that clinical response is usually achieved within 14 to 16 weeks of treatment (after 4 doses). Continued therapy should be carefully reconsidered in a patient not responding within this time period.
Data from clinical trials for RA and PsA suggest that efficacy does not increase with doses higher than 50 mg. Doses higher than 50 mg have not been studied in nr-Ax SpA.
Adult Ulcerative Colitis: 200 mg initially administered by subcutaneous injection at Week 0, followed by 100 mg at Week 2 and then 50 mg every 4 weeks, thereafter.
The maintenance dose of 100 mg every 4 weeks can be considered at the discretion of the treating physician. In addition to the clinical assessment, measurement of golimumab levels may be taken into account before considering dose optimization as some patients may not benefit from dose escalation.
During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.
Missed Dose: Patients who miss a dose of SIMPONI, should be advised to inject this missed dose as soon as they become aware of it, and then follow with their next scheduled dose.
Special Populations: Geriatrics: Pharmacokinetic parameters including apparent clearance were not influenced by age in SIMPONI clinical trials. Dose adjustment is not required in elderly patients (see Use in the Elderly under Precautions).
Pediatrics: The safety and efficacy of SIMPONI have not been established in pediatric patients aged 17 years and younger.
Renal impairment: Specific studies of SIMPONI have not been conducted in patients with renal impairment.
Hepatic impairment: Specific studies of SIMPONI have not been conducted in patients with hepatic impairment. SIMPONI should be used with caution in subject with impaired hepatic function.
Administration: SIMPONI is supplied as a single-use, sterile solution in a pre-filled syringe and single-use autoinjector administered by subcutaneous injection (see Dosing Considerations as previously mentioned).

The maximum tolerated dose of golimumab has not been established in humans. Single doses up to 10 mg/kg intravenously have been administered in a clinical study without dose-limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment be instituted immediately.

Patients with severe infections such as sepsis, tuberculosis and opportunistic infections (see Warnings and Precautions).
Patients with moderate or severe (NYHA class III/IV) congestive heart failure (see Precautions).
Patients who are hypersensitive to golimumab, or any other ingredient in the formulation or component of the container. For a complete listing, see Description.

Infections: Serious infections leading to hospitalization or death, including sepsis, tuberculosis (TB), invasive fungal, and other opportunistic infections have been observed with the use of TNF antagonists including SIMPONI. Administration of SIMPONI should be discontinued if a patient develops a serious infection or sepsis. Treatment with SIMPONI should not be initiated in patients with active infections including chronic or localized infections (see Precautions).
Physicians should exercise caution when considering the use of SIMPONI in patients with a history of recurring or latent infections, including TB, or with underlying conditions, which may predispose patients to infections, who have resided in regions where TB and invasive fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis are endemic.
Tuberculosis (frequently disseminated or extrapulmonary at clinical presentation) has been observed in patients receiving TNF-blocking agents, including SIMPONI. Tuberculosis may be due to reactivation of latent tuberculosis infection or to new infection.
Before starting treatment with SIMPONI, all patients should be evaluated for both active and latent tuberculosis.
If latent tuberculosis is diagnosed, treatment for latent tuberculosis should be started with anti-tuberculosis therapy before initiation of SIMPONI.
Physicians should monitor patients receiving SIMPONI for signs and symptoms of active tuberculosis, including patients who tested negative for latent tuberculosis infection.
Malignancy: Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF-blockers, of which SIMPONI is a member.

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 golimumab. 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.
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.
Patients must be monitored closely for infections including tuberculosis before, during and after treatment with golimumab. Because the elimination of golimumab may take up to 5 months, monitoring should be continued throughout this period. Further treatment with SIMPONI must not be given if a patient develops a serious infection or sepsis.
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.
Opportunistic Infections: 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.
For patients who have resided in or travelled 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. 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, 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.
Hepatitis B Virus (HBV) Reactivation: As observed with the use of other immunosuppressive drugs, the use of TNF-blocking agents, including golimumab has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of the virus (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. 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.
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: 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 golimumab is a member. Approximately half of 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, such as methotrexate, azathioprine, or 6-mercaptopurine. These cases were reported post-marketing and are derived from a variety of sources, including registries and spontaneous post-marketing reports.
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 post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with other TNF-blocking agents. 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 two-fold) than the general population for the development of leukemia.
Non-lymphoma Malignancy: 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. 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 golimumab (see Post-Market Adverse Drug Reactions under Adverse Reactions). Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer.
Cardiovascular: Congestive Heart Failure (CHF): Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF-blockers, including golimumab. Some cases had a fatal outcome. Cases of CHF in patients with known cardiovascular risk factors have been observed with SIMPONI. 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 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.
Concurrent Administration with Anakinra: Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocking agent, etanercept, with an increased risk of neutropenia and 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 (see Drug-Drug Interactions under Interactions).
Concurrent Administration 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 (see Drug-Drug Interactions under Interactions).
Concurrent Administration with other Biological Therapeutics: There is insufficient information regarding the concomitant use of golimumab 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, aplastic anemia and thrombocytopenia in patients receiving TNF-blockers, including golimumab. In clinical studies, cases of pancytopenia, leukopenia, neutropenia and thrombocytopenia have occurred in SIMPONI I.V.-treated patients. Caution should be exercised in patients treated with SIMPONI 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 SIMPONI therapy should be considered in patients with confirmed significant hematologic abnormalities.
Immune: Immunosuppression: The possibility exists for TNF-blocking agents, including golimumab, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In Phase 1 RA studies, in 81 patients evaluated, there were no substantial differences between subjects receiving SIMPONI and placebo with respect to responses to delayed-type hypersensitivity antigens. The impact of treatment with golimumab on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood (see as previously mentioned and Adverse Reactions).
Immunizations: 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. It is recommended that live vaccines not be given concurrently with SIMPONI.
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 two-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: Hypersensitivity Reactions: Allergic reactions (e.g., rash, urticaria, and rarely anaphylaxis and serum sickness-like reactions) have been observed in patients treated with TNF-blocking agents. 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 any serious allergic or anaphylactic reaction occurs, administration of SIMPONI should be discontinued immediately and appropriate therapy initiated.
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.
Autoimmune Processes: Treatment with TNF-blockers, including golimumab may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms of a lupus-like syndrome following treatment with SIMPONI, treatment should be discontinued (see Clinical Trial Adverse Drug Reactions: Immune: Autoantibodies under Adverse Reactions).
Autoimmune hepatitis has been reported for other members of the anti-TNFα class.
Demyelinating Disorders: Use of TNF-blocking agents, of which golimumab is a member, have been associated with cases of new onset or exacerbation of central nervous system (CNS) demyelinating disorders, including multiple sclerosis (MS), optic neuritis and peripheral demyelinating disorders, including Guillain-Barré syndrome. In clinical trials, cases of central demyelination, MS, and peripheral demyelinating polyneuropathy have been reported in patients treated with SIMPONI. 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.
Sexual Function/Reproduction: It is not known whether golimumab can impair fertility in humans. No impairment of fertility was observed in a fertility and general reproduction toxicity study conducted in mice using the analogous anti-mouse TNFα antibody.
Surgery: There is limited safety experience of SIMPONI treatment in patients who have undergone surgical procedures, including arthroplasty. The long half-life should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on SIMPONI should be closely monitored for infections, and appropriate actions should be taken.
Women of Childbearing Potential: Women of childbearing potential must use adequate contraception to prevent pregnancy and continue its use for at least 6 months after the last golimumab treatment.
Renally and Hepatically Impaired: Specific studies of SIMPONI have not been conducted in these patient populations. SIMPONI should be used with caution in subject with impaired hepatic function.
Monitoring and Laboratory Tests: There is no known interference between SIMPONI and laboratory tests.
Potential for Medication Errors: SIMPONI is registered in 50 mg strength for subcutaneous administration. It is important that the right strength is used to administer the correct dose as indicated in Dosage & Administration. Care should be taken to provide the right strength to ensure that patients are not underdosed or overdosed.
Effects on Ability to Drive and Use Machines: No studies on the effect on the ability to drive and use machines have been performed. SIMPONI may have a minor influence on the ability to drive and use machines. Dizziness may occur following administration of SIMPONI.
Use in Pregnancy: See Pregnant Women under Use in Pregnancy & Lactation.
Use in Lactation: See Nursing Women under Use in Pregnancy & Lactation.
Use in Children: The safety and efficacy of SIMPONI have not been established in pediatric patients aged 17 years and younger.
Use in the Elderly: In the Phase 3 SIMPONI trials in RA, PsA, and AS, 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 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-Ax SpA trial.

Pregnant Women: An embryo-fetal developmental toxicology study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the first trimester at dosages up to 50 mg/kg twice weekly (over 500-fold higher in terms of dose/body weight ratio than the proposed clinical dose of 50 mg every 4 weeks). The mean peak maternal serum concentration obtained in this study (1,576 μg/mL) is over 900-fold higher than median steady-state C_max value (1.71 μg/mL) following 50 mg every 4-week subcutaneous (SC) dosing in patients with RA, PsA, and AS. Umbilical cord blood samples collected at the end of the second trimester showed that fetuses were exposed to golimumab during gestation. Fetal serum concentrations were approximately 50% of the maternal serum concentrations. In this study, in utero exposure to golimumab produced no developmental defects to the fetus.
A pre- and postnatal developmental study was performed in which pregnant cynomolgus monkeys were treated with golimumab during the second and third trimesters, and during lactation. Golimumab was present in the neonatal serum from the time of birth and for up to six months postpartum. The mean peak maternal serum concentration obtained in this study (1,482 μg/mL) is over 860-fold higher than median steady-state C_max value (1.71 μg/mL) following 50 mg every 4-week SC dosing in patients with RA, PsA, and AS. Golimumab was detected in the breast milk at concentrations that were approximately 350-fold lower than the maternal serum concentrations. Exposure to golimumab during gestation and during the postnatal period caused no developmental defects in the infants.
Golimumab crosses the placenta. Following treatment with another TNF-blocking monoclonal antibody during pregnancy, the antibody has been detected for up to 6 months in the serum of the infant born by the treated women. Consequently, these infants may be at increased risk of infection. Administration of live vaccines to infants exposed to golimumab in utero is not recommended for 6 months following the mother's last golimumab injection during pregnancy (see Precautions).
There have been no studies in pregnant women. It is not known whether SIMPONI can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. SIMPONI should be given to a pregnant woman only if clearly needed.
Nursing Women: In a pre- and post-natal developmental toxicology study in cynomolgus monkeys golimumab was detected in the breast milk at concentrations that were approximately 350-fold lower than the maternal serum concentrations.
It is not known whether golimumab 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, women must not breast feed during and for at least 6 months after golimumab treatment. 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.

Adverse Drug Reaction Overview: Safety data from golimumab trials that include Phase 3 SIMPONI I.V. and Phase 2 and 3 SIMPONI clinical trials are available from 6161 SIMPONI I.V. or SIMPONI-treated patients including 3090 with rheumatoid arthritis, 634 with psoriatic arthritis, 768 with ankylosing spondylitis, 193 with active non-radiographic axial spondyloarthritis (nr-Ax SpA), 1240 with ulcerative colitis and 231 with severe persistent asthma.
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.)

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Ulcerative 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.)

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Other 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.

Overview: SIMPONI can be used in combination with methotrexate in adult patients with RA, AS or PsA. Specific drug interaction studies have not been conducted with SIMPONI.
Drug-Drug Interactions: Concurrent Use of SIMPONI with other Biological Therapeutics: The combination of SIMPONI with other biological therapeutics used to treat the same conditions as SIMPONI, including anakinra or abatacept is not recommended (see Precautions).
Live Vaccines/Therapeutic Infectious Agents: Live vaccines should not be given concurrently with SIMPONI (see Immune: Immunizations under Precautions).
Therapeutic infectious agents should not be given concurrently with SIMPONI.
Methotrexate: Although concomitant use of methotrexate (MTX) results in higher steady-state trough concentrations of SIMPONI and reduction of its apparent clearance (approximately by 36%) in patients with RA, PsA, or AS, the data do not suggest the need for dose adjustment of either SIMPONI or methotrexate (see Pharmacology: Pharmacokinetics under Actions).
Cytochrome P450 Substrates: The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as golimumab, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of SIMPONI in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.
Drug-Herb Interactions: Interactions with herbal products have not been established.

Store SIMPONI refrigerated at 2°C to 8°C (36°F to 46°F). Keep the product in original carton until time of use to protect from light. Do not freeze. Do not shake.

Instructions for Injecting SIMPONI Using a Single-Use SmartJect Autoinjector: If you would like to self-inject SIMPONI, you must be trained by a healthcare professional to prepare an injection and give it to yourself. If you have not been trained, please contact your healthcare professional to schedule a training session.
Step 1: Preparing to Use the SmartJect Autoinjector.
Do not shake the autoinjector at any time.
Do not remove the autoinjector cap until instructed to do so.
Check Expiration Date: Check the expiration date (indicated as "EXP") on the autoinjector. You can also check the expiration date printed on the carton. If the expiration date has passed, do not use the autoinjector. Please contact your doctor or pharmacist for assistance.
Check Security Seal: Check the security seal around the cap of the autoinjector. If the security seal is broken, do not use the autoinjector and please contact your doctor or pharmacist for assistance.
Wait 30 Minutes: To ensure proper injection, allow the autoinjector to sit at room temperature outside the carton for 30 minutes out of the reach of children.
Do not warm the autoinjector in any other way (for example, do not warm it in a microwave or in hot water).
Do not remove the autoinjector cap while allowing it to reach room temperature.
Assemble Additional Supplies: Assemble additional supplies you will need for your injection. These include an alcohol swab, a cotton ball or gauze, and a sharps container.
Check the Liquid in the SmartJect Autoinjector: Look through the viewing window to make sure that the liquid in the autoinjector is clear to slightly opalescent and colourless to slightly yellow. You may also notice an air bubble - this is normal.
Do not use if the liquid is discoloured, cloudy or contains particles. If this is the case, please contact your doctor or pharmacist for assistance.
Step 2: Choosing and Preparing the Injection Site.
Choose the Injection Site: The recommended injection site is the front of the middle thighs. You can also use the lower abdomen below the belly button, except for the two-inch area directly underneath the belly button. If a caregiver is giving you the injection, the caregiver can also use the outer area of the upper arms. Injection sites should be rotated. At the time of dosing, if multiple injections are required, the injections should be administered at different sites on the body.
Do not inject into areas where the skin is tender, bruised, red, scaly or hard. Avoid areas with scars or stretch marks.
Preparing the Injection Site: Thoroughly wash your hands with soap and warm water. Wipe the injection site with an alcohol swab.
Do not touch this area again before giving the injection. Allow the skin to dry before injecting.
Do not fan or blow on the clean area.
Step 3: Injecting SIMPONI Using the Single-Use SmartJect Autoinjector.
Remove the Cap: The cap should not be removed until you are ready to inject the medication. The medication should be injected within 5 minutes after the cap has been removed. When you are ready to inject, twist the cap slightly to break the security seal. Pull the cap off and immediately place the cap into the trash.
Do not put the cap back on because it may damage the needle inside the autoinjector.
Note: Do not use the autoinjector if it is dropped without the cap in place. If you drop the autoinjector without the cap in place, please contact your doctor, pharmacist for assistance.
Push the SmartJect Autoinjector Against the Skin: Hold the autoinjector comfortably in your hand. Do not press the button at this time. Push the open end of the autoinjector firmly against the skin at a 90-degree angle so that the Safety Sleeve slides up into the clear cover. Do not press the button until after the autoinjector is pushed firmly against the skin and the Safety Sleeve slides fully into the Clear Cover. Injecting without pinching the skin is recommended. However, if you prefer, you may pinch the skin to create a firmer surface for your injection.
Press Button to Inject: Continue to hold the autoinjector firmly against the skin, and press the front raised part of the button with your fingers or thumb. You will not be able to press in the button unless the autoinjector is pushed firmly against your skin and the Safety Sleeve slides into the Clear Cover. Once the button is pressed, it will remain pressed in so you do not need to keep pressure on it. You will hear a loud 'click' sound - don't be alarmed. The first loud 'click' indicates that the needle has been inserted and the injection has started. You may or may not feel a needle prick at this time.
Do not lift the autoinjector away from your skin. If you pull the autoinjector away from the skin, you may not get your full dose of medicine.
Wait for Second 'Click': Continue to hold the autoinjector against the skin until you hear the second 'click' (it usually takes about 3-6 seconds, but may take up to 15 seconds for you to hear the second 'click' sound). The second click indicates that the injection is finished and the needle has retracted into the autoinjector. Lift the autoinjector from the injection site.
Note: If you have hearing impairment, count 15 seconds from the time you press the button and then lift the autoinjector from the injection site.
Step 4: After the Injection.
Check the Viewing Window: After injecting, check the viewing window to make sure that the yellow indicator is visible. This indicates that the autoinjector has worked properly. The yellow indicator may not fill the entire viewing window. This is normal. If you do not think you received your injection, check the yellow indicator again to confirm that the dose was delivered. If the yellow indicator is not visible in the viewing window, please contact your doctor or pharmacist for assistance. Do not administer a second dose without speaking to your doctor.
Disposing of the SmartJect Autoinjector: Immediately dispose of the autoinjector in the sharps container. Dispose of the sharps container according to your local regulations.
Use Cotton Ball or Gauze: There may be a small amount of blood or liquid at the injection site, which is normal. You can press a cotton ball or gauze over the injection site for 10 seconds.
Do not rub the injection site.
You may cover the injection site with a small adhesive bandage, if necessary.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs) / Immunosuppressants

L04AB06 - golimumab ; Belongs to the class of tumor necrosis factor alpha (TNF-alpha) inhibitors. Used as immunosuppressants.

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