英文药名: Simponi(Golimumab Injection) 中文药名: 戈利木单抗注射剂 生产厂家: 德国(MSD)
Infections 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 100 subject-years: 60.8; 95% CI: 55.0, 67.1) compared with 11.0% of control patients (incidence per 100 subject-years: 54.5; 95% CI: 46.1, 64.0). In controlled and uncontrolled portions of the studies with a median follow-up of approximately 2 years, the incidence per 100 subject-years of upper respiratory tract infections was 36.0 events; 95% CI: 34.9, 37.2 for golimumab treated patients. In the controlled period of pivotal trials, infections were observed in 23.0% of golimumab-treated patients (incidence per 100 subject-years: 132.0; 95% CI: 123.3, 141.1) compared with 20.2% of control patients (incidence per 100 subject-years: 122.3; 95% CI: 109.5, 136.2). In controlled and uncontrolled portions of the trials with a median follow-up of approximately 2 years, the incidence per 100 subject-years of infections was 83.5 events; 95% CI: 81.8, 85.3 for golimumab treated patients. In the controlled period of RA, PsA, AS, and nr-Axial SpA trials, serious infections were observed in 1.2% of golimumab-treated patients and 1.2% of control-treated patients. The incidence of serious infections per 100 subject-years of follow-up in the controlled period of RA, PsA, AS, and nr-Axial SpA trials was 7.3; 95% CI: 4.6, 11.1 for the golimumab 100 mg group, 2.9; 95% CI: 1.2, 6.0 for the golimumab 50 mg group and 3.6; 95% CI: 1.5, 7.0 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. Serious infections observed in golimumab-treated patients included tuberculosis, bacterial infections including sepsis and pneumonia, invasive fungal infections and other opportunistic infections. Some of these infections have been fatal. In the controlled and uncontrolled portions of the pivotal trials with a median follow-up of approximately 2 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 100 subject-years of all serious infections was 4.3; 95% CI: 3.8, 4.8, in patients receiving golimumab 100 mg and 2.6; 95% CI: 2.1, 3.2, in patients receiving golimumab 50 mg. Malignancies 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 trials with a median follow-up of approximately 2 years, a greater incidence of lymphoma was observed in patients receiving golimumab 100 mg compared with patients receiving golimumab 50 mg. Lymphoma was diagnosed in 9 subjects (1 in the golimumab 50 mg treatment groups and 8 in the golimumab 100 mg treatment groups) with an incidence (95% CI) per 100 subject-years of follow-up of 0.03 (0.00, 0.16) and 0.12 (0.05, 0.24) events for golimumab 50 mg and 100 mg respectively and 0.00 (0.00, 0.59) events for the placebo. The majority of lymphomas occurred in study GO-AFTER, which enrolled patients previously exposed to anti-TNF agents who had longer disease duration and more refractory disease (see section 4.4). Malignancies other than lymphoma In the controlled periods of pivotal trials and through approximately 2 years of follow-up, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar between the golimumab and the control groups. Through approximately 2 years of follow-up, the incidence of non-lymphoma malignancies (excluding non-melanoma skin cancer) was similar to the general population. In the controlled and uncontrolled periods of pivotal trials with a median follow-up of approximately 2 years, non-melanoma skin cancer was diagnosed in 5 placebo-treated, 10 golimumab 50 mg-treated and 29 golimumab 100 mg-treated subjects with an incidence (95% CI) per 100 subject-years of follow-up of 0.38 (0.27, 0.52) for combined golimumab and 0.90 (0.29, 2.10) for placebo. In the controlled and uncontrolled period of pivotal trials with a median follow-up of approximately 2 years, malignancies besides melanoma, non-melanoma skin cancer and lymphoma were diagnosed in 5 placebo-treated, 19 golimumab 50 mg-treated and 30 golimumab 100 mg-treated subjects with an incidence (95% CI) per 100 subject-years of follow-up of 0.47 (0.35, 0.63) for combined golimumab and 0.90 (0.29, 2.10) for placebo (see section 4.4). Cases reported in clinical studies in asthma In an exploratory clinical study, patients with severe persistent asthma received a golimumab loading dose (150% of the assigned treatment dose) subcutaneously at week 0 followed by golimumab 200 mg, golimumab 100 mg or golimumab 50 mg every 4 weeks subcutaneously through week 52. Eight malignancies in the combined golimumab treatment group (n = 230) and none in the placebo treatment group (n = 79) were reported. Lymphoma was reported in 1 patient, non-melanoma skin cancer in 2 patients, and other malignancies in 5 patients. There was no specific clustering of any type of malignancy. During the placebo-controlled portion of the study, the incidence (95% CI) of all malignancies per 100 subject-years of follow-up was 3.19 (1.38, 6.28) in the golimumab group. In this study, the incidence (95% CI) per 100 subject-years of follow-up in golimumab-treated subjects was 0.40 (0.01, 2.20) for lymphoma, 0.79 (0.10, 2.86) for non-melanoma skin cancers, and 1.99 (0.64, 4.63) for other malignancies. For placebo subjects, the incidence (95% CI) per 100 subject-years of follow-up of these malignancies was 0.00 (0.00, 2.94). The significance of this finding is unknown. Neurological events In the controlled and uncontrolled periods of the pivotal trials with a median follow-up of approximately 2 years, a greater incidence of demyelination was observed in patients receiving golimumab 100 mg compared with patients receiving golimumab 50 mg (see section 4.4). Liver enzyme elevations In the controlled period of RA and PsA pivotal trials, mild ALT elevations (> 1 and < 3 x upper limit of normal (ULN)) occurred in similar proportions of golimumab and control patients in the RA and PsA studies (22.1% to 27.4% of patients); in the AS and nr-Axial SpA studies, more golimumab-treated patients (26.9%) than control patients (10.6%) had mild ALT elevations. In the controlled and uncontrolled periods of the RA and PsA pivotal trials, with a median follow-up of approximately 5 years, the incidence of mild ALT elevations was similar in golimumab-treated and control patients in RA and PsA studies. In the controlled period of the UC pivotal trials of golimumab induction, mild ALT elevations (> 1 and < 3 x ULN) occurred in similar proportions of golimumab-treated and control patients (8.0% to 6.9%, respectively). In controlled and uncontrolled periods of the UC pivotal trials with a mean follow-up of 1 year, the incidence of mild ALT elevations was 19.4% in patients receiving golimumab during the maintenance portion of the UC study. In the controlled period of RA and AS pivotal trials, ALT elevations ≥ 5 x ULN were uncommon and seen in more golimumab-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, the incidence of ALT elevations ≥ 5 x ULN was similar in both golimumab-treated and control patients. In general these elevations were asymptomatic and the abnormalities decreased or resolved with either continuation or discontinuation of golimumab or modification of concomitant medicinal products. In the controlled periods of the pivotal UC trials, of golimumab induction, ALT elevations ≥ 5 x ULN occurred in similar proportions of golimumab-treated patients compared to placebo-treated patients (0.3% to 1.0%, respectively). In the controlled and uncontrolled periods of the pivotal UC trials with a mean follow-up of 1 year, the incidence of ALT elevations ≥ 5 x ULN was 0.7% in patients receiving golimumab during the maintenance portion of the UC study. Within the RA, PsA, AS, and nr-Axial SpA pivotal trials, one patient in an RA trial with pre-existing liver abnormalities and confounding medicinal products treated with golimumab developed non-infectious fatal hepatitis with jaundice. The role of golimumab as a contributing or aggravation factor cannot be excluded. Injection site reactions In the controlled periods of pivotal trials, 5.4% of golimumab-treated patients had injection site reactions compared with 2.0% in control patients. The presence of antibodies to golimumab may increase the risk of injection site reactions. The majority of the injection site reactions were mild and moderate and the most frequent manifestation was injection site erythema. Injection site reactions generally did not necessitate discontinuation of the medicinal product. In controlled Phase IIb and/or III trials in RA, PsA, AS, nr-Axial SpA, severe persistent asthma, and Phase II/III trials in UC, no patients treated with golimumab developed anaphylactic reactions. Autoimmune antibodies In the controlled and uncontrolled periods of 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 titres 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 uncommon. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. 4.9 Overdose Single doses up to 10 mg/kg intravenously have been administered in a clinical study without dose-limiting toxicity. In case of an overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse effects and appropriate symptomatic treatment be instituted immediately. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Immunosuppressants, tumour necrosis factor alpha (TNF-α) inhibitors, ATC code: L04AB06 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-α, which prevents the binding of TNF-α to its receptors. Pharmacodynamic effects The binding of human TNF by golimumab was shown to neutralise TNF-α-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. In vitro, 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. 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 (MMP)-3 and vascular endothelial growth factor (VEGF) compared to control treatment. In addition, levels of TNF-α were 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 maintained through week 24. Clinical efficacy Rheumatoid arthritis The efficacy of Simponi was demonstrated in three multi-centre, randomised, double-blind, placebo-controlled studies in over 1500 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. Patients had at least 4 swollen and 4 tender joints. Simponi or placebo were subcutaneously administered every 4 weeks. 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 randomised to receive placebo + MTX, Simponi 50 mg + MTX, Simponi 100 mg + MTX or Simponi 100 mg + placebo. Patients receiving placebo + MTX were switched to Simponi 50 mg + MTX after week 24. At week 52, patients entered an open label long-term extension. GO-AFTER evaluated 445 patients who were previously treated with one or more of the anti-TNF agents adalimumab, etanercept, or infliximab. Patients were randomised to receive placebo, Simponi 50 mg, or Simponi 100 mg. Patients were allowed to continue concomitant DMARD therapy with MTX, sulfasalazine (SSZ), and/or hydroxychloroquine (HCQ) during the study. The stated reasons for discontinuation of prior anti TNF therapies were lack of efficacy (58%), intolerance (13%), and/or reasons other than safety or efficacy (29%, mostly for financial reasons). 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 randomised to receive placebo + MTX, Simponi 50 mg + MTX, Simponi 100 mg + MTX or Simponi 100 mg + placebo. At week 52, patients entered an open label long-term extension in which patients receiving placebo + MTX who had at least 1 tender or swollen joint were switched to Simponi 50 mg + MTX. In GO-FORWARD, the (co-)primary endpoints were the percentage of patients achieving an ACR 20 response at week 14 and the improvement from baseline in Health Assessment Questionnaire (HAQ) at week 24. In GO-AFTER, the primary endpoint was the percentage of patients achieving an ACR 20 response at week 14. In GO-BEFORE, the co-primary endpoints were the percentage of patients achieving ACR 50 response at week 24 and the change from baseline in the van der Heijde-modified Sharp (vdH-S) score at week 52. In addition to the primary endpoint(s), additional assessments of the impact of Simponi treatment on the signs and symptoms of arthritis, radiographic response, physical function and health-related quality of life were performed. In general, no clinically meaningful differences in measures of efficacy were observed between the Simponi 50 mg and 100 mg dosing regimens with concomitant MTX, through week 104 in GO-FORWARD and GO-BEFORE and through week 24 in GO-AFTER. In each of the RA studies by study design, patients in the long-term extension may have switched between the 50 mg and 100 mg Simponi doses at the discretion of the study physician. Signs and symptoms Key ACR results for the Simponi 50 mg dose at weeks 14, 24 and 52 for GO-FORWARD, GO-AFTER and GO-BEFORE are shown in Table 2 and are described below. Responses were observed at the first assessment (week 4) after the initial Simponi administration. In GO-FORWARD, among 89 subjects randomised to Simponi 50 mg + MTX, 48 were still on this treatment at week 104. Among those, 40, 33 and 24 patients had ACR 20/50/70 response, respectively at week 104. Among patients remaining in the study and treated with Simponi, similar rates of ACR 20/50/70 response was observed from week 104 through week 256. In GO-AFTER, the percentage of patients achieving an ACR 20 response was greater for patients receiving Simponi than for patients receiving placebo regardless of the reason reported for discontinuation of one or more prior anti-TNF therapies. Table 2 Key efficacy outcomes from the controlled portions of GO-FORWARD, GO-AFTER and GO-BEFORE.
In GO-FORWARD and GO-AFTER, clinically meaningful and statistically significant responses in Disease Activity Scale (DAS)28 were observed at each prespecified time point, at week 14 and at week 24 (p ≤ 0.001). Among patients who remained on the Simponi treatment to which they were randomised at study start, DAS28 responses were maintained through week 104. Among patients remaining in the study and treated with Simponi, DAS28 responses were similar from week 104 through week 256. In GO-BEFORE, major clinical response, defined as the maintenance of an ACR 70 response over a continuous 6-month period, was measured. At week 52, 15% of patients in the Simponi 50 mg + MTX group achieved a major clinical response compared with 7% of patients in the placebo + MTX group (p = 0.018). Among 159 subjects randomised to Simponi 50 mg + MTX, 96 were still on this treatment at week 104. Among those, 85, 66 and 53 patients had ACR 20/50/70 response, respectively, at week 104. Among patients remaining in the study and treated with Simponi, similar rates of ACR 20/50/70 response were observed from week 104 through week 256. Radiographic response: In 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 results for the Simponi 50 mg dose at week 52 are presented in Table 3. The number of patients with no new erosions or a change from baseline in total vdH-S Score ≤ 0 was significantly higher in the Simponi treatment group than in the control group (p = 0.003). The radiographic effects observed at week 52 were maintained through week 104. Among patients remaining in the study and treated with Simponi, radiographic effects were similar from week 104 through week 256. Table 3 Radiographic mean (SD) changes from baseline in total vdH-S score at week 52 in the overall population of GO-BEFORE
Physical function and disability were assessed as a separate endpoint in GO-FORWARD and GO-AFTER using the disability index of the HAQ DI. In these studies, Simponi demonstrated clinically meaningful and statistically significant improvement in HAQ DI from baseline versus control at week 24. Among patients who remained on the Simponi treatment to which they were randomised at study start, improvement in HAQ DI was maintained through week 104. Among patients remaining in the study and treated with Simponi, improvement in HAQ DI was similar from week 104 through week 256. In GO-FORWARD clinically meaningful and statistically significant improvements were demonstrated in health-related quality of life as measured by the physical component score of the SF-36 in patients treated with Simponi versus placebo at week 24. Among patients who remained on the Simponi treatment to which they were randomised at study start, improvement of the SF-36 physical component was maintained through week 104. Among patients remaining in the study and treated with Simponi, improvement of the SF-36 physical component was similar from week 104 through week 256. In GO-FORWARD and GO-AFTER, statistically significant improvements were observed in fatigue as measured by functional assessment of chronic illness therapy-fatigue scale (FACIT-F). Psoriatic arthritis The safety and efficacy of Simponi were evaluated in a multi-centre, randomised, double-blind, placebo-controlled study (GO-REVEAL) in 405 adult patients with active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite non-steroidal anti-inflammatory (NSAID) or DMARD therapy. Patients in this study had a diagnosis of PsA for at least 6 months and had at least mild psoriatic disease. Patients with each sub-type 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%). Previous treatment with an anti-TNF agent was not allowed. Simponi or placebo were administered subcutaneously every 4 weeks. Patients were randomly assigned to placebo, Simponi 50 mg, or Simponi 100 mg. Patients receiving placebo were switched to Simponi 50 mg after week 24. Patients entered an open label long-term extension at week 52. Approximately forty-eight percent of patients continued on stable doses of methotrexate (≤ 25 mg/week). The co-primary endpoints were the percentage of patients achieving ACR 20 response at week 14 and change from baseline in total PsA modified vdH-S score at week 24. In general, no clinically meaningful differences in measures of efficacy were observed between the Simponi 50 mg and 100 mg dosing regimens through week 104. By study design, patients in the long-term extension may have switched between the 50 mg and 100 mg Simponi doses at the discretion of the study physician. Signs and symptoms Key results for the 50 mg dose at weeks 14 and 24 are shown in Table 4 and described below. Table 4 Key efficacy outcomes from GO-REVEAL
Statistically significant responses in DAS28 were also observed at weeks 14 and 24 (p < 0.05). At week 24 improvements in parameters of peripheral activity characteristic of psoriatic arthritis (e.g. number of swollen joints, number of painful/tender joints, dactylitis and enthesitis) were seen in the Simponi-treated patients. Simponi treatment resulted in significant improvement in physical function as assessed by HAQ DI, as well as significant improvements in health-related quality of life as measured by the physical and mental component summary scores of the SF-36. Among patients who remained on the Simponi treatment to which they were randomised at study start, DAS28 and HAQ DI responses were maintained through week 104. Among patients remaining in the study and treated with Simponi, DAS28 and HAQ DI responses were similar from week 104 through week 256. Radiographic response: Structural damage in both hands and feet was assessed radiographically by the change from baseline in the vdH-S score, modified for PsA by addition of hand distal interphalangeal (DIP) joints. Simponi 50 mg treatment reduced the rate of progression of peripheral joint damage compared with placebo treatment at week 24 as measured by change from baseline in total modified vdH-S Score (mean ± SD score was 0.27 ± 1.3 in the placebo group compared with -0.16 ± 1.3 in the Simponi group; p = 0.011). Out of 146 patients who were randomized to Simponi 50 mg, 52 week X-ray data were available for 126 patients, of whom 77% showed no progression compared to baseline. At week 104, X-ray data were available for 114 patients, and 77% showed no progression from baseline. Among patients remaining in the study and treated with Simponi, similar rates of patients showed no progression from baseline from week 104 through week 256. Axial spondyloarthritis Ankylosing spondylitis The safety and efficacy of Simponi were evaluated in a multi-centre, randomised, double-blind, placebo-controlled study (GO-RAISE) in 356 adult patients with active ankylosing spondylitis (defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4 and a VAS for total back pain of ≥ 4, on a scale of 0 to 10 cm). Patients enrolled in this study had active disease despite current or previous NSAID or DMARD therapy and had not previously been treated with anti-TNF therapy. Simponi or placebo were administered subcutaneously every 4 weeks. Patients were randomly assigned to placebo, Simponi 50 mg and Simponi 100 mg and were allowed to continue concomitant DMARD therapy (MTX, SSZ and/or HCQ). The primary endpoint was the percentage of patients achieving Ankylosing Spondylitis Assessment Study Group (ASAS) 20 response at week 14. Placebo-controlled efficacy data were collected and analysed through week 24. Key results for the 50 mg dose are shown in Table 5 and described below. In general, no clinically meaningful differences in measures of efficacy were observed between the Simponi 50 mg and 100 mg dosing regimens through week 24. By study design, patients in the long-term extension may have switched bewtween the 50 mg and 100 mg Simponi doses at the discretion of the study physician. Table 5 Key efficacy outcomes from GO-RAISE.
Statistically significant responses in BASDAI 50, 70 and 90 (p ≤ 0.017) were also seen at weeks 14 and 24. Improvements in key measures of disease activity were observed at the first assessment (week 4) after the initial Simponi administration and were maintained through week 24. Among patients remaining in the study and treated with Simponi, similar rates of change from baseline in BASDAI were observed from week 24 through week 256. Consistent efficacy was seen in patients regardless of use of DMARDs (MTX, sulfasalazine and/or hydroxychloroquine), HLA-B27 antigen status or baseline CRP levels as assessed by ASAS 20 responses at week 14. Simponi treatment resulted in significant improvements in physical function as assessed by changes from baseline in BASFI at weeks 14 and 24. Health-related quality of life as measured by the physical component score of the SF-36 was also improved significantly at weeks 14 and 24. Among patients remaining in the study and treated with Simponi, improvements in physical function and health-related quality of life were similar from week 24 through week 256. Non-radiographic axial spondyloarthritis The safety and efficacy of Simponi were evaluated in a multi-centre, randomised, double-blind, placebo-controlled study (GO-AHEAD) in 197 adult patients with severe active nr-Axial SpA (defined as those patients meeting the ASAS classification criteria of axial spondyloarthritis but did not meet the modified New York criteria for AS). Patients enrolled in this study had active disease (defined as a BASDAI ≥ 4 and a Visual Analogue Scale (VAS) for total back pain of ≥ 4, each on a scale of 0-10 cm) despite current or previous NSAID therapy and had not previously been treated with any biological agents including anti-TNF therapy. Patients were randomly assigned to placebo or Simponi 50 mg administered subcutaneously every 4 weeks. At week 16, patients entered an open label period in which all patients received Simponi 50 mg administered subcutaneously every 4 weeks through week 48. Analyses were performed on both the All Treated (AT, N = 197) and Objective Signs of Inflammation (OSI, N = 158, defined by elevated CRP and/or evidence of sacroiliitis on MRI at baseline) populations. Placebo-controlled efficacy data were collected and analysed through week 16. The primary endpoint was the proportion of patients achieving ASAS 20 response at week 16. Key results are shown in Table 6 and described below. Table 6 Key efficacy outcomes from GO-AHEAD at week 16
Statistically significant improvements in spinal mobility as assessed by BASMI (Bath Ankylosing Spondylitis Metrology Index) and in physical function as assessed by the BASFI were demonstrated in Simponi 50 mg-treated patients as compared to placebo-treated patients (p < 0.0001). Patients treated with Simponi experienced significantly more improvements in health-related quality of life as assessed by ASQoL, EQ-5D, and physical and mental components of SF-36, and experienced significantly more improvements in productivity as assessed by greater reductions in overall work impairment and in activity impairment as assessed by the WPAI questionnaire than patients receiving placebo. For all of the endpoints described above, statistically significant results were also demonstrated in the OSI population. Similar improvements in signs and symptoms, spinal mobility, and physical function were observed at week 16 through week 24 among patients remaining in the study and treated with Simponi 50 mg. Ulcerative colitis The efficacy of Simponi was evaluated in two randomized, double-blind, placebo-controlled clinical studies in adult patients. The induction study (PURSUIT-Induction) evaluated patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12; Endoscopy subscore ≥ 2) who had an inadequate response to or failed to tolerate conventional therapies, or were corticosteroid dependent. In the dose confirming portion of the study, 761 patients 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. The efficacy of Simponi through week 6 was assessed in this study. The results of the maintenance study (PURSUIT-Maintenance) were based on evaluation of 456 patients who achieved clinical response from previous induction with Simponi. 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. Table 7 Key efficacy outcomes from PURSUIT - Induction and PURSUIT - Maintenance
Among the 54% of patients (247/456) who were receiving concomitant corticosteroids at the start of PURSUIT-Maintenance, the proportion of patients who maintained clinical response through week 54 and were not receiving concomitant corticosteroids at week 54 was greater in the 50 mg group (38%, 30/78) and 100 mg group (30%, 25/82) compared with the placebo group (21%, 18/87). The proportion of patients who eliminated corticosteroids by week 54 was greater in the 50 mg group (41%, 32/78) and 100 mg group (33%, 27/82) compared with the placebo group (22%, 19/87). At week 6, Simponi significantly improved quality of life as measured by change from baseline in a disease specific measure, IBDQ (inflammatory bowel disease questionnaire). Among patients who received Simponi maintenance treatment, the improvement in quality of life as measured by IBDQ was maintained through week 54. Immunogenicity Across the Phase III RA, PsA and AS studies through week 52, antibodies to golimumab were detected in 5% (105/2115) of golimumab treated patients and, where tested, nearly all antibodies were neutralising in vitro. Similar rates were shown across rheumatologic indications. Treatment with concomitant MTX resulted in a lower proportion of patients with antibodies to golimumab than patients receiving golimumab without MTX (approximately 3% [41/1262] versus 8% [64/853], respectively). In nr-Axial SpA, antibodies to golimumab were detected in 4% (4/93) of golimumab treated patients through week 16. In the Phase II and III UC studies through week 54, antibodies to golimumab were detected in 3% (26/946) of golimumab treated patients. Sixty-eight percent (21/31) of antibody-positive patients had neutralizing antibodies in vitro. Treatment with concomitant immunomodulators (azathioprine, 6-mercaptopurine and MTX) resulted in a lower proportion of patients with antibodies to golimumab than patients receiving golimumab without immunomodulators (1% (4/308) versus 3% (22/638), respectively). The presence of antibodies to golimumab may increase the risk of injection site reactions (see section 4.4). The small number of patients positive for antibodies to golimumab limits the ability to draw definitive conclusions regarding the relationship between antibodies to golimumab and clinical efficacy or safety measures. Because immunogenicity analyses are product- and assay-specific, comparison of antibody rates with those from other products is not appropriate. Paediatric population The European Medicines Agency has waived the obligation to conduct studies with Simponi in all subsets of the paediatric population in ankylosing spondylitis and rheumatoid arthritis (see section 4.2 for information on paediatric use). The European Medicines Agency has deferred the obligation to submit the results of studies with Simponi in one or more subsets of the paediatric population in juvenile idiopathic arthritis, psoriatic arthritis, and ulcerative colitis (see section 4.2 for information on paediatric use). 5.2 Pharmacokinetic properties Absorption Following a single subcutaneous administration of golimumab to healthy subjects or patients with RA, the median time to reach maximum serum concentrations (Tmax) ranged from 2 to 6 days. A subcutaneous injection of 50 mg golimumab to healthy subjects produced a mean ± standard deviation maximum serum concentration (Cmax) of 3.1 ± 1.4 μg/mL. Following a single subcutaneous injection of 100 mg, the absorption of golimumab was similar in the upper arm, abdomen, and thigh, with a mean absolute bioavailability of 51%. Since golimumab exhibited approximately dose proportional PK following a subcutaneous administration, the absolute bioavailability of a golimumab 50 mg or 200 mg dose is expected to be similar. Distribution Following a single IV administration, the mean volume of distribution was 115 ± 19 mL/kg. Elimination The systemic clearance of golimumab was estimated to be 6.9 ± 2.0 mL/day/kg. Terminal half-life value was estimated to be approximately 12 ± 3 days in healthy subjects and similar values were observed in patients with RA, PsA, AS, or UC. When 50 mg golimumab was administered subcutaneously to patients with RA, PsA or AS every 4 weeks, serum concentrations reached steady state by week 12. With concomitant use of MTX, treatment with 50 mg golimumab subcutaneously every 4 weeks resulted in a mean (± standard deviation) steady-state trough serum concentration of approximately 0.6 ± 0.4 μg/mL in RA patients with active RA despite MTX therapy, and approximately 0.5 ± 0.4 μg/mL in patients with active PsA and approximately 0.8 ± 0.4 μg/mL in patients with AS. Steady-state trough mean serum golimumab concentrations in patients with nr-Axial SpA were similar to those observed in patients with AS following subcutaneous administration of 50 mg golimumab every 4 weeks. Patients with RA, PsA or AS who did not receive concomitant MTX had approximately 30% lower steady-state trough concentrations of golimumab than those who received golimumab with MTX. In a limited number of RA patients treated with subcutaneous golimumab over a 6-month period, concomitant use of MTX reduced the apparent clearance of golimumab by approximately 36%. However, population pharmacokinetic analysis indicated that concomitant use of NSAIDs, oral corticosteroids or sulfasalazine did not influence the apparent clearance of golimumab. Following induction doses of 200 mg and 100 mg golimumab at week 0 and 2, respectively, and maintenance doses of 50 mg or 100 mg golimumab subcutaneously every 4 weeks thereafter to patients with UC, serum golimumab concentrations reached steady state approximately 14 weeks after the start of therapy. Treatment with 50 mg or 100 mg golimumab subcutaneous every 4 weeks during maintenance resulted in a mean steady-state trough serum concentration of approximately 0.9 ± 0.5 μg/mL and 1.8 ± 1.1 μg/mL, respectively. In UC patients treated with 50 mg or 100 mg golimumab subcutaneously every 4 weeks, concomitant use of immunomodulators did not have a substantial effect on steady-state trough levels of golimumab. Patients who developed anti-golimumab antibodies generally had low trough steady-state serum concentrations of golimumab (see section 5.1). Linearity Golimumab exhibited approximately dose-proportional pharmacokinetics in patients with RA over the dose range of 0.1 to 10.0 mg/kg following a single intravenous dose. Following a single SC dose in healthy subjects, approximately dose-proportional pharmacokinetics were also observed over a dose range of 50 mg to 400 mg. Effect of weight on pharmacokinetics There was a trend toward higher apparent clearance of golimumab with increasing weight (see section 4.2). 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, toxicity to reproduction and development. No mutagenicity studies, animal fertility studies nor long-term carcinogenic studies have been conducted with golimumab. In a fertility and general reproductive function study in mouse, using an analogous antibody that selectively inhibits the functional activity of mouse TNFα, the number of pregnant mice was reduced. It is not known whether this finding was due to effects on the males and/or the females. In a developmental toxicity study conducted in mice following administration of the same analogous antibody, and in cynomolgus monkeys using golimumab, there was no indication of maternal toxicity, embryotoxicity or teratogenicity. 6. Pharmaceutical particulars 6.1 List of excipients Sorbitol(E420) L-histidine L-histidine monohydrochloride monohydrate Polysorbate 80 Water for injection. 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 18 months 6.4 Special precautions for storage Store in a refrigerator (2°C – 8°C). Do not freeze. Keep the pre-filled pen or pre-filled syringe in the outer carton in order to protect it from light. 6.5 Nature and contents of container 0.5 mL solution in a pre-filled syringe (Type 1 glass) with a fixed needle (stainless steel) and a needle cover (rubber containing latex) in a pre-filled pen or pre-filled syringe. Simponi is available in packs containing 1 pre-filled pen or pre-filled syringe and multipacks containing 3 (3 packs of 1) pre-filled pens or pre-filled syringes. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling Simponi is supplied in a single use pre-filled pen called SmartJect or pre-filled syringe. Each Simponi pack is provided with instructions for use that fully describe the use of the pen or syringe. After removing the pre-filled pen or syringe from the refrigerator this should be allowed to reach room temperature by waiting for 30 minutes, before injecting Simponi. The pen or syringe should not be shaken. The solution is clear to slightly opalescent, colourless to light yellow and may contain a few small translucent or white particles of protein. This appearance is not unusual for solutions containing protein. Simponi should not be used if the solution is discoloured, cloudy or containing visible foreign particles. Comprehensive instructions for the preparation and administration of Simponi in a pre-filled pen or pre-filled syringe are given in the package leaflet. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Janssen Biologics B.V. Einsteinweg 101 2333 CB Leiden The Netherlands 8. Marketing authorisation number(s) EU/1/09/546/001 1 pre-filled pen EU/1/09/546/002 3 pre-filled pens EU/1/09/546/003 1 pre-filled syringe EU/1/09/546/004 3 pre-filled syringes 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 1 October 2009 Date of latest renewal: 19 June 2014 10. Date of revision of the text 22 June 2015 11. Legal category Prescription Only Medicine Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 附:Simponi 100 mg solution for injection(http://www.medicines.org.uk/emc/medicine/28316)
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戈利木单抗注射剂|SIMPONI(GOLIMUMAB)INJECTABLE简介:
英文药名: Simponi(Golimumab Injection)
中文药名: 戈利木单抗注射剂
生产厂家: 德国(MSD)药品介绍2013年9月23日,欧盟委员会批准SIMPONI(戈利木单抗)用于治疗对常规疗法(如激素、6-巯基嘌呤、咪 ... 责任编辑:admin |
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