英文药名：Orentia（abatacept injection in prefilled pen） 中文药名：阿巴西普预充笔注射溶液 生产厂家：百时美施贵宝公司 药品介绍 商品名：Orentia 通用名：阿巴西普abatacept 开发与上市厂商：本品由百时美施贵宝公司(Bristol-MyersSquibb)开发，2005年3月在美国首次上市，同年在加拿大上市。 适应证： 本品适用于经1种或多种缓解病情抗风湿药(OMARQ),如甲氨蝶呤、肿瘤坏死因子TNF)阻断剂洽疗但应答不足的中、重度活动性类风湿关节炎成年患者。本品可延缓疾病带来的结构性损伤进程.改善患者躯体功能减轻息者体征和症状。 药理: 本品为选择性T细胞共刺激调节剂，通过与抗原递呈细胞上的CDBO和CD86结合.抑制T细胞的激活。激活的T-细胞与类风湿性关节炎(RA)发病机制相关，且大里存在于RA患者的关节滑膜中。T-细胞完全瀚活至少需要得到来自抗原递呈细胞的2种信号传导，其中下细胞上的CD28与抗原递呈细胞上CD80或CD86的相互作用就是共刺激信号传导的关键步骤。本品通过与抗原递星细胞上CD80和CD8结合』进而阻断两者与下细胞上的CD28的相互作用.从而抑制T-细胞的激活。 临床研究显示，本品剂最达到约IOmglkg时，血浆中可溶性IL-2受体(slL一2R)，IL一6、类风湿因子(RF)、C反应蛋白(CRP).间质金属蛋白酶-3(MMP-3y及丁NF一a的水平均出现下降。但上述生物反应标记物水平的变化与本品治疗RA的作用关联尚待明确。 临床评价 5项随机双盲安慰剂对照的临床研究对本品疗效和安全性进行了评价.入选息者为18岁及以上经美国风湿病学会(ACR)标准确诊的活动性RA患者。研究中患者静脉输注本品或安慰剂』起始时及第2和4周各给药1次此后每R周1次。 一项针对122例经至少一种非生物制品类DMARD药物治疗或依那西普(etanercept)治疗无效的活动性RA 一项针对122例经至少一种非生物制品类DMARD药物治疗或依那西普tetanercepty治疗无效的活动性RA患者的研究中患者随机接受本品(0.5、2或9Omg/kg)或安慰剂治疗为期8周。另3项研究评价了本品的疗效和安全性.第2和3项纳入患者为对甲氨蝶呤治疗应答不足并继续接受维持剂量甲氨蝶吟治疗者第4项研究纳入患者为对TNF阻断剂应答不足并随机停用TNF阻断剂的患者，而其他DMARD药物则可继续使用.这3项研究均为期12个月口第5项研究纳入的患者为虽接受现有OMARD药物治疗但仍须其他疗法介入的活动性RA患者.其首要目的也是评价本品的安全性.该项研究为期B个月. 不良反应 本品最严重不良反应为严重感染和恶性肿瘤。最常见的不良反应(治疗组发生率》10%)为头痛、上呼吸道感染‘鼻咽炎和恶心。 需要临床干预(中断或停用本品)的最常见不良反应为感染.其中需要中断治疗的最常见感染为上呼吸道感染(1.0%).支气管炎{0.7%]和带状疙疹(0.7%).需要停药的最常见感染为肺炎(0.2%》、局部感染(0.2%)和支气管炎(0.1%)。 注意事项 本品不宜用于对其活性成分及其他成分过敏者 安慰剂对照临床研究显示接受本品十下NF阻断剂联合治疗的患者感染发生率高于仅接受下N「阻断剂者，前者的感染和严重感染发生率分别为63%和4.4%,后者则分别为43%和0.8%。但临床研究并未证明两者联用对疗效提高有重要作用.所以目前不推荐本品与TNF阻断剂联用。当患者由下NF阻断剂疗法转用本品治疗时.应监测患者的感染体征。 用法与用量 本品需在有条件下的医疗机构静脉输注给药。本品剂量达54mg/kg时.未见表观毒性作用。对于过量用药者.建议监测其不良反应体征和症状.并给予适当的对症疗法。本品用药剂量详见表，，应以30分钟静脉输注方式给药. 制剂 本品为一次性使用玻璃小瓶装低压冻干粉制剂.每瓶含本品254mg.美国规定使用时』本品须溶解于14mL美国药典(USP)标准的无菌注射用水中.并且只能使用随瓶配备的无硅酮一次性使用注射器及，8-21号计量注射针。 ORENCIA 125mg solution for injection in pre-filled pen 1. Name of the medicinal product ORENCIA 125 mg solution for injection in pre-filled pen. 2. Qualitative and quantitative composition Each pre-filled pen contains 125 mg of abatacept in one mL. Abatacept is a fusion protein produced by recombinant DNA technology in Chinese hamster ovary cells. For the full list of excipients, see section 6.1. 3. Pharmaceutical form Solution for injection (injection) in pre-filled pen (ClickJect). The solution is clear, colorless to pale yellow with a pH of 6.8 to 7.4. 4. Clinical particulars 4.1 Therapeutic indications Rheumatoid arthritis ORENCIA in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who responded inadequately to previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) or a tumour necrosis factor (TNF)-alpha inhibitor. A reduction in the progression of joint damage and improvement of physical function have been demonstrated during combination treatment with abatacept and methotrexate. 4.2 Posology and method of administration Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis. If a response to abatacept is not present within 6 months of treatment, the continuation of the treatment should be reconsidered (see section 5.1). Posology Adults ORENCIA subcutaneous (SC) may be initiated with or without an intravenous (IV) loading dose. ORENCIA SC should be administered weekly at a dose of 125 mg by subcutaneous injection regardless of weight (see section 5.1). If a single IV infusion is given to initiate treatment (IV loading dose before SC administration), the first 125 mg abatacept SC should be administered within a day of the IV infusion, followed by the weekly 125 mg abatacept SC injections (for the posology of the intravenous loading dose, please refer to section 4.2 of ORENCIA 250 mg powder for concentrate for solution for infusion). Patients transitioning from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose. No dose adjustment is required when used in combination with other DMARDs, corticosteroids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics. Missed dose If a patient misses an injection of ORENCIA and is within three days of the planned date, he/she should be instructed to take the missed dose immediately and remain on the original weekly schedule. If the dose is missed by more than three days, the patient should be instructed when to take the next dose based on medical judgment (condition of the patient, status of disease activity, etc). Elderly patients No dose adjustment is required (see section 4.4). Renal and hepatic impairment ORENCIA has not been studied in these patient populations. No dose recommendations can be made. Paediatric population The safety and efficacy of ORENCIA subcutaneous administration in children below 18 years of age have not been established. No data are available. The safety and efficacy of ORENCIA intravenous administration have been studied in children. The currently available data are described in the Summary of Product Characteristics of ORENCIA 250 mg powder for concentrate for solution for infusion. Method of administration For subcutaneous use. ORENCIA is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous injection technique, a patient may self-inject with ORENCIA if a physician/healthcare professional determines that it is appropriate. The total content (1 mL) of the pre-filled pen should be administered as a subcutaneous injection only. Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard. Comprehensive instructions for the preparation and administration of ORENCIA in a ClickJect pre-filled pen are given in the package leaflet and "Important instructions for use". For instructions on preparation, see section 6.6. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Severe and uncontrolled infections such as sepsis and opportunistic infections (see section 4.4). 4.4 Special warnings and precautions for use Combination with TNF-inhibitors There is limited experience with use of abatacept in combination with TNF-inhibitors (see section 5.1). In placebo-controlled clinical trials, in comparison with patients treated with TNF-inhibitors and placebo, patients who received combination TNF-inhibitors with abatacept experienced an increase in overall infections and serious infections (see section 4.5). Abatacept is not recommended for use in combination with TNF-inhibitors. While transitioning from TNF-inhibitor therapy to ORENCIA therapy, patients should be monitored for signs of infection (see section 5.1, Study VII). Allergic reactions Allergic reactions have been reported uncommonly with intravenous abatacept administration in clinical trials, where patients were not required to be pretreated to prevent allergic reactions (see section 4.8). Anaphylaxis or anaphylactoid reactions can occur after the first infusion and can be life-threatening. In postmarketing experience, a case of fatal anaphylaxis following the first infusion of ORENCIA has been reported. If any serious allergic or anaphylactic reaction occurs, intravenous or subcutaneous ORENCIA therapy should be discontinued immediately and appropriate therapy initiated, and the use of ORENCIA should be permanently discontinued (see section 4.8). Effects on the immune system Medicinal products which affect the immune system, including ORENCIA, may affect host defences against infections and malignancies, and affect vaccination responses. Co-administration of ORENCIA with biologic immunosuppressive or immunomodulatory agents could potentiate the effects of abatacept on the immune system (see section 4.5). Infections Serious infections, including sepsis and pneumonia, have been reported with abatacept (see section 4.8). Some of these infections have been fatal. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy which in addition to their underlying disease, could further predispose them to infections. Treatment with ORENCIA should not be initiated in patients with active infections until infections are controlled. Physicians should exercise caution when considering the use of ORENCIA in patients with a history of recurrent infections or underlying conditions which may predispose them to infections. Patients who develop a new infection while undergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIA should be discontinued if a patient develops a serious infection. No increase of tuberculosis was observed in the pivotal placebo-controlled studies; however, all ORENCIA patients were screened for tuberculosis. The safety of ORENCIA in individuals with latent tuberculosis is unknown. There have been reports of tuberculosis in patients receiving ORENCIA (see section 4.8). Patients should be screened for latent tuberculosis prior to initiating ORENCIA. The available medical guidelines should also be taken into account. Anti-rheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening for viral hepatitis should be performed in accordance with published guidelines before starting therapy with ORENCIA. Treatment with immunosuppressive therapy, such as ORENCIA, may be associated with progressive multifocal leukoencephalopathy (PML). If neurological symptoms suggestive of PML occur during ORENCIA therapy, treatment with ORENCIA should be discontinued and appropriate diagnostic measures initiated. Malignancies In the placebo-controlled clinical trials, the frequencies of malignancies in abatacept- and placebo-treated patients were 1.4% and 1.1%, respectively (see section 4.8). Patients with known malignancies were not included in these clinical trials. In carcinogenicity studies in mice, an increase in lymphomas and mammary tumours were noted. The clinical significance of this observation is unknown (see section 5.3). The potential role of abatacept in the development of malignancies, including lymphoma, in humans is unknown. There have been reports of non-melanoma skin cancers in patients receiving ORENCIA (see section 4.8). Periodic skin examination is recommended for all patients, particularly those with risk factors for skin cancer. Vaccinations Patients treated with ORENCIA may receive concurrent vaccinations, except for live vaccines. Live vaccines should not be given concurrently with abatacept or within 3 months of its discontinuation. Medicinal products that affect the immune system, including abatacept, may blunt the effectiveness of some immunisations (see section 4.5). Elderly patients A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received intravenous abatacept in placebo-controlled clinical trials. A total of 270 patients 65 years of age and older, including 46 patients 75 years and older, received subcutaneous abatacept in controlled clinical trials. The frequencies of serious infection and malignancy relative to placebo among intravenous abatacept-treated patients over age 65 were higher than among those under age 65. Similarly, the frequencies of serious infection and malignancy among subcutaneous abatacept-treated patients over age 65 were higher than among those under age 65. Because there is a higher incidence of infections and malignancies in the elderly in general, caution should be used when treating the elderly (see section 4.8). Autoimmune processes There is a theoretical concern that treatment with abatacept might increase the risk for autoimmune processes in adults, for example deterioration of multiple sclerosis. In the placebo-controlled clinical trials, abatacept treatment did not lead to increased autoantibody formation, such as antinuclear and anti-dsDNA antibodies, relative to placebo treatment (see sections 4.8 and 5.3). Patients on controlled sodium diet This medicinal product contains 0.014 mmol sodium (0.322 mg) per pre-filled syringe, i.e. essentially 'sodium- free'. 4.5 Interaction with other medicinal products and other forms of interaction Combination with TNF-inhibitors There is limited experience with the use of abatacept in combination with TNF-inhibitors (see section 5.1). While TNF-inhibitors did not influence abatacept clearance, in placebo-controlled clinical trials, patients receiving concomitant treatment with abatacept and TNF-inhibitors experienced more infections and serious infections than patients treated with only TNF-inhibitors. Therefore, concurrent therapy with ORENCIA and a TNF-inhibitor is not recommended. Combination with other medicinal products Population pharmacokinetic analyses did not detect any effect of methotrexate, NSAIDs, and corticosteroids on abatacept clearance (see section 5.2). No major safety issues were identified with use of abatacept in combination with sulfasalazine, hydroxychloroquine, or leflunomide. Combination with other medicinal products that affect the immune system and with vaccinations Co-administration of ORENCIA with biologic immunosuppressive or immunomodulatory agents could potentiate the effects of abatacept on the immune system. There is insufficient evidence to assess the safety and efficacy of ORENCIA in combination with anakinra or rituximab (see section 4.4). Vaccinations Live vaccines should not be given concurrently with abatacept or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. Medicinal products that affect the immune system, including ORENCIA, may blunt the effectiveness of some immunisations (see section 4.4). Exploratory studies to assess the effect of abatacept on the antibody response to vaccination in healthy subjects as well as the antibody response to influenza and pneumococcal vaccines in rheumatoid arthritis patients suggested that abatacept may blunt the effectiveness of the immune response, but did not significantly inhibit the ability to develop a clinically significant or positive immune response. Abatacept was evaluated in an open-label study in rheumatoid arthritis patients administered the 23-valent pneumococcal vaccine. After pneumococcal vaccination, 62 of 112 abatacept-treated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine. Abatacept was also evaluated in an open-label study in rheumatoid arthritis patients administered the seasonal influenza trivalent virus vaccine. After influenza vaccination, 73 of 119 abatacept-treated patients without protective antibody levels at baseline were able to mount an adequate immune response of at least a 4-fold increase in antibody titers to trivalent influenza vaccine. 4.6 Fertility, pregnancy and lactation Pregnancy and Women of childbearing potential There are no adequate data from use of abatacept in pregnant women. In pre-clinical embryo-fetal development studies no undesirable effects were observed at doses up to 29-fold a human 10 mg/kg dose based on AUC. In a pre- and postnatal development study in rats limited changes in immune function were observed at 11-fold a human 10 mg/kg dose based on AUC (see section 5.3). ORENCIA should not be used in pregnant women unless clearly necessary. Women of child-bearing potential should use effective contraception during treatment with ORENCIA and up to 14 weeks after the last dose of abatacept treatment. Breast-feeding Abatacept has been shown to be present in rat milk. It is not known whether abatacept is excreted in human milk. Women should not breastfeed while treated with ORENCIA and for up to 14 weeks after the last dose of abatacept treatment. Fertility Formal studies of the potential effect of abatacept on human fertility have not been conducted. In rats, abatacept had no undesirable effects on male or female fertility (see section 5.3). 4.7 Effects on ability to drive and use machines Based on its mechanism of action, abatacept is expected to have no or negligible influence on the ability to drive and use machines. However, dizziness and reduced visual acuity have been reported as common and uncommon adverse reactions respectively from patients treated with ORENCIA, therefore if a patient experiences such symptoms, driving and use of machinery should be avoided. 4.8 Undesirable effects Summary of the safety profile Intravenous abatacept has been studied in patients with active rheumatoid arthritis in placebo-controlled clinical trials (2,111 patients with abatacept, 1,099 with placebo). In placebo-controlled clinical trials with intravenous abatacept, adverse reactions (ARs) were reported in 51.8% of abatacept-treated patients and 46.4% of placebo-treated patients. The most frequently reported adverse reactions (≥ 5%) among abatacept-treated patients were headache, nausea, and upper respiratory tract infections. The proportion of patients who discontinued treatment due to ARs was 3.3% for abatacept-treated patients and 2.0% for placebo-treated patients. Tabulated list of adverse reactions Listed in Table 1 are adverse reactions observed in clinical trials and post-marketing experience presented by system organ class and frequency, using the following categories: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 1: Adverse Reactions *(e.g. pruritus, throat tightness, dyspnea) Description of selected adverse reactions Infections In the placebo-controlled clinical trials with intravenous abatacept, infections at least possibly related to treatment were reported in 23.1% of abatacept-treated patients and 20.7% of placebo-treated patients. Serious infections at least possibly related to treatment were reported in 1.8% of abatacept-treated patients and 1.1% of placebo-treated patients. Serious infections reported in at least one patient treated with abatacept (0.05% of patients) included the following: pneumonia, cellulitis, localised infection, urinary tract infection, bronchitis, diverticulitis, pyelonephritis acute, sepsis, abscess, arthritis bacterial, bacteraemia, bronchopneumonia, bronchopulmonary aspergillosis, bursitis infective, cellulitis staphylococcal, empyema, gastrointestinal infection, hepatitis E, infected skin ulcer, peridiverticular abscess, pneumonia bacterial, pneumonia haemophilus, pneumonia influenzal, sinusitis, streptococcal sepsis, tuberculosis, urosepsis (see section 4.4). In double blind and open-label clinical trials in 4,149 patients treated with intravenous abatacept during 11,584 patient-years, the incidence rate of serious infections was 2.87 per 100 patient -years, and the annualized incidence rate remained stable. Malignancies In placebo-controlled clinical trials with intravenous abatacept, malignancies were reported in 29 of 2,111 abatacept-treated patients observed during 1,829 patient-years, and in 12 of 1,099 placebo-treated patients observed during 849 patient-years. In double blind and open-label clinical trials in 4,149 patients treated with intravenous abatacept during 11,932 patient-years (of which over 1,000 were treated with abatacept for over 5 years), the incidence rate of malignancy was 1.42 per 100 patient-years, and the annualized incidence rate remained stable. The incidence rates per 100 patient-years were 0.73 for non-melanomatous skin cancer, 0.59 for solid malignancies and 0.13 for hematologic malignancies. The most frequently reported organ cancer was lung cancer (0.15 per 100 patient-years), and the most common hematologic malignancy was lymphoma (0.07 per 100 patient-years). The incidence rate did not increase for malignancies overall, by major type (non-melanomatous skin cancer, solid tumors, and hematologic malignancies), or for individual tumor types in the double blind and open label period compared to the double-blind experience. The type and pattern of malignancies reported during the open-label period of the trials were similar to those reported for the double-blind experience. The incidence rate of observed malignancies was consistent with that expected in an age- and gender-matched rheumatoid arthritis population (see section 4.4). Adverse reactions in patients with chronic obstructive pulmonary disease (COPD) In Study IV, there were 37 patients with COPD treated with intravenous abatacept and 17 treated with placebo. The COPD patients treated with abatacept developed adverse reactions more frequently than those treated with placebo (51.4% vs. 47.1%, respectively). Respiratory disorders occurred more frequently in abatacept-treated patients than in placebo-treated patients (10.8% vs. 5.9%, respectively); these included COPD exacerbation, and dyspnea. A greater percentage of abatacept- than placebo-treated patients with COPD developed a serious adverse reaction (5.4% vs. 0%), including COPD exacerbation (1 of 37 patients [2.7%]) and bronchitis (1 of 37 patients [2.7%]). Autoimmune processes Abatacept therapy did not lead to increased formation of autoantibodies, i.e., antinuclear and anti-dsDNA antibodies, compared with placebo. The incidence rate of autoimmune disorders remained stable during open-label experience (1.95 per 100 patient -years) compared to the double blind experience (2.36 per 100 patient -years).The most frequently reported autoimmune-related disorders during the open-label experience were psoriasis, vasculitis, and Sjogren's syndrome. Immunogenicity in adults treated with intravenous abatacept Antibodies directed against the abatacept molecule were assessed by ELISA assays in 3,985 rheumatoid arthritis patients treated for up to 8 years with abatacept. One hundred and eighty-seven of 3,877 (4.8%) patients developed anti-abatacept antibodies while on treatment. In patients assessed for anti-abatacept antibodies after discontinuation of abatacept (> 42 days after last dose), 103 of 1,888 (5.5%) were seropositive. Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies. Twenty-two of 48 evaluable patients showed significant neutralizing activity. The potential clinical relevance of neutralizing antibody formation is not known. Overall, there was no apparent correlation of antibody development to clinical response or adverse events. However, the number of patients that developed antibodies was too limited to make a definitive assessment. Because immunogenicity analyses are product-specific, comparison of antibody rates with those from other products is not appropriate. Immunogenicity in adults treated with subcutaneous abatacept Study SC-I compared the immunogenicity to abatacept following subcutaneous or intravenous administration as assessed by ELISA assay. During the double blind 6 months period, the overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no effect of immunogenicity on pharmacokinetics, safety, or efficacy. Immunogenicity to abatacept following long-term subcutaneous administration was assessed by a new ECL assay. Comparison of incidence rates across different assays is not appropriate, as the ECL assay was developed to be more sensitive and drug tolerant than the previous ELISA assay. The overall immunogenicity frequency to abatacept by the ECL assay was 9.3% (128/1369) while on abatacept, mean duration of 29.9 months, and 12.7% (17/134) after discontinuation (> 21 days after last dose). Consistent with previous experience, titers were generally low and did not persist or increase upon continued dosing (1.6% subjects were seropositive on 2 consecutive visits) and there was no apparent correlation of antibody development to clinical response, adverse events, or PK. Immunogenicity and safety of abatacept upon withdrawal (three months) and restart of treatment A study in the subcutaneous program was conducted to investigate the effect of withdrawal (three months) and restart of abatacept subcutaneous treatment on immunogenicity. Upon withdrawal of abatacept subcutaneous treatment, the increased rate of immunogenicity was consistent with that seen upon discontinuation of abatacept administered intravenously. Upon reinitiating therapy, there were no injection reactions and no other safety concerns in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in the treatment arm that reinitiated therapy without an intravenous loading dose was also consistent with that observed in the other studies. Injection Reactions in adult patients treated with subcutaneous abatacept Study SC-I compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the subcutaneous placebo group (intravenous abatacept), respectively. All injection site reactions were described as mild to moderate (hematoma, pruritus, or erythema) and generally did not necessitate drug discontinuation. Postmarketing reports of systemic injection reactions (e.g. pruritus, throat tightness, dyspnea) have been received following the use of subcutaneous ORENCIA. Safety information related to the pharmacological class Abatacept is the first selective co-stimulation modulator. Information on the relative safety in a clinical trial versus infliximab is summarized in section 5.1. 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 Doses up to 50 mg/kg have been administered intravenously without apparent toxic effect. In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions and appropriate symptomatic treatment instituted. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA24 Abatacept is a fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in Chinese hamster ovary cells. Mechanism of action Abatacept selectively modulates a key costimulatory signal required for full activation of T lymphocytes expressing CD28. Full activation of T lymphocytes requires two signals provided by antigen presenting cells: recognition of a specific antigen by a T cell receptor (signal 1) and a second, costimulatory signal. A major costimulatory pathway involves the binding of CD80 and CD86 molecules on the surface of antigen presenting cells to the CD28 receptor on T lymphocytes (signal 2). Abatacept selectively inhibits this costimulatory pathway by specifically binding to CD80 and CD86. Studies indicate that naive T lymphocyte responses are more affected by abatacept than memory T lymphocyte responses. Studies in vitro and in animal models demonstrate that abatacept modulates T lymphocyte-dependent antibody responses and inflammation. In vitro, abatacept attenuates human T lymphocyte activation as measured by decreased proliferation and cytokine production. Abatacept decreases antigen specific TNFα, interferon-γ, and interleukin-2 production by T lymphocytes. Pharmacodynamic effects Dose-dependent reductions were observed with abatacept in serum levels of soluble interleukin-2 receptor, a marker of T lymphocyte activation; serum interleukin-6, a product of activated synovial macrophages and fibroblast-like synoviocytes in rheumatoid arthritis; rheumatoid factor, an autoantibody produced by plasma cells; and C-reactive protein, an acute phase reactant of inflammation. In addition, serum levels of matrix metalloproteinase-3, which produces cartilage destruction and tissue remodelling, were decreased. Reductions in serum TNFα were also observed. Clinical efficacy and safety in adult rheumatoid arthritis The efficacy and safety of intravenous abatacept were assessed in randomised, double-blind, placebo-controlled clinical trials in adult patients with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, V, and VI required patients to have at least 12 tender and 10 swollen joints at randomization. Study IV did not require any specific number of tender or swollen joints. Study SC-I was a randomized, double-blind, double-dummy non-inferiority study administered to patients stratified by body weight (< 60 kg, 60 to 100 kg, > 100 kg) that compared the efficacy and safety of abatacept administered subcutaneously and intravenously in subjects with rheumatoid arthritis (RA), receiving background methotrexate (MTX), and experiencing an inadequate response to MTX (MTX-IR). In Studies I, II, and V the efficacy and safety of abatacept compared to placebo were assessed in patients with an inadequate response to methotrexate and who continued on their stable dose of methotrexate. In addition, Study V investigated the safety and efficacy of abatacept or infliximab relative to placebo. In Study III the efficacy and safety of abatacept were assessed in patients with an inadequate response to a TNF-inhibitor, with the TNF-inhibitor discontinued prior to randomization; other DMARDs were permitted. Study IV primarily assessed safety in patients with active rheumatoid arthritis requiring additional intervention in spite of current therapy with non-biological and/or biological DMARDs; all DMARDs used at enrollment were continued. In Study VI, the efficacy and safety of abatacept were assessed in methotrexate-naive, Rheumatoid Factor (RF) and/or anti-Cyclic Citrullinated Peptide 2 (Anti-CCP2)-positive patients with early, erosive rheumatoid arthritis (≤ 2 years disease duration) who were randomized to receive abatacept plus methotrexate or methotrexate plus placebo. In Study SC-I, the goal was to demonstrate non-inferiority of the efficacy and comparability of the safety of abatacept subcutaneous relative to intravenous administration in subjects with moderate to severely active RA and experiencing inadequate response to MTX. Study SC-II investigated the relative efficacy and safety of abatacept and adalimumab, both given subcutaneously without an intravenous loading dose and with background MTX, in patients with moderate to severely active RA and an inadequate response to previous MTX therapy. Study I patients were randomized to receive abatacept 2 or 10 mg/kg or placebo for 12 months. Study II, III, IV, and VI patients were randomized to receive a fixed dose approximating 10 mg/kg of abatacept or placebo for 12 (Studies II, IV, and VI) or 6 months (Study III). The dose of abatacept was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg. In Study SC-I, abatacept was given subcutaneously to patients after a single loading dose of intravenous abatacept and then every week thereafter. Subjects continued taking their current dose of MTX from the day of randomization. Study V patients were randomized to receive this same fixed dose of abatacept or 3 mg/kg infliximab or placebo for 6 months. Study V continued for an additional 6 months with the abatacept and infliximab groups only. Studies I, II, III, IV, V, VI, SC-I, and SC-II evaluated 339, 638, 389, 1,441, 431, 509 1,371, and 646 adult patients, respectively. Clinical response ACR response The percent of abatacept-treated patients achieving ACR 20, 50, and 70 responses in Study II (patients with inadequate response to methotrexate), Study III (patients with inadequate response to TNF-inhibitor), Study VI (methotrexate-naive patients), and Study SC-I (subcutaneous abatacept) are shown in Table 2. In abatacept-treated patients in Studies II and III, statistically significant improvement in the ACR 20 response versus placebo was observed after administration of the first dose (day 15), and this improvement remained significant for the duration of the studies. In Study VI, statistically significant improvement in the ACR 20 response in abatacept plus methotrexate-treated patients versus methotrexate plus placebo-treated patients was observed at 29 days, and was maintained through the duration of the study. In Study II, 43% of the patients who had not achieved an ACR 20 response at 6 months developed an ACR 20 response at 12 months. In Study SC-I, abatacept administered subcutaneously (SC) was non-inferior relative to intravenous (IV) infusions of abatacept with respect to ACR 20 responses up to 6 months of treatment. Patients treated with abatacept subcutaneously also achieved similar ACR 50 and 70 responses as those patients receiving abatacept intravenously at 6 months. No difference in clinical response between subcutaneous and intravenous abatacept was seen across the 3 weight groups. In SC-1, the ACR 20 response rates at Day 169 for subcutaneous and intravenous abatacept were respectively 78.3% (472/603 SC) and 76.0% (456/600 IV) in patients < 65 years, versus 61.1% (55/90 SC) and 74.4% (58/78 IV) for patients ≥ 65 years. Table 2: Clinical Responses in Controlled Trials * p < 0.05, abatacept vs. placebo. p < 0.01, abatacept vs. placebo. p < 0.001, abatacept vs. placebo. p < 0.01, abatacept plus MTX vs. MTX plus placebo p < 0.001, abatacept plus MTX vs. MTX plus placebo p < 0.05, abatacept plus MTX vs. MTX plus placebo 95% CI: −4.2, 4.8 (based on prespecified margin for non-inferiority of −7.5%) TT data is presented in table a Fixed dose approximating 10 mg/kg (see section 4.2). b Concurrent DMARDs included one or more of the following: methotrexate, chloroquine/hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, gold, and anakinra. c Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period. d After 6 months, patients were given the opportunity to enter an open-label study. e DAS28-CRP Remission is defined as a DAS28-CRP score < 2.6 f Per protocol data is presented in table. For ITT; n=736, 721 for subcutaneous (SC) and intravenous (IV) abatacept, respectively In the open-label extension of Studies I, II, III, and VI durable and sustained ACR 20, 50, and 70 responses have been observed through 7 years, 5 years, 5 years, and 2 years, respectively, of abatacept treatment. In study I, ACR responses were assessed at 7 years in 43 patients with 72% ACR 20 responses, 58% ACR 50 responses, and 44% ACR 70 responses. In study II, ACR responses were assessed at 5 years in 270 patients with 84% ACR 20 responses, 61% ACR 50 responses, and 40% ACR 70 responses. In study III, ACR responses were assessed at 5 years in 91 patients with 74% ACR 20 responses, 51% ACR 50 responses, and 23% ACR 70 responses. In study VI, ACR responses were assessed at 2 years in 232 patients with 85% ACR 20 responses, 74% ACR 50 responses, and 54% ACR 70 responses. Greater improvements were seen with abatacept than with placebo in other measures of rheumatoid arthritis disease activity not included in the ACR response criteria, such as morning stiffness. DAS28 response Disease activity was also assessed using the Disease Activity Score 28. There was a significant improvement of DAS in Studies II, III, V, and VI as compared to placebo or comparator. In study VI, which only included adults, a significantly higher proportion of patients in the abatacept plus methotrexate group (41%) achieved DAS28 (CRP)-defined remission (score < 2.6) versus the methotrexate plus placebo group (23%) at year 1. The response at year 1 in the abatacept group was maintained through year 2. Study V: abatacept or infliximab versus placebo A randomized, double-blind study was conducted to assess the safety and efficacy of intravenous abatacept or infliximab versus placebo in patients with an inadequate response to methotrexate (Study V). The primary outcome was the mean change in disease activity in abatacept- treated patients compared to placebo-treated patients at 6 months with a subsequent double-blind assessment of safety and efficacy of abatacept and infliximab at 12 months. Greater improvement (p < 0.001) in DAS28 was observed with abatacept and with infliximab compared to placebo at six months in the placebo-controlled portion of the trial; the results between the abatacept and infliximab groups were similar. The ACR responses in Study V were consistent with the DAS28 score. Further improvement was observed at 12 months with abatacept. At 6 months, the incidence of AE of infections were 48.1% (75), 52.1% (86), and 51.8% (57) and the incidence of serious AE of infections were 1.3% (2), 4.2% (7), and 2.7% (3) for abatacept, infliximab and placebo groups, respectively. At 12 months, the incidence of AE of infections were 59.6% (93), 68.5% (113), and the incidence of serious AE of infections were 1.9% (3) and 8.5% (14) for abatacept and infliximab groups, respectively. The open label period of the study provided an assessment of the ability of abatacept to maintain efficacy for subjects originally randomized to abatacept and the efficacy response of those subjects who were switched to abatacept following treatment with infliximab. The reduction from baseline in mean DAS28 score at day 365 (-3.06) was maintained through day 729 (-3.34) in those patients who continued with abatacept. In those patients who initially received infliximab and then switched to abatacept, the reduction in the mean DAS28 score from baseline were 3.29 at day 729 and 2.48 at day 365. Study SC-II: abatacept versus adalimumab A randomized, single(investigator)-blinded, non-inferiority study was conducted to assess the safety and efficacy of weekly subcutaneous (SC) abatacept without an abatacept intravenous (IV) loading dose versus every-other-weekly subcutaneous adalimumab, both with background MTX, in patients with an inadequate response to methotrexate (Study SC-II). The primary endpoint showed non-inferiority (predefined margin of 12%) of ACR20 response after 12 months of treatment, 64.8% (206/318) for the abatacept SC group and 63.4% (208/328) for the adalimumab SC group; treatment difference was 1.8% [95% confidence interval (CI): -5.6, 9.2], with comparable responses throughout the 24-month period. The respective values for ACR 20 at 24 months were 59.7% (190/318) for the abatacept SC group and 60.1% (197/328) for the adalimumab SC group. The respective values for ACR 50 and ACR 70 at 12 months and 24 months were consistent and similar for abatacept and adalimumab. The adjusted mean changes (standard error; SE) from baseline in DAS28-CRP were -2.35 (SE 0.08) [95% CI: -2.51, -2.19] and -2.33 (SE 0.08) [95% CI: -2.50, -2.17] in the SC abatacept group and the adalimumab group, respectively, at 24 months, with similar changes over time. At 24 months, 50.6% (127/251) [95% CI: 44.4, 56.8] of patients in abatacept and 53.3% (130/244) [95% CI: 47.0, 59.5] of patients in adalimumab groups achieved DAS 28 < 2.6. Improvement from baseline as measured by HAQ-DI at 24 months and over time was also similar between abatacept SC and adalimumab SC. Safety and structural damage assessments were conducted at one and two years. The overall safety profile with respect to adverse events was similar between the two groups over the 24-month period. After 24 months, adverse reactions were reported in 41.5% (132/318) and 50% (164/328) of abatacept and adalimumab-treated patients. Serious adverse reactions were reported in 3.5% (11/318) and 6.1% (20/328) of the respective group. At 24 months, 20.8 % (66/318) of patients in abatacept and 25.3 % (83/328) on adalimumab had discontinued. In SC-II, serious infections were reported in 3.8 % (12/318) of patients treated with abatacept SC weekly, none of which led to discontinuation and in 5.8 % (19/328) of patients treated with adalimumab SC every-other-week, leading to 9 discontinuations in the 24-month period. The frequency of local injection site reactions was 3.8% (12/318) and 9.1% (30/328) at 12 months (p=0.006) and 4.1% (13/318) and 10.4% (34/328) at 24 months for abatacept SC and adalimumab SC, respectively. Over the 2 year study period, 3.8 % (12/318) and 1.5 % (5/328) patients treated with abatacept SC and adalimumab SC respectively reported autoimmune disorders mild to moderate in severity (e.g., psoriasis, Raynaud's phenomenon, erythema nodosum). Radiographic response Structural joint damage was assessed radiographically over a two-year period in Studies II, VI, and SC-II. The results were measured using the Genant-modified total Sharp score (TSS) and its components, the erosion score and joint space narrowing (JSN) score. In Study II, the baseline median TSS was 31.7 in abatacept-treated patients and 33.4 in placebo-treated patients. Abatacept/methotrexate reduced the rate of progression of structural damage compared to placebo/methotrexate after 12 months of treatment as shown in Table 3. The rate of progression of structural damage in year 2 was significantly lower than that in year 1 for patients randomized to abatacept (p < 0.0001). Subjects entering the long term extension after 1 year of double blind treatment all received abatacept treatment and radiographic progression was investigated through year 5. Data were analyzed in an as-observed analysis using mean change in total score from the previous annual visit. The mean change was, 0.41 and 0.74 from year 1 to year 2 (n=290, 130), 0.37 and 0.68 from year 2 to year 3 (n=293, 130), 0.34 and 0.43 year from 3 to year 4 (n=290, 128) and the change was 0.26 and 0.29 (n=233, 114) from year 4 to year 5 for patients originally randomized to abatacept plus MTX and placebo plus MTX respectively. Table 3: Mean Radiographic Changes Over 12 Months in Study II a Based on non-parametric analysis. In Study VI, the mean change in TSS at 12 months was significantly lower in patients treated with abatacept plus methotrexate compared to those treated with methotrexate plus placebo. At 12 months 61% (148/242) of the patients treated with abatacept plus methotrexate and 53% (128/242) of the patients treated with methotrexate plus placebo had no progression (TSS ≤ 0). The progression of structural damage was lower in patients receiving continuous abatacept plus methotrexate treatment (for 24 months) compared to patients who initially received methotrexate plus placebo (for 12 months) and were switched to abatacept plus methotrexate for the next 12 months. Among the patients who entered the open-label 12 month period, 59% (125/213) of patients receiving continuous abatacept plus methotrexate treatment and 48% (92/192) of patients who initially received methotrexate and switched to combination with abatacept had no progression. In Study SC-II, structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde-modified Total Sharp Score (mTSS) and its components. Similar inhibition was observed in both treatment groups up to 24 months (mTSS (mean ± standard deviation [SD] = 0.89 ± 4.13 vs 1.13 ±8.66), erosion score (0.41 ± 2.57 vs 0.41 ±5.04), and JSN score (0.48 ±2.18 vs 0.72 ±3.81)) for the abatacept (n=257) and adalimumab (n=260) groups, respectively. Physical function response Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQ-DI) in Studies II, III, IV, V, and VI and the modified HAQ-DI in Study I. In Study SC-I, improvement from baseline as measured by HAQ-DI at 6 months and over time was similar between subcutaneous and intravenous administration. The results from Studies II, III, and VI are shown in Table 4. Table 4: Improvement in Physical Function in Controlled Trials p < 0.001, abatacept vs. placebo. p < 0.05, abatacept plus MTX vs MTX plus placebo a Fixed dose approximating 10 mg/kg (see section 4.2). b Concurrent DMARDs included one or more of the following: methotrexate, chloroquine/hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, gold, and anakinra. c Health Assessment Questionnaire; 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. d Reduction in HAQ-DI of ≥ 0.3 units from baseline. e After 6 months, patients were given the opportunity to enter into an open-label study. In Study II, among patients with clinically meaningful improvement at month 12, 88% retained the response at month 18, and 85% retained the response at month 24. During the open-label periods of Studies I, II, III, and VI the improvement in physical function has been maintained through 7 years, 5 years, 5 years, and 2 years, respectively. Health-related outcomes and quality of life Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in Studies I, II, and III and at 12 months in Studies I and II. In these studies, clinically and statistically significant improvement was observed in the abatacept group as compared with the placebo group in all 8 domains of the SF-36 (4 physical domains: physical function, role physical, bodily pain, general health; and 4 mental domains: vitality, social function, role emotional, mental health), as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS). In Study VI, improvement was observed at 12 months in abatacept plus methotrexate group as compared with the methotrexate plus placebo group in both PCS and MCS, and was maintained through 2 years. Study VII: Safety of abatacept in patients with or without washout of previous TNF-inhibitor therapy A study of open-label intravenous abatacept on a background of nonbiologic DMARDs was conducted in patients with active RA who had an inadequate response to previous (washout for at least 2 months; n=449) or current (no washout period; n=597) TNF-inhibitor therapy (Study VII). The primary outcome, incidence of AEs, SAEs, and discontinuations due to AEs during 6 months of treatment, was similar between those who were previous and current TNF-inhibitor users at enrollment, as was the frequency of serious infections. The European Medicines Agency has deferred the obligation to submit the results of studies with ORENCIA subcutaneous in one or more subsets of the paediatric population in chronic idiopathic arthritis (including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis) (see section 4.2 for information on paediatric use). Study SC-I: Pre-filled pen (ClickJect) sub-study Patients in the sub-study (n=117) of the open-label extension of study SC-I received 125 mg of subcutaneous (SC) abatacept administered weekly via the pre-filled syringe for at least 4 months, and were then switched to receive 125 mg SC abatacept administered weekly via the pre-filled pen for 12 weeks. The adjusted geometric mean of abatacept at steady state trough concentration (Cminss) was 25.3 µg/mL for the SC pre-filled pen and 27.8 µg/mL for the SC pre-filled syringe with a ratio of 0.91 [90% CI: 0.83, 1.00]. During the 12-week pre-filled pen period of the sub-study, there were no deaths or related SAEs. Three patients had SAEs (postoperative wound infection, H1N1 influenza, and myocardial ischemia in 1 patient each) that were not considered related to the study drug. There were six overall discontinuations during this period, only one of which was due to an AE (the SAE of post-operative wound infection). Two patients (2/117, 1.7%) using the SC pre-filled pen experienced local injection site reactions. 5.2 Pharmacokinetic properties The geometric mean estimate (90% confidence interval) for the bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6% (64.7%, 95.6%). The mean (range) for Cmin and Cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 l/kg), and terminal half-life (14.3 days) were comparable between subcutaneous and intravenous administration. A single study was conducted to determine the effect of monotherapy use of abatacept on immunogenicity following subcutaneous administration without an intravenous load. When the intravenous loading dose was not administered, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing. The efficacy response over time in this study appeared consistent with studies that included an intravenous loading dose, however, the effect of no intravenous load on the onset of efficacy has not been formally studied. Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in RA patients revealed that there was a trend toward higher clearance of abatacept with increasing body weight. Age and gender (when corrected for body weight) did not affect apparent clearance. Concomitant MTX, NSAIDs, corticosteroids, and TNF-inhibitors did not influence abatacept apparent clearance. 5.3 Preclinical safety data No mutagenicity or clastogenicity was observed with abatacept in a battery of in vitro studies. In a mouse carcinogenicity study, increases in the incidence of malignant lymphomas and mammary gland tumours (in females) occurred. The increased incidence of lymphomas and mammary tumours observed in mice treated with abatacept may have been associated with decreased control of murine leukaemia virus and mouse mammary tumour virus, respectively, in the presence of long-term immunomodulation. In a one-year toxicity study in cynomolgus monkeys, abatacept was not associated with any significant toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centres in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphological changes was observed, despite the presence of a virus, lymphocryptovirus, which is known to cause such lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of abatacept is unknown. In rats, abatacept had no undesirable effects on male or female fertility. Embryo-foetal development studies were conducted with abatacept in mice, rats, and rabbits at doses up to 20 to 30 times a human 10 mg/kg dose and no undesirable effects were observed in the offspring. In rats and rabbits, abatacept exposure was up to 29-fold a human 10 mg/kg exposure based on AUC. Abatacept was shown to cross the placenta in rats and rabbits. In a pre- and postnatal development study with abatacept in rats, no undesirable effects were observed in pups of dams given abatacept at doses up to 45 mg/kg, representing 3-fold a human 10 mg/kg exposure based on AUC. At a dose of 200 mg/kg, representing 11-fold a human exposure at 10 mg/kg based on AUC, limited changes in immune function (a 9-fold increase in the mean T-cell-dependent antibody response in female pups and inflammation of the thyroid of 1 female pup out of 10 male and 10 female pups evaluated at this dose) were observed. Non-clinical studies relevant for use in the paediatric population Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (juvenile rats). In addition, inflammation of the thyroid and pancreas was frequently seen in both juvenile and adult rats exposed to abatacept. Juvenile rats seemed to be more sensitive to lymphocytic inflammation of thyroid. Studies in adult mice and monkeys have not demonstrated similar findings. It is likely that the increased susceptibility to opportunistic infections observed in juvenile rats is associated with the exposure to abatacept before development of memory responses. The relevance of these results to humans greater than 6 years of age is unknown. 6. Pharmaceutical particulars 6.1 List of excipients Sucrose Poloxamer 188 Sodium dihydrogen phosphate monohydrate Disodium phosphate anhydrous Water for injections 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. 6.3 Shelf life 2 years 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Do not freeze. Store in the original package in order to protect from light. 6.5 Nature and contents of container One mL pre-filled syringe (Type 1 glass) in a ClickJect pre-filled pen. The Type 1 glass syringe has a coated stopper and fixed stainless steel needle covered with a rigid needle shield. Pack of 4 pre-filled pens and multipack containing 12 pre-filled pens (3 packs of4). Not all pack-sizes may be marketed. 6.6 Special precautions for disposal and other handling The medicinal product is for single use only. After removing the pre-filled pen from the refrigerator the pre-filled pen should be allowed to reach room temperature by waiting 30 minutes, before injecting ORENCIA. The pen should not be shaken. Any unused product or waste material should be disposed of in accordance with local requirements. 7. Marketing authorisation holder Bristol-Myers Squibb Pharma EEIG Uxbridge Business Park Sanderson Road Uxbridge UB8 1DH United Kingdom 8. Marketing authorisation number(s) EU/1/07/389/011 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 21 May 2007 Date of latest Renewal: 21 May 2012 10. Date of revision of the text April 2015 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. http://www.medicines.org.uk/emc/medicine/30346 附： ORENCIA 125 mg solution for injection (pre-filled syringe)（http://www.medicines.org.uk/emc/medicine/27216） ORENCIA 250 mg powder for concentrate for solution for infusion（http://www.medicines.org.uk/emc/medicine/19714） 类风湿性关节炎治疗药Orencia的新型皮下制剂可由患者自行给药 2012年10月5日，百时美施贵宝（BMS）已批准了皮下配方ORENCIA（阿巴西普）的上市许可申请，联合氨甲喋呤（MTX），用于中度至重度活动性类风湿性关节炎（RA）成人患者的治疗。 ORENCIA是唯一一个可自我注射、具有皮下注射及静脉注射2种配方的RA治疗性生物试剂，通过一种不同的作用机制（T细胞共刺激调节）发挥作用。而大多数当前可用于治疗RA的生物制剂均为抗肿瘤坏死因子（anti-TNF）制剂。 鉴于有些患者出于某些原因偏好于其中一种给药途径，这2种配方将解决患者和医生的需求和喜好。 欧盟对ORENCIA皮下配方的批准，是基于关键性III期ACQUIRE注册研究的数据及II期临床试验的长期疗效和安全性数据。ACQUIRE研究，是RA患者中所开展的最大的生物制剂III期注册研究，将ORENCIA皮下配方及静脉注射配方进行了比较，证明了类似的安全性及疗效（非劣效性比较）。 ORENCIA静脉注射配方于2007年5月获欧盟批准，是一种行之有效的RA治疗药物，用于氨甲喋呤单药治疗反应不足或经DMARD治疗失败的RA成人患者的治疗。 ORENCIA结合氨甲喋呤（MTX），用于既往对1种或多种疾病修饰性抗 风湿药（DMARDs）治疗反应不足的RA成人患者，包括MTX或TNF-α抑制剂。 ORENCIA（阿巴西普，abatacept）是一种通过重组脱氧核糖核酸（DNA）技术产生的合成蛋白质，属于生物制剂，用于治疗类风湿关节炎。这种药可以单独使用，或者与其它药物结合治疗那些没有经过其它治疗关节炎的药物治疗过的成人中度到重度的类风湿关节炎。阿巴西普通过静脉输液给药，并且在免疫系统中起作用， 防止细胞活化造成关节组织破坏和引起类风湿关节炎的症候和症状。由于阿巴西普抑制了免疫系统，它可能会降低患者抗感染和抗癌症的能力。 ---------------------------------------------------- 产地国家：美国  原产地英文商品名: ORENCIA 125MG/ML 4Pen Injector  原产地英文药品名: ABATACEPT 中文参考商品译名: ORENCIA 125毫克/毫升 4支筆式注射器  中文参考药品译名: 阿巴西普 生产厂家中文参考译名: ER SQUIBB & SONS LLC  生产厂家英文名: ER SQUIBB & SONS LLC ---------------------------------------------------- 产地国家：美国  原产地英文商品名: ORENCIA 250MG 15ML SDV PWD 1/EA 原产地英文药品名: ABATACEPT 中文参考商品译名: ORENCIA 250毫克/15毫升/瓶 1瓶/盒 中文参考药品译名: 阿巴西普 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: Bristol-Myers Squi  曾用名: 麦芽糖  ---------------------------------------------------- 产地国家：美国  原产地英文商品名: ORENCIA VL 250MG 15ML NR 原产地英文药品名: ABATACEPT/MALTOSE 中文参考商品译名: ORENCIA 250毫克/15毫升/瓶 1瓶/盒 中文参考药品译名: 阿巴西普 生产厂家中文参考译名: ER SQUIBB＆SONS LLC 生产厂家英文名: ER SQUIBB＆SONS LLC  曾用名: 麦芽糖  ---------------------------------------------------- 产地国家：德国  原产地英文商品名: ORENCIA 125MG/ML 3Pen Injector  原产地英文药品名: ABATACEPT 中文参考商品译名: ORENCIA 125毫克/毫升 3支筆式注射器  中文参考药品译名: 阿巴西普 生产厂家中文参考译名: 百时美施贵宝  生产厂家英文名: Bristol-Myers Squibb ---------------------------------------------------- 产地国家：德国  原产地英文商品名: ORENCIA 250mg/ml/vial 2vial/box 原产地英文药品名: ABATACEPT 中文参考商品译名: ORENCIA 250毫克/毫升/瓶 2瓶/盒 中文参考药品译名: 阿巴西普 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: Bristol-Myers Squi    ---------------------------------------------------- 产地国家：德国  原产地英文商品名: ORENCIA 250mg/ml/vial 3vial/box 原产地英文药品名: ABATACEPT 中文参考商品译名: ORENCIA 250毫克/毫升/瓶 3瓶/盒 中文参考药品译名: 阿巴西普 生产厂家中文参考译名: 百时美施贵宝 生产厂家英文名: Bristol-Myers Squi