ORENCIA 250 mg powder for concentrate for solution for infusion.

Each vial contains 250 mg of abatacept.

Each ml contains 25 mg of abatacept, after reconstitution.

Abatacept is a fusion protein produced by recombinant DNA technology in Chinese hamster ovary cells.

Excipient with known effect: sodium: 0.375 mmol (8.625 mg) per vial

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

The powder is a white to off-white whole or fragmented cake.

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.

Polyarticular juvenile idiopathic arthritis

ORENCIA in combination with methotrexate is indicated for the treatment of moderate to severe active polyarticular juvenile idiopathic arthritis (JIA) in paediatric patients 6 years of age and older who have had an insufficient response to other DMARDs including at least one TNF inhibitor.

Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis or JIA.

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

Rheumatoid arthritis

Adults

To be administered as a 30-minute intravenous infusion at the dose specified in Table 1. Following the initial administration, ORENCIA should be given 2 and 4 weeks after the first infusion, then every 4 weeks thereafter.

^a Approximating 10 mg/kg.

^b Each vial provides 250 mg of abatacept for administration.

No dose adjustment is required when used in combination with other DMARDs, corticosteroids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), or analgesics.

Juvenile Idiopathic Arthritis

Paediatric population

The recommended dose of ORENCIA for patients 6 to 17 years of age with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg calculated based on the patient's body weight at each administration. Paediatric patients weighing 75 kg or more should be administered ORENCIA following the adult dosing regimen, not to exceed a maximum dose of 1,000 mg. ORENCIA should be administered as a 30-minute intravenous infusion. Following the initial administration, ORENCIA should be given at 2 and 4 weeks after the first infusion and every 4 weeks thereafter.

The safety and efficacy of ORENCIA in children below 6 years of age have not been studied and therefore, ORENCIA is not recommended for use in children under six years old.

Special population

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.

Method of administration

The entire, fully diluted ORENCIA solution should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 to 1.2 μm). See section 6.6 for information on reconstitution and dilution.

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).

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 abatacept administration in clinical trials, where patients were not required to be pretreated to prevent allergic reactions (see section 4.8). Anaphylactic reactions have been reported rarely. Special caution should be exercised in patients with a history of allergic reactions to abatacept or to any of the excipients. If any serious allergic or anaphylactic reaction occurs, ORENCIA therapy should be discontinued immediately and appropriate therapy initiated.

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. Nevertheless, 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.

Vaccinations

Live vaccines should not be given concurrently with ORENCIA or within 3 months of its discontinuation. Medicinal products that affect the immune system, including ORENCIA, may blunt the effectiveness of some immunisations (see section 4.5).

It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy (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 abatacept in placebo-controlled clinical trials. Similar efficacy was observed in these patients and in younger patients. The frequencies of serious infection and malignancy relative to placebo among 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 ORENCIA might increase the risk for autoimmune processes in adults and children, 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).

Blood glucose testing

Parenteral medicinal products containing maltose can interfere with the readings of blood glucose monitors that use test strips with glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ). The GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA, resulting in falsely elevated blood glucose readings on the day of infusion. When receiving ORENCIA, patients that require blood glucose monitoring should be advised to consider methods that do not react with maltose, such as those based on glucose dehydrogenase nicotine adenine dinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods.

Patients on controlled sodium diet

This medicinal product contains 1.5 mmol (or 34.5 mg) sodium per maximum dose of 4 vials (0.375 mmol or 8.625 mg sodium per vial). To be taken into consideration when treating patients on a controlled sodium diet.

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 ORENCIA 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 ORENCIA 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. Insufficient data are available on the effects of vaccinations in patients receiving ORENCIA. Medicinal products that affect the immune system, including ORENCIA, may blunt the effectiveness of some immunisations (see section 4.4).

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 ORENCIA on human fertility have not been conducted.

In rats, abatacept had no undesirable effects on male or female fertility (see section 5.3).

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 adverse reactions from patients treated with ORENCIA, therefore if a patient experiences such symptoms, driving and use of machinery should be avoided.

Adverse reactions in adults

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 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.

Listed in Table 2 are adverse reactions 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 2: Adverse Reactions

Description of selected adverse reactions

Infections

In the placebo-controlled clinical trials, 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 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, 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 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).

Infusion-related reactions

Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies II, III, IV and V (see section 5.1) were more common in the abatacept-treated patients than the placebo-treated patients (9.4% for abatacept, 7.2% for placebo). The most frequently reported events with abatacept (1-2%) were dizziness, headache, and hypertension.

Acute infusion-related events that were reported in > 0.1% and 1% of patients treated with abatacept included cardiopulmonary symptoms such as hypotension, increased blood pressure, decreased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild to moderate.

The occurrence of anaphylaxis remained rare between the double blind and long-term open-label experience. Hypersensitivity was reported uncommonly. Other reactions potentially associated with hypersensitivity to the medicinal product, such as hypotension, urticaria, and dyspnea, that occurred within 24 hours of ORENCIA infusion, were uncommon.

Discontinuation due to an acute infusion-related reaction occurred in 0.3% of patients receiving abatacept and in 0.2% of placebo-treated patients.

Adverse reactions in patients with chronic obstructive pulmonary disease (COPD)

In Study IV, there were 37 patients with COPD treated with 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

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.

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.

Adverse reactions in paediatric patients with polyarticular juvenile idiopathic arthritis

ORENCIA has been studied in 190 paediatric patients, 6 to 17 years of age, with polyarticular JIA (see section 5.1). Adverse reactions occurring in the 4 month, lead-in, open-label period of the study were similar in type and frequency to those seen in adults (Table 2) with the following exceptions:

Common: upper respiratory tract infection (including sinusitis, nasopharyngitis and rhinitis), otitis (media and externa), haematuria, pyrexia.

Description of selected adverse reactions

Infections

The types of infections were consistent with those commonly seen in outpatient paediatric populations. The infections resolved without sequelae. One serious infection (varicella) was reported during the initial 4 months of treatment with ORENCIA.

Infusion-related reactions

Of the 190 patients with JIA treated with ORENCIA in this study, one (0.5%) patient discontinued due to non-consecutive infusion reactions, consisting of bronchospasm and urticaria. During Periods A, B, and C, acute infusion-related reactions occurred at a frequency of 4%, 2%, and 3%, respectively, and were consistent with the types of reactions reported in adults.

Immunogenicity

Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with polyarticular JIA following repeated treatment with ORENCIA. The rate of seropositivity while patients were receiving abatacept therapy was 0.5% (1/189) during Period A; 13.0% (7/54) during Period B; and 11.4% (17/149) during Period C. For patients in Period B who were randomized to placebo (therefore withdrawn from therapy for up to 6 months) the rate of seropositivity was 40.7% (22/54). Anti-abatacept antibodies were generally transient and of low titer. The absence of concomitant methotrexate (MTX) did not appear to be associated with a higher rate of seropositivity in Period B placebo recipients. The presence of antibodies was not associated with adverse reactions or infusional reactions, or with changes in efficacy or serum abatacept concentrations. Of the 54 patients withdrawn from ORENCIA during the double-blind period for up to 6 months, none had an infusion reaction upon re-initiation of ORENCIA.

Open-label extension period

Upon continued treatment in the open-label extension period, the adverse reactions were similar in type to those seen in adult patients. One patient was diagnosed with multiple sclerosis while in Period C (open-label extension).

Doses up to 50 mg/kg have been administered 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.

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 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.

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.

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. 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, and VI evaluated 339, 638, 389, 1,441, 431, and 509 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), and Study VI (methotrexate-naive patients) are shown in Table 3.

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.

* 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

^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

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.

In the substudy of study VI, patients who had achieved remission at 2 years (DAS 28 ESR < 2.6) and after at least 1 year of treatment with abatacept in Study VI were eligible to enter a substudy. In the substudy 108 subjects were randomized 1:1 in double blinded fashion to receive abatacept at doses approximating 10 mg/kg (ABA 10) or 5 mg/kg (ABA 5). After 1 year of treatment, the maintenance of remission was assessed by the relapse of the disease. The time to and proportion of patients with the relapse of the disease observed between the two groups were similar.

Study V: abatacept or infliximab versus placebo

A randomized, double-blind study was conducted to assess the safety and efficacy of 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.

Radiographic response

Structural joint damage was assessed radiographically over a two-year period in Studies II, and VI. 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 4. 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 + MTX and placebo + MTX respectively.

^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.

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. The results from Studies II, III, and VI are shown in Table 5.

*** 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 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.

Paediatric population in polyarticular juvenile idiopathic arthritis

Children and adolescents with moderate to severe active JIA, ages 6 to 17 years with an inadequate response or intolerance to at least one DMARD, which may have included biologic agents, were enrolled. The safety and efficacy of abatacept were assessed in a three-part study. Period A was a 4-month open-label lead-in designed to induce an ACR Pedi 30 response. Patients achieving at least a ACR Pedi 30 response at the end of Period A were randomized into a double-blind, withdrawal phase (Period B), and received either abatacept or placebo for 6 months or until JIA disease flare as defined in the study. Unless they had discontinued due to safety reasons, all patients who completed, or had a flare during Period B or were non-responders in Period A were offered entry into Period C, the open-label extension, which assessed long-term safety and efficacy.

In Period A all patients received 10 mg/kg of abatacept on days 1, 15, 29, 57 and 85 and were assessed on day 113. During period A, 74% were taking methotrexate (mean dose at study entry, 13.2 mg/m²/week) thus, 26% of patients received abatacept monotherapy in Period A. Of the 190 patients entering the study, 57 (30%) had previously been treated with TNF-inhibitor therapy.

ACR Pedi 30 responders at the end of Period A were randomized into Period B, the double-blind, withdrawal phase, to receive either abatacept or placebo for 6 months or until JIA flare.

Flare was defined as:

•  30% worsening in at least 3 of the 6 polyarticular JIA core set variables

•  30% improvement in not more than 1 of the 6 polyarticular JIA core set variables

• 2 cm (possible up to 10 cm) of worsening must have been present if the Physician or Parent Global Assessment was used to define flare

• worsening in 2 joints must have been present if the number of active joints or joints with limited range of motion was used to define flare

The patients entered in the trial were a mean of 12.4 years of age with mean disease duration of 4.4 years. They had active disease, with baseline mean active joint count of 16 and a mean number of joints with loss of motion of 16; and elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dl) and ESRs (mean, 32 mm/h). Their JIA subtypes at disease onset were: Oligoarticular (16%), Polyarticular (64%; 20% of the total were rheumatoid factor positive), and Systemic (20%).

Of the 190 patients enrolled, 170 completed Period A, 65% (123/190) achieved an ACR Pedi 30 response, and 122 were randomized to Period B. Responses were similar in all subtypes of JIA studied and for patients with or without methotrexate use. Of the 133 (70%) patients with no prior TNF-inhibitor therapy, 101 (76%) achieved at least an ACR Pedi 30 response; of the 57 patients who had received prior TNF-inhibitor therapy, 22 (39%) achieved at least an ACR Pedi 30 response.

During Period B, the time to disease flare for the patients randomized to placebo was significantly shorter than for those randomized to abatacept (primary endpoint, p=0.0002; log-rank test). Significantly more placebo recipients flared during Period B (33/62; 53%) than those maintained on abatacept (12/60; 20%; chi-square p<0.001). The risk of disease flare for patients continuing on abatacept was less than one third that for placebo-treated patients (hazard ratio estimate=0.31; 95% CI 0.16, 0.59).

Most randomized Period B patients entered Period C (58/60 Period B abatacept recipients; 59/62 Period B placebo recipients), as did 36 of the 47 Period A non-responders (n=153 total patients).

Response rates at the end of Period A, at the end of Period B and after 21 months exposure in Period C are summarized in Table 6:

^a Day 169 Last Observation Carried Forward (LOCF) for patients treated in Period C

Participants in Period C at day 589 included 51 of the 58 Period B abatacept recipients, 47 of the 59 Period B placebo recipients, and 22 of the 36 Period A non-responders. At the time of database lock all patients remaining in Period C had received at least 21 months (589 days) of treatment. The median duration of abatacept treatment in Period C was 898 days (range 56-1,322 days; nearly 32 months). Fifty-three (35%) of the subjects had received at least 1,020 days (~ 36 months) of abatacept therapy in Period C. All patients had at least 4 months of prior, open-label abatacept treatment in Period A.

The European Medicines Agency has waived the obligation to submit the results of studies with ORENCIA in all subsets of the paediatric population from birth to less than 18 years of age with Rheumatoid arthritis (see section 4.2 for information on paediatric use).

After multiple intravenous infusions (days 1, 15, 30, and every 4 weeks thereafter), the pharmacokinetics of abatacept in rheumatoid arthritis patients showed dose-proportional increases of C_max and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, the mean terminal half-life was 13.1 days, ranging from 8 to 25 days. The mean distribution volume (Vss) was 0.07 l/kg and ranged from 0.02 to 0.13 l/kg. The systemic clearance was approximately 0.22 ml/h/kg. Mean steady-state trough concentrations were approximately 25 μg/ml, and mean C_max concentrations were approximately 290 μg/ml. No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in rheumatoid arthritis patients.

Population pharmacokinetic analyses 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 clearance. Methotrexate, NSAIDs, corticosteroids, and TNF-inhibitors were not found to influence abatacept clearance. No studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of abatacept.

Paediatric population

Population pharmacokinetic analysis of abatacept serum concentration data from patients with JIA 6 to 17 years of age following administration of abatacept 10 mg/kg revealed that the estimated clearance of abatacept, when normalized for baseline body weight, was higher in JIA patients (0.4 ml/h/kg for a child weighing 40 kg) versus adult rheumatoid arthritis patients. Typical estimates for distribution volume and elimination half-life were 0.12 l/kg and 11.4 days, respectively, for a child weighing 40 kg. As a result of the higher body-weight normalized clearance and volume of distribution in JIA patients, the predicted and observed systemic exposures of abatacept were lower than that observed in adults, such that the observed mean (range) peak and trough concentrations were 204 (66 to 595) μg/ml and 10.6 (0.15 to 44.2) μg/ml, respectively, in patients weighing less than 40 kg, and 229 (58 to 700) μg/ml and 13.1 (0.34 to 44.6) μg/ml, respectively, in patients weighing 40 kg or greater.

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 ORENCIA 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.

Maltose

Sodium dihydrogen phosphate monohydrate

Sodium chloride

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. ORENCIA should not be infused concomitantly in the same intravenous line with other medicinal products.

ORENCIA should NOT be used with siliconised syringes (see section 6.6).

Unopened vial: 3 years

After reconstitution: chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C. From a microbiological point of view, the reconstituted solution should be diluted immediately.

After dilution: when the reconstituted solution is diluted immediately, the chemical and physical in-use stability of the diluted infusion solution has been demonstrated for 24 hours at 2°C - 8°C. From a microbiological point of view, the product should be used immediately.

Store in a refrigerator (2°C - 8°C).

Store in the original package in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Powder in a vial (15 ml Type 1 glass) with a stopper (halobutyl-rubber) and flip off seal (aluminium) with a silicone-free syringe (polyethylene).

Packs of 1 vial and 1 silicone-free syringe, and multipacks containing 2, or 3 vials and 2, or 3 silicone-free syringes (2 or 3 packs of 1).

Not all pack-sizes may be marketed.

Reconstitution and dilution should be performed in accordance with good practices rules, particularly with respect to asepsis.

Reconstitution

1. Determine the dose and the number of ORENCIA vials needed (see section 4.2).

2. Under aseptic conditions, reconstitute each vial with 10 ml of water for injections, using the silicone free-disposable syringe provided with each vial (see section 6.2) and an 18-21 gauge needle.

- Remove the flip-top from the vial and wipe the top with an alcohol swab.

- Insert the syringe needle into the vial through the centre of the rubber stopper and direct the stream of water for injections to the glass wall of the vial.

- Do not use the vial if the vacuum is not present.

- Remove the syringe and needle after 10 ml of water for injections have been injected into the vial.

- To minimise foam formation in solutions of ORENCIA, the vial should be rotated with gentle swirling until the contents are completely dissolved. Do not shake. Avoid prolonged or vigorous agitation.

- Upon complete dissolution of the powder, the vial should be vented with a needle to dissipate any foam that may be present.

- After reconstitution the solution should be clear and colourless to pale yellow. Do not use if opaque particles, discolouration, or other foreign particles are present.

Dilution

3. Immediately after reconstitution, the concentrate must be further diluted to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injection.

- From a 100 ml infusion bag or bottle, withdraw a volume of sodium chloride 9 mg/ml (0.9%) solution for injection equal to the volume of the reconstituted vials.

- Slowly add the reconstituted ORENCIA solution from each vial to the infusion bag or bottle using the same silicone-free disposable syringe provided with each vial.

- Gently mix. The final concentration of abatacept in the bag or bottle will depend upon the amount of active substance added, but will be no more than 10 mg/ml.

- Any unused portion in the vials must be immediately discarded in accordance with local requirements.

4. When reconstitution and dilution are performed under aseptic conditions ORENCIA infusion solution can be used immediately or within 24 hours if stored refrigerated at 2°C to 8°C. Prior to administration, the ORENCIA solution should be inspected visually for particulate matter and discolouration. Discard the solution if any particulate matter or discolouration is observed.

- Do not store any unused portion of the infusion solution for reuse.

Any unused product or waste material should be disposed of in accordance with local requirements.

Bristol-Myers Squibb Pharma EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

EU/1/07/389/001-003

Date of first authorisation: 21 May 2007

15 March 2012

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.