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: sodium: 0.375 mmol per vial

For a full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

The powder is a white to offwhite 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 have had an insufficient response or intolerance to other diseasemodifying antirheumatic drugs (DMARDs) including at least one tumour necrosis factor (TNF) 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. ORENCIA has not been studied in children under 6 years old.

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 recondsidered (see section 5.1).

Adults

To be administered as a 30minute 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 antiinflammatory drugs (NSAIDs), or analgesics.

Elderly patients

No dose adjustment is required.

Paediatric patients

Juvenile Idiopathic Arthritis. 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 patients'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.

Renal and hepatic impairment

ORENCIA has not been studied in these patient populations. No dose recommendations can be made.

Method of administration

Each vial of ORENCIA 250 mg must be reconstituted with 10 ml of water for injections, using the silicone-free syringe provided. The reconstituted solution must then be diluted to 100 ml with sodium chloride 9 mg/ml (0.9%) solution for injection, before administration by intravenous infusion (see section 6.6).

Hypersensitivity to the active substance or to any of the excipients.

Severe and uncontrolled infections such as sepsis and opportunistic infections (see section 4.4).

Combination with TNF-antagonists

There is limited experience with use of abatacept in combination with TNF-antagonists (see section 5.1). In placebocontrolled clinical trials, in comparison with patients treated with TNF-antagonists and placebo, patients who received combination TNF-antagonists 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-antagonists.

While transitioning from TNF-antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection.

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.

Coadministration of ORENCIA with biological 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.

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.

Antirheumatic 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 placebocontrolled clinical trials, the frequencies of malignancies in abatacept and placebotreated 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 ORENCIA 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. 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.

It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immmunisations in agreement with current immunisation guidelines pror to initiating ORENCIA therapy.

Elderly patients

A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received abatacept in placebocontrolled clinical trials. Similar efficacy was observed in these patients and in younger patients. The frequencies of serious infection and malignancy relative to placebo among abatacepttreated 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 (GDHPQQ). The GDHPQQ 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 (GDHNAD), 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-antagonists

There is limited experience with the use of abatacept in combination with TNF-antagonists (see section 5.1). While TNF-antagonists did not influence abatacept clearance, in placebocontrolled clinical trials, patients receiving concomitant treatment with abatacept and TNF-antagonists experienced more infections and serious infections than patients treated with only TNF-antagonists. Therefore, concurrent therapy with ORENCIA and a TNF-antagnoist 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.

See section 4.4 regarding combination with other medicinal products that affect the immune system and with vaccinations.

There are no adequate data from use of abatacept in pregnant women. In embryofetal development studies no undesirable effects were observed at doses up to 29fold a human 10 mg/kg dose based on AUC. In a pre and postnatal development study limited changes in immune function were observed at 11fold 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 childbearing potential should use effective contraception during treatment with ORENCIA and up to 14 weeks after the last dose of abatacept treatment.

Use during lactation

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).

No studies on the effects on the ability to drive and use machines have been performed.

Undesirable effects in adults

Abatacept has been studied in patients with active rheumatoid arthritis in placebocontrolled clinical trials (1,955 patients with abatacept, 989 with placebo). The trials had either a doubleblind, placebocontrolled period of 6 months (258 patients with abatacept, 133 with placebo) or 1 year (1,697 patients with abatacept, 856 with placebo). Most patients in these trials were taking methotrexate (81.9% with abatacept, 83.3% with placebo). Other concomitant medications included: NSAIDs (83.9% with abatacept, 85.1% with placebo); systemic corticosteroids (74.7% with abatacept, 75.8% with placebo); nonbiological DMARD therapy, most commonly chloroquine/hydroxychloroquine, leflunomide and/or sulfasalazine (26.9% with abatacept, 32.1% with placebo); TNF-antagonists, mainly etanercept (9.4% with abatacept, 12.3% with placebo); and anakinra (1.1% with abatacept, 1.6% with placebo).

In placebocontrolled clinical trials with abatacept, adverse drug reactions (ADRs) were reported in 52.2% of abatacepttreated patients and 46.1% of placebotreated patients. The most frequently reported adverse drug reactions ( 5%) among abatacepttreated patients were headache and nausea. The proportion of patients who discontinued treatment due to ADRs was 3.4% for abatacepttreated patients and 2.2% for placebotreated patients.

Listed in Table 2 are adverse drug reactions based on experience in controlled clinical trials in adults that occurred with greater frequency (difference> 0.2%) in abatacepttreated patients than in placebotreated patients. The list is 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: Undesirable Effects in PlaceboControlled Trials

ADRs reported in abatacepttreated patients which did not occur with an excess incidence (i.e. the difference was not> 0.2%) over placebo but were considered to be medically relevant include the following events:

Common: herpes zoster;

Uncommon: pneumonia, hypersensitivity, pyelonephritis, bronchospasm, urticaria, psoriasis, cystitis, migraine, throat tightness, dry eye;

Rare: sepsis, bacteraemia.

Additional information

Infections

In the placebocontrolled clinical trials, infections at least possibly related to treatment were reported in 23.2% of abatacepttreated patients and 19.5% of placebotreated patients.

Serious infections at least possibly related to treatment were reported in 1.8% of abatacepttreated patients and 1.0% of placebotreated patients. Serious infections reported in at least one patient treated with abatacept (0.05% of patients) included the following: pneumonia; bronchitis; cellulitis; acute pyelonephritis; urinary tract infection; diverticulitis, intestinal abscess; localised infection; skin abscess; musculoskeletal infections; sepsis; empyema; hepatitis E; and tuberculosis (see section 4.4).

Malignancies

In placebocontrolled clinical trials, malignancies were reported in 27 of 1,955 abatacepttreated patients observed during 1,687 patientyears, and in 11 of 989 placebotreated patients observed during 794 patientyears.

In double-blind and open-label clinical trials in 4,149 patients treated with abatacept during 10,365 patient-years, the incidence rate of malignancy was 1.41 per 100 patient-years. The incidence rates per 100 patients-years were 0.74 for non-melanomatous skin cancer, 0.59 for solid malignancies and 0.12 for hematological malignancies. The most frequently reported organ cancer was lung cancer (0.16 per 100 patient-years), and the most common hematological 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 hematological malignancies), or for individual tumour types in the double-blind and open-label period compared to the double-blind experience. The type and pattern of malignancies reported during the openlabel period of the trials were similar to those reported for the doubleblind experience.

The incidence rate of observed malignancies was consistent with that expected in an age and gendermatched rheumatoid arthritis population (see section 4.4).

Infusionrelated reactions

Acute infusionrelated events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies II, III, and IV (see section 5.1) were more common in the abatacepttreated patients than the placebotreated patients (9.8% for abatacept, 6.7% for placebo). The most frequently reported events with abatacept (12%) were dizziness, headache, and hypertension.

Acute infusionrelated 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.

Hypersensitivity, anaphylaxis, and drug hypersensitivity reactions were rarely reported in patients treated with abatacept during controlled and open-label clinical trials. 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 infusionrelated reaction occurred in 0.4% of patients receiving abatacept and in 0.2% of placebotreated patients.

Adverse drug 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 drug reactions more frequently than those treated with placebo (51.4% vs. 47.1%, respectively). Respiratory disorders occurred more frequently in abatacepttreated patients than in placebotreated patients (10.8% vs. 5.9%, respectively); these included COPD exacerbation, and dyspnea. A greater percentage of abatacept than placebotreated 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%]).

Autoantibodies

Abatacept therapy did not lead to increased formation of autoantibodies, i.e., antinuclear and anti-dsDNA antibodies, compared with placebo.

Immunogenicity

Antibodies directed against the abatacept molecule were assessed by ELISA assays in rheumatoid arthritis patients treated for up to 3 years with abatacept. Sixtytwo of 2,237 (2.8%) patients developed binding antibodies. In patients assessed for antibodies at least 56 days after discontinuation of abatacept, 15 of 203 (7.4%) developed antibodies.

Samples with confirmed binding activity to CTLA4 were assessed for the presence of neutralizing antibodies. Eight of 13 evaluable patients were shown to possess neutralizing antibodies.

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. The potential clinical relevance of neutralizing antibody formation is not known. 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 costimulation modulator. Information on the relative safety in a clinical trial versus infliximab is summarized in section 5.1.

Undesirable effects in paediatric patients with polyarticular juvenile idiopathic arthritis

Very common: headache, nausea;

Common: diarrhoea, cough, upper respiratory tract infection, pyrexia, masopharyngitis, upper abdominal pain.

ORENCIA has been studied in 190 paediatric patients, 6 to 17 years of age, with polyarticular JIA (see section 5.1). Adverse reactions (adverse events occurring at a prevalence of at least 5% in the 4 month, lead-in, open-label period of the study) were similar in type to those seen in adults (Table 2) with the exception that pyrexia was reported in paediatric patients.

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 abatcepat 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 randomised to placebo (therefore withdrawn from therapy for up to 6 months) the rate of seropositivity was 40.7% (22/54). Anti-abatacept antibodies wer generally transient and of low titre. 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 Tlymphocyteassociated antigen 4 (CTLA4) 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 lymphocytedependent 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, interferonγ, and interleukin2 production by T lymphocytes.

Pharmacodynamic effects

Dosedependent reductions were observed with abatacept in serum levels of soluble interleukin2 receptor, a marker of T lymphocyte activation; serum interleukin6, a product of activated synovial macrophages and fibroblastlike synoviocytes in rheumatoid arthritis; rheumatoid factor, an autoantibody produced by plasma cells; and Creactive protein, an acute phase reactant of inflammation. In addition, serum levels of matrix metalloproteinase3, 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, doubleblind, placebocontrolled clinical trials in adult patients with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Studies I, II, III, and V 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-antagonist, with the TNF-antagnoist 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 nonbiological and/or biological DMARDs; all DMARDs used at enrollment were continued.

Study I patients were randomized to receive abatacept 2 or 10 mg/kg or placebo for 12 months. Study II, III, and IV patients were randomized to receive a fixed dose approximating 10 mg/kg of abatacept or placebo for 12 (Studies II and IV) 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 1000 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, and V evaluated 339, 638, 389, 1,441, and 431 adult patients, respectively.

Clinical response

ACR response

The percent of abatacepttreated patients achieving ACR 20, 50, and 70 responses in Study II (patients with inadequate response to methotrexate) and Study III (patients with inadequate response to TNF-antagonist) are shown in Table 3.

In abatacepttreated 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 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.

^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 6month period.

^d After 6 months, patients were given the opportunity to enter an openlabel study.

In the openlabel extension of Studies I, II, and III durable and sustained ACR 20, 50, and 70 responses have been observed through 48, 24, and 18 months, respectively, of abatacept treatment. In study I, ACR 20 responses were observed in 71% (42/59) of patients, ACR 50 in 41% (24/59), and ACR 70 in 31% (18/58) at 48 months. In study II, ACR 20 responses were observed in 88% (291/332) of patients, ACR 50 in 62% (205/332), and ACR 70 in 38% (127/334) at 24 months. In study III, ACR 20 responses were observed in 70% (118/167) of patients, ACR 50 in 43% (73/168), and ACR 70 in 22% (37/169) at 18 months.

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 (DAS28 ESR). There was a significant improvement of DAS in Studies II, III, and V as compared to placebo.

Study V: abatacept or infliximab versus placebo

A randomized, doubleblind 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 placebotreated patients at 6 months with a subsequent doubleblind 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 placebocontrolled 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.

Radiographic response

Structural joint damage was assessed radiographically over a twoyear period in Study II. The results were measured using the Genantmodified total Sharp score (TSS) and its components, the erosion score and joint space narrowing (JSN) score. The baseline median TSS was 31.7 in abatacepttreated patients and 33.4 in placebotreated 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).

^a Based on nonparametric analysis.

Physical function response

Improvement in physical function was measured by the Health Assessment Questionnaire Disability Index (HAQDI) in Studies II, III, IV and V and the modified HAQDI in Study I. The results from Studies II and III are shown in Table 5.

*** p < 0.001, abatacept vs. 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 HAQDI of 0.3 units from baseline.

^e After 6 months, patients were given the opportunity to enter into an openlabel 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 openlabel period of Studies I, II, and III, the improvement in physical function has been maintained through 48, 24, and 18 months, respectively.

Healthrelated outcomes and quality of life

Healthrelated quality of life was assessed by the SF36 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 SF36 (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 and the Mental Component Summary.

Paediatric population in polyarticular juvenile idiopathic arthritis

Children and adolescents with moderate to severe JIA, ages 6 to 17 years with an inadequate response or intolerance to at least one DMARD, which may have included biological agents, were enrolled. The safety and efficacy of ORENCIA 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 an ACR Pedi 30 response at the end of Period A were randomised into a double-blind, withdrawal phase (Period B), and received either ORENCIA 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 ORENCIA monotherapy in Period A. Of the 190 patients entering the study, 57 (30%) had previously been treated with anti-TNF therapy.

ACR Pedi 30 responders at the end of Period A were randomized into Period B, the double-blind, withdrawal phase, to receive either ORENCIA 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-antagonist therapy, 101 (76%) achieved at least an ACR Pedi 30 response; of the 57 patients who had received prior TNF-antagonist 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.

After multiple intravenous infusions (days 1, 15, 30, and every 4 weeks thereafter), the pharmacokinetics of abatacept in rheumatoid arthritis patients showed doseproportional 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 halflife 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 steadystate 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-antagonists 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 normalised 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 normalised clearance and volume of distributionin 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 longterm immunomodulation. In a oneyear 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. Embryofoetal 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 29fold 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 3fold a human 10 mg/kg exposure based on AUC. At a dose of 200 mg/kg, representing 11fold a human exposure at 10 mg/kg based on AUC, limited changes in immune function (a 9fold increase in the mean Tcelldependent 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 inuse 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 inuse 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 of the reconstituted product see section 6.3.

250 mg powder in a vial (Type 1 glass) with a stopper (halobutylrubber) and flip off seal (aluminium) with a siliconefree syringe (polyethylene).

Packs of 1, 2, or 3 vials (each 15 ml) and 1, 2, or 3 silicone-free syringes, respectively.

Not all packsizes 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 freedisposable syringe provided with each vial (see section 6.2) and an 1821 gauge needle.

- Remove the fliptop 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 product 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 siliconefree disposable syringe provided with each vial.

- Gently mix. The final concentration of abatacept in the bag or bottle will depend upon the amount of drug 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. 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, nonpyrogenic, lowproteinbinding filter (pore size of 0.2 to 1.2 μm).

- 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.

BristolMyers Squibb Pharma EEIG

Uxbridge Business Park

Sanderson Road

Uxbridge UB8 1DH

United Kingdom

EU/1/07/389/001 (1 vial)

21/05/2007

January 2010

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/