Bristol-Myers Squibb Pharmaceutical Limited

In section 5.1 the following has been added :

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.

4.1     Therapeutic indications

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 TNF-alpha inhibitor.

4.4     Special warnings and precautions for use

While transitioning from TNF-antagonist therapy to ORENCIA therapy, patients should be monitored for signs of infection (see section 5.1, Study VII).

4.6     Pregnancy and lactation

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)

In double blind and open-label clinical trials in 4,149 patients treated with abatacept during 11,658 patient-years, the incidence rate of serious infections was 2.87 per 100 patient -years, and the annualized incidence rate remained stable.

n double blind and open-label clinical trials in 4,149 patients treated with abatacept during 11,658 patient-years (of which over 1,000 were treated with abatacept for over 5 years), the incidence rate of malignancy was 1.43 per 100 patient-years, and the annualized incidence rate remained stable. The incidence rates per 100 patient-years were 0.72 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 (0.17 per 100 patient-years), and the most common hematologic malignancy was lymphoma (0.06 per 100 patient-years)

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.

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 (1.63 per 100 patient -years) compared to the double blind experience (2.07 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.

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-antagonist 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.

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-antagonist), 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.

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.

In study VI, 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 Day 365 in the abatacept group was maintained through year 2.

....

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.

....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.

In Study VI, the mean change in TSS at 12 months was significantly lower in patients treated with abatacept plus methotrexate compared to those treated with methotrexate plus placebo. At 12 months 61% (148/242) of the patients treated with abatacept plus methotrexate and 53% (128/242) of the patients treated with methotrexate plus placebo had no progression (TSS ≤ 0). The progression of structural damage was lower in patients receiving continuous abatacept plus methotrexate treatment (for 24 months) compared to patients who initially received methotrexate plus placebo (for 12 months) and were switched to abatacept plus methotrexate for the next 12 months. Among the patients who entered the open-label 12 month period, 59% (125/213) of patients receiving continuous abatacept plus methotrexate treatment and 48% (92/192) of patients who initially received methotrexate and switched to combination with abatacept had no progression.

In Study 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 blocking agent 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-antagonist 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-antagonist users at enrollment, as was the frequency of serious infections.

10.     DATE OF REVISION OF THE TEXT

July 2010

Main changes are to:

Section 4.1 Polyarticular juvenile idiopathic arthritsi
Orencia in combination with methotrexate is indicated for the treatment of moderate to severe active polyarticular juvenile idiopathic arthirtis (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.

Section 4.2

Paediatric patients

There is no experience in children or adolescents. As a result, the use of ORENCIA in children or adolescents is not recommended until further data become available.

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.

4.4     Special warnings and precautions for use

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.

4.8     Undesirable effects

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 abatacept‑treated patients than in placebo‑treated 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.

4.8     Undesirable effects

Malignancies

In placebo‑controlled clinical trials, malignancies were reported in 27 of 1,955 abatacept‑treated patients observed during 1,687 patient‑years, and in 11 of 989 placebo‑treated patients observed during 794 patient‑years.

In double‑ blind and open‑-label clinical trials, malignancies were reported in 66 of 2,688 abatacept‑treated 4,149 patients treated with abatacept during 4,76410,365 patient‑-years. This included 33 patients with non‑melanoma skin cancers, 28 with solid organ cancers, and 6 with hematologic malignancies (4 with lymphomas and 2 with myelodysplastic syndromes)., 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 hematologic malignancies. The most commonlyfrequently reported solid organ cancer was lung cancer (11 cases).0.16 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 numberincidence 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, and IV (see section 5.1) were more common in the abatacept‑treated patients than the placebo‑treated patients (9.8% for abatacept, 6.7% 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.

Hypersensitivity, anaphylaxis, and drug hypersensitivity reactions were uncommon. In 2,688 rarely reported in patients treated with abatacept‑treated patients during 4,764 patient‑years, there was 1 case of anaphylaxis. during controlled and open-label clinical trials. Other eventsreactions potentially associated with hypersensitivity to the medicinal product, such as hypotension, urticaria, and dyspnea, eachthat occurred in less than 0.6% of abatacept‑treated patients.within 24 hours of ORENCIA infusion, were uncommon.

6.3     Shelf life

Unopened vial: 23 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.

8.       MARKETING AUTHORISATION NUMBER(S)

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

10.     DATE OF REVISION OF THE TEXT

21 May 200705/2009

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