ORENCIA 250 mg powder for concentrate for solution for infusion

Change to PIL : Removal or legal representatives and update to revision date

Date of revision to the text updated to 24 September

Date of revision to the text updated to 24 September

To change the name/address of BMS-Anagni to CATALENT Pharma Solutions, Inc - batch release site of ORENCIA Drug Product

Date of revision of the text updated to align with the Patient Leaflet Date of revision of the text - 30 March 2020

This leaflet was last revised in December 2019

Patients on controlled sodium diet

This medicinal product contains 34.5 mg sodium per maximum dose of 4 vials (8.625 mg sodium per vial), equivalent to 1.7% of the WHO recommended maximum daily dietary intake of 2 g sodium for an adult.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Open-label extension periodLong-term extension period

During the extension period of the pJIA studies (20 months in the pJIA SC study and 5 years in the pJIA IV study), the safety profile in the pJIA patients aged 6 to 17 years was comparable to that seen in adult patients. One patient was diagnosed with multiple sclerosis while in the extension period of the pJIA IV study. One serious adverse reaction of infection (limb abscess) was reported in the 2 to 5 year age cohort during the 20-month extension period of the pJIA SC study.

Long-term safety data in 2 to 5 year age cohortold patients with pJIA was limited, but the existing evidence did not reveal any new safety concern in this younger paediatric population. During the 24-month cumulative period of the pJIA SC study (4-month short term period plus 20-month extension period), a higher frequency of infections was reported in the 2 to 5 year age cohort (87.0%) compared to that reported in the 6 to 17 year age cohort (68.2%). This was mostly due to non-serious upper respiratory tract infections in the 2 to 5 year age cohort.

Section 7: Change to MAH Address

Section 4.1 has been updated with a new  indication

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Section 4.2 has been updated with the method of administration

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Section 4.8   has been updated with a summary of the summary of the safety profile in psoriatic arthritis

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In addition the reporting details for the yellow card scheme has been updated following update to Appendix 5

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Section 5.1 has been updated with Clinical efficacy and safety in adult psoriatic arthritis

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section 5.2  has been updated with the data from adults with psoriatic arthritis

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Section 10 has been updated with the date of revision - 25th July 2017

Section 4.4 - The patient numbers  and percentages from some of the clinical studies  have been updated

Section 4.5 -Changes to the frequencies of adverse events

4.1     Therapeutic indications

Rheumatoid arthritis

ORENCIA, in combination with methotrexate, is indicated for:

§    the treatment of moderate to severe active rheumatoid arthritis (RA) 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.

§    the treatment of highly active and progressive disease in adult patients with rheumatoid arthritis not previously treated with methotrexate.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

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 SC-II investigated the relative efficacy and safety of abatacept and adalimumab, both given subcutaneously without an intravenous loading dose and with background MTX, in patients with moderate to severely active RA and an inadequate response to previous MTX therapy. In study SC-III, abatacept SC was evaluated in combination with methotrexate (MTX), or as abatacept monotherapy, and compared to MTX monotherapy in induction of remission following 12 months of treatment, and the possible maintenance of drug-free remission after complete drug withdrawal, in adult MTX-naive patients with highly active early, rheumatoid arthritis (mean DAS28‑CRP of 5.4; mean symptom duration less than 6.7 months) with poor prognostic factors for rapidly progressive disease (e.g., anti-citrullinated protein antibodies [ACPA+], as measured by anti-CCP2 assay, and/or RF+, baseline joint erosions).

Studies I, II, III, IV, V, VI, and SC-II, and SC-III evaluated 339, 638, 389, 1,441, 431, 509, and 646, and 351 adult patients, respectively.

Study SC-III: Induction of remission in methotrexate-naive RA patients

A randomized and double-blinded study evaluated abatacept SC in combination with methotrexate (abatacept + MTX), abatacept SC monotherapy, or methotrexate monotherapy (MTX group) in induction of remission following 12 months of treatment, and maintenance of drug-free remission after complete drug withdrawal in MTX-naive adult patients with highly active early rheumatoid arthritis with poor prognostic factors. Complete drug withdrawal led to loss of remission (return to disease activity) in all three treatment arms (abatacept with methotrexate, abatacept or methotrexate alone) in a majority of patients (Table 4).

^a DAS28-defined remission (DAS28-CRP <2.6)

^b SDAI criterion (SDAI ≤ 3.3)

In SC-III the safety profiles of the three treatment groups (abatacept + MTX, abatacept monotherapy, MTX group) were overall similar. During the 12-month treatment period, adverse reactions were reported in 44.5% (53/119), 41.4% (48/116), and 44.0% (51/116) and serious adverse reactions were reported in 2.5% (3/119), 2.6% (3/116) and 0.9% (1/116) of patients treated in the three treatment groups, respectively. Serious infections were reported in 0.8% (1/119), 3.4% (4/116) and 0% (0/116) patients.

In Study SC-III, structural joint damage was assessed by MRI. The abatacept + MTX group had less progression in structural damage compared with MTX group as reflected by mean treatment difference of the abatacept + MTX group versus MTX group (Table 6).

In Study SC-III, the proportion of subjects with a HAQ response as a measure of clinically meaningful improvement in physical function (reduction from baseline in HAQ-D1 score of > 0.3) was greater for the abatacept+ MTX group vs. the MTX group at Month 12 (65.5% vs 44.0%, respectively; treatment difference vs. MTX group of 21.6% [95% CI: 8.3, 34.9]).

Response rates at the end of Period A, at the end of Period B and after 5 years exposure in Period C are summarized in Table 68:

10.     DATE OF REVISION OF THE TEXT

August 2016

4.6     Fertility, pregnancy and lactation

Pregnancy and Women of childbearing potential

There are no adequate data from use of abatacept in pregnant women. In pre-clinical embryo‑fetal development studies no undesirable effects were observed at doses up to 29‑fold a human 10 mg/kg dose based on AUC. In a pre‑ and postnatal development study in rats limited changes in immune function were observed at 11‑fold higher than 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.

Abatacept may cross the placenta into the serum of infants born to women treated with abatacept during pregnancy. Consequently, these infants may be at increased risk of infection. The safety of administering live vaccines to infants exposed to abatacept in utero is unknown. Administration of live vaccines to infants exposed to abatacept in utero is not recommended for 14 weeks following the mother’s last exposure to abatacept during pregnancy.

10.     DATE OF REVISION OF THE TEXT

December 2015

Minor typographical changes:-

-          ml to mL

-          SC to subcutaneous

-          IV to intravenous

Changes made as part of EMEA/H/C/000701/II/0087/G variation to add a new container / presentation (pre filled pen)

CHMP opinion received on 24 April 2015.

Vaccinations

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

In section 4.5  (Interaction with other medicinal products and other forms of interaction)

Vaccinations

Live vaccines should not be given concurrently with abatacept or within 3 months of its discontinuation. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ORENCIA. Medicinal products that affect the immune system, including ORENCIA, may blunt the effectiveness of some immunisations (see section 4.4).

Exploratory studies to assess the effect of abatacept on the antibody response to vaccination in healthy subjects as well as the antibody response to influenza and pneumococcal vaccines in rheumatoid arthritis patients suggested that abatacept may blunt the effectiveness of the immune response, but did not significantly inhibit the ability to develop a clinically significant or positive immune response.

Abatacept was evaluated in an open-label study in rheumatoid arthritis patients administered the 23-valent pneumococcal vaccine. After pneumococcal vaccination, 62 of 112 abatacept-treated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine.

Abatacept was also evaluated in an open-label study in rheumatoid arthritis patients administered the seasonal influenza trivalent virus vaccine. After influenza vaccination, 73 of 119 abatacept-treated patients without protective antibody levels at baseline were able to mount an adequate immune response of at least a 4-fold increase in antibody titers to trivalent influenza vaccine.

In section 10 (Date of revision)

May 2013

4.2 Posology and method of administration

Posology

Adults

Treatment should be initiated with a loading dose using an intravenous infusion (for the posology of the intravenous loading dose, please refer to section 4.2 of ORENCIA 250 mg powder for concentrate for solution for infusion). Following this loading dose, the first 125 mg subcutaneous injection of ORENCIA should be given within a day, followed by 125 mg subcutaneous injections once weekly.

4.4       Special warnings and precautions for use

Allergic reactions

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

b As observed

Participants in Period C at day 589 1765 included 51 33 of the 58 Period B abatacept recipients, 47 30 of the 59 Period B placebo recipients, and 22 13 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 1815 days (range 5657–1,3222,415 days; nearly 32 61 months). Fifty-threeOne hundred and two (3567%) of the subjects had received at least 1,0201,080 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.

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, non‑pyrogenic, low‑protein‑binding filter (pore size of 0.2 to 1.2 μm).

10.     DATE OF REVISION OF THE TEXT

17 January 2013

11.       LEGAL CATEGORY

POM

In section 4.2 - Posology and method of administration. The below text were added:                    
                    Special population
                    No dose adjustment is required (see section 4.4). 
            
                     - The below text were deleted 
                       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 9mg/ml (0.9%) solution for injection, before administration by intravenous infusion  

          (see section 6.6).

And replaced with:
                  

  -  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.

In section 4.5 -  Interaction with other medicinal products and other forms of interaction.The below text were added:
                      - 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).

In section 4.7 - Effects on ability to drive and use machines. This below text were updated.

                       - Base on the effectsits 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 performedreported as common adverse reactions from patients treated with

                        ORENCIA, therefore if a patient experiences such symptoms, driving and use of machinery

                        should be avoided.

In section 4.8 - Undesirable side effects. The below text were deleted. 
                        -The trials had either a double-blind, placebo-controlled 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); non-biological DMARD

                        therapy, most commonly chloroquine/hydroxychloroquine, leflunomide and/or sulfasalazine (26.9%

                        with abatacept, 32.1% with placebo); TNF-inhibitors, mainly etanercept (9.4% with abatacept,

                       12.3% with placebo); and anakinra (1.1% with abatacept, 1.6% with placebo). And Table 2 was

                       updated. In section 10 - Date of Revision of text. The date was changed to: - 
                     - 15 March 2012

                 

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

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.


and 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/