ORENCIA 250mg powder for concentrate infusion solution medication leaflet

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 ovarycells.

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

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

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

ORENCIA, in combination with methotrexate, is indicated for: the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients whoresponded inadequately to previous therapy with one or more disease-modifying anti-rheumaticdrugs (DMARDs) including methotrexate (MTX) or a tumour necrosis factor (TNF)-alphainhibitor.

 the treatment of highly active and progressive disease in adult patients with rheumatoid arthritisnot previously treated with methotrexate.

A reduction in the progression of joint damage and improvement of physical function have beendemonstrated during combination treatment with abatacept and methotrexate.

ORENCIA, alone or in combination with methotrexate (MTX), is indicated for the treatment of activepsoriatic arthritis (PsA) in adult patients when the response to previous DMARD therapy including

MTX has been inadequate, and for whom additional systemic therapy for psoriatic skin lesions is notrequired.

ORENCIA in combination with methotrexate is indicated for the treatment of moderate to severeactive polyarticular juvenile idiopathic arthritis (pJIA) in paediatric patients 6 years of age and olderwho have had an inadequate response to previous DMARD therapy.

ORENCIA can be given as monotherapy in case of intolerance to methotrexate or when treatment withmethotrexate is inappropriate.

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

If a response to abatacept is not present within 6 months of treatment, the continuation of the treatmentshould be reconsidered (see section 5.1).

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

Table 1: Dose of ORENCIAa

Body Weight of Patient Dose Number of Vialsb< 60 kg 500 mg 2≥ 60 kg to ≤ 100 kg 750 mg 3> 100 kg 1,000 mg 4a Approximating 10 mg/kg.b Each vial provides 250 mg of abatacept for administration.

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

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

The recommended dose of ORENCIA for patients 6 to 17 years of age with polyarticular juvenileidiopathic arthritis who weigh less than 75 kg is 10 mg/kg calculated based on the patient’s bodyweight 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 initialadministration, ORENCIA should be given at 2 and 4 weeks after the first infusion and every 4 weeksthereafter.

The safety and efficacy of intravenous ORENCIA in children below 6 years of age have not beenstudied and therefore, intravenous ORENCIA is not recommended for use in children under six yearsold.

ORENCIA solution for injection in pre-filled syringe for subcutaneous administration is available forpaediatric patients 2 years of age and older for the treatment of pJIA (see Summary of Product

Characteristics for ORENCIA solution for injection in pre-filled syringe).

No dose adjustment is required (see section 4.4).

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

For intravenous use.

The entire, fully diluted ORENCIA solution should be administered over a period of 30 minutes andmust be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (poresize of 0.2 to 1.2 μm). For instructions on reconstitution and dilution of the medicinal product beforeadministration, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Combination with TNF-inhibitors

There is limited experience with use of abatacept in combination with TNF-inhibitors (seesection 5.1). In placebo-controlled clinical trials, in comparison with patients treated with

TNF-inhibitors and placebo, patients who received combination TNF-inhibitors with abataceptexperienced an increase in overall infections and serious infections (see section 4.5). Abatacept is notrecommended for use in combination with TNF-inhibitors.

While transitioning from TNF-inhibitor therapy to ORENCIA therapy, patients should be monitoredfor signs of infection (see section 5.1, study VII).

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).

Anaphylaxis or anaphylactoid reactions can occur after the first infusion and can be life-threatening. Inpostmarketing experience, a case of fatal anaphylaxis following the first infusion of ORENCIA hasbeen reported. If any serious allergic or anaphylactic reaction occurs, intravenous or subcutaneous

ORENCIA therapy should be discontinued immediately and appropriate therapy initiated, and the useof ORENCIA should be permanently discontinued.

Effects on the immune system

Medicinal products which affect the immune system, including ORENCIA, may affect host defencesagainst infections and malignancies, and affect vaccination responses.

Co-administration of ORENCIA with biologic immunosuppressive or immunomodulatory agentscould potentiate the effects of abatacept on the immune system (see section 4.5).

Serious infections, including sepsis and pneumonia, have been reported with abatacept (seesection 4.8). Some of these infections have been fatal. Many of the serious infections have occurred inpatients on concomitant immunosuppressive therapy which in addition to their underlying disease,could further predispose them to infections. Treatment with ORENCIA should not be initiated inpatients with active infections until infections are controlled. Physicians should exercise caution whenconsidering the use of ORENCIA in patients with a history of recurrent infections or underlyingconditions which may predispose them to infections. Patients who develop a new infection whileundergoing treatment with ORENCIA should be monitored closely. Administration of ORENCIAshould be discontinued if a patient develops a serious infection.

No increase of tuberculosis was observed in the pivotal placebo-controlled studies; however, all

ORENCIA patients were screened for tuberculosis. The safety of ORENCIA in individuals with latenttuberculosis is unknown. There have been reports of tuberculosis in patients receiving ORENCIA (seesection 4.8). Patients should be screened for latent tuberculosis prior to initiating ORENCIA. Theavailable medical guidelines should also be taken into account.

Anti-rheumatic therapies have been associated with hepatitis B reactivation. Therefore, screening forviral hepatitis should be performed in accordance with published guidelines before starting therapywith ORENCIA.

Cases of PML have been reported in patients receiving abatacept mostly in combination with otherimmunosuppressive medication. PML can be fatal and should be considered in the differentialdiagnosis in immunosuppressed patients with new onset or worsening neurological, psychiatric andcognitive symptoms. If symptoms suggestive of PML occur during ORENCIA therapy, treatment with

ORENCIA should be discontinued and appropriate diagnostic measures initiated.

In the placebo-controlled clinical trials, the frequencies of malignancies in abatacept- and placebo-treated patients were 1.2% and 0.9%, respectively (see section 4.8). Patients with known malignancieswere not included in these clinical trials. In carcinogenicity studies in mice, an increase in lymphomasand mammary tumours were noted. The clinical significance of this observation is unknown (seesection 5.3). The potential role of abatacept in the development of malignancies, including lymphoma,in humans is unknown. There have been reports of non-melanoma skin cancers in patients receiving

ORENCIA (see section 4.8). Periodic skin examination is recommended for all patients, particularlythose with risk factors for skin cancer.

Patients treated with ORENCIA may receive concurrent vaccinations, except for live vaccines. Livevaccines 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 ofsome immunisations.

It is recommended that patients with juvenile idiopathic arthritis be brought up to date with allimmunisations in agreement with current immunisation guidelines prior to initiating ORENCIAtherapy (see section 4.5).

A total of 404 patients 65 years of age and older, including 67 patients 75 years and older, receivedabatacept in placebo-controlled clinical trials. Similar efficacy was observed in these patients and inyounger patients. The frequencies of serious infection and malignancy relative to placebo amongabatacept-treated patients over age 65 were higher than among those under age 65. Because there is ahigher incidence of infections and malignancies in the elderly in general, caution should be used whentreating the elderly (see section 4.8).

There is a theoretical concern that treatment with abatacept might increase the risk for autoimmuneprocesses 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 asantinuclear 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 glucosemonitors that use test strips with glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ). The

GDH-PQQ based glucose monitoring systems may react with the maltose present in ORENCIA,resulting in falsely elevated blood glucose readings on the day of infusion. When receiving

ORENCIA, patients that require blood glucose monitoring should be advised to consider methods thatdo not react with maltose, such as those based on glucose dehydrogenase nicotine adeninedinucleotide (GDH-NAD), glucose oxidase, or glucose hexokinase test methods.

Patients on controlled sodium diet

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

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

Combination with TNF-inhibitors

There is limited experience with the use of abatacept in combination with TNF-inhibitors (seesection 5.1). While TNF-inhibitors did not influence abatacept clearance, in placebo-controlled clinicaltrials, patients receiving concomitant treatment with abatacept and TNF-inhibitors experienced moreinfections and serious infections than patients treated with only TNF-inhibitors. Therefore, concurrenttherapy with abatacept and a TNF-inhibitor is not recommended.

Combination with other medicinal products

Population pharmacokinetic analyses did not detect any effect of methotrexate, NSAIDs, andcorticosteroids on abatacept clearance (see section 5.2).

No major safety issues were identified with use of abatacept in combination with sulfasalazine,hydroxychloroquine, or leflunomide.

Combination with other medicinal products that affect the immune system and with vaccinations

Co-administration of abatacept with biologic immunosuppressive or immunomodulatory agents couldpotentiate the effects of abatacept on the immune system. There is insufficient evidence to assess thesafety and efficacy of abatacept in combination with anakinra or rituximab (see section 4.4).

Live vaccines should not be given concurrently with abatacept or within 3 months of itsdiscontinuation. No data are available on the secondary transmission of infection from personsreceiving live vaccines to patients receiving abatacept. Medicinal products that affect the immunesystem, including abatacept, may blunt the effectiveness of some immunisations (see sections 4.4 and4.6).

Exploratory studies to assess the effect of abatacept on the antibody response to vaccination in healthysubjects as well as the antibody response to influenza and pneumococcal vaccines in rheumatoidarthritis patients suggested that abatacept may blunt the effectiveness of the immune response, but didnot 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 the23-valent pneumococcal vaccine. After pneumococcal vaccination, 62 of 112 abatacept-treatedpatients were able to mount an adequate immune response of at least a 2-fold increase in antibodytiters to pneumococcal polysaccharide vaccine.

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

Pregnancy and women of childbearing potential

There are no adequate data from use of abatacept in pregnant women. In pre-clinical embryo-foetaldevelopment studies no undesirable effects were observed at doses up to 29-fold a human 10 mg/kgdose based on AUC. In a pre- and postnatal development study in rats, limited changes in immunefunction were observed at 11-fold higher than a human 10 mg/kg dose based on AUC (seesection 5.3).

ORENCIA should not be used during pregnancy unless the clinical condition of the woman requirestreatment with abatacept. Women of childbearing potential have to use effective contraception duringtreatment and up to 14 weeks after the last dose of abatacept.

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

Abatacept has been shown to be present in rat milk.

It is unknown whether abatacept is excreted in human milk.

A risk to the newborns/infants cannot be excluded.

Breast-feeding should be discontinued during treatment with ORENCIA and for up to 14 weeks afterthe last dose of abatacept treatment.

Formal studies of the potential effect of abatacept on human fertility have not been conducted.

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

Based on its mechanism of action, abatacept is expected to have no or negligible influence on theability to drive and use machines. However, dizziness and reduced visual acuity have been reported ascommon and uncommon adverse reactions respectively from patients treated with ORENCIA,therefore if a patient experiences such symptoms, driving and use of machinery should be avoided.

Summary of the safety profile in rheumatoid arthritis

Abatacept has been studied in patients with active rheumatoid arthritis in placebo-controlled clinicaltrials (2,653 patients with abatacept, 1,485 with placebo).

In placebo-controlled clinical trials with abatacept, adverse reactions (ARs) were reported in 49.4% ofabatacept-treated patients and 45.8% of placebo-treated patients. The most frequently reported adversereactions (≥ 5%) among abatacept-treated patients were headache, nausea, and upper respiratory tractinfections (including sinusitis). The proportion of patients who discontinued treatment due to ARswas 3.0% for abatacept-treated patients and 2.0% for placebo-treated patients.

Summary of the safety profile in psoriatic arthritis

Abatacept has been studied in patients with active psoriatic arthritis in two placebo-controlled clinicaltrials (341 patients with abatacept, 253 patients with placebo) (see section 5.1). During the 24-weekplacebo-controlled period in the larger study PsA-II, the proportion of patients with adverse reactionswas similar in the abatacept and placebo treatment groups (15.5% and 11.4%, respectively). Therewere no adverse reactions that occurred at ≥ 2% in either treatment group during the 24-weekplacebo-controlled period. The overall safety profile was comparable between studies PsA-I and

PsA-II and consistent with the safety profile in rheumatoid arthritis (Table 2).

Listed in Table 2 are adverse reactions observed in clinical trials and post-marketing experiencepresented 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); veryrare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order ofdecreasing seriousness.

Table 2: Adverse reactions

Infections and infestations Very Common Upper respiratory tract infection (includingtracheitis, nasopharyngitis, and sinusitis)

Common Lower respiratory tract infection (includingbronchitis), urinary tract infection, herpesinfections (including herpes simplex, oral herpes,and herpes zoster), pneumonia, influenza

Uncommon Tooth infection, onychomycosis, sepsis,musculoskeletal infections, skin abscess,pyelonephritis, rhinitis, ear infection

Rare Tuberculosis, bacteraemia, gastrointestinalinfection, pelvic inflammatory disease

Neoplasms benign, malignant Uncommon Basal cell carcinoma, skin papillomaand unspecified (incl. cysts and Rare Lymphoma, lung neoplasm malignant, squamouspolyps) cell carcinoma

Blood and lymphatic system Uncommon Thrombocytopenia, leukopeniadisorders

Immune system disorders Uncommon Hypersensitivity

Psychiatric disorders Uncommon Depression, anxiety, sleep disorder (includinginsomnia)

Nervous system disorders Common Headache, dizziness

Uncommon Migraine, paraesthesia

Eye disorders Uncommon Conjunctivitis, dry eye, visual acuity reduced

Ear and labyrinth disorders Uncommon Vertigo

Cardiac disorders Uncommon Palpitations, tachycardia, bradycardia

Vascular disorders Common Hypertension, blood pressure increased

Uncommon Hypotension, hot flush, flushing, vasculitis, bloodpressure decreased

Respiratory, thoracic and Common Coughmediastinal disorders Uncommon Chronic obstructive pulmonary diseaseexacerbated, bronchospasm, wheezing, dyspnoea,throat tightness

Gastrointestinal disorders Common Abdominal pain, diarrhoea, nausea, dyspepsia,mouth ulceration, aphthous stomatitis, vomiting

Uncommon Gastritis

Hepatobiliary disorders Common Liver function test abnormal (includingtransaminases increased)

Skin and subcutaneous tissue Common Rash (including dermatitis)disorders Uncommon Increased tendency to bruise, dry skin, alopecia,pruritus, urticaria, psoriasis, acne, erythema,hyperhidrosis

Musculoskeletal and connective Uncommon Arthralgia, pain in extremitytissue disorders

Reproductive system and breast Uncommon Amenorrhea, menorrhagiadisorders

General disorders and Common Fatigue, astheniaadministration site conditions Uncommon Influenza like illness, weight increased

In the placebo-controlled clinical trials with abatacept, infections at least possibly related to treatmentwere reported in 22.7% of abatacept-treated patients and 20.5% of placebo-treated patients.

Serious infections at least possibly related to treatment were reported in 1.5% of abatacept-treatedpatients and 1.1% of placebo-treated patients. The type of serious infections was similar between theabatacept and placebo treatment groups (see section 4.4).

The incidence rates (95% CI) for serious infections was 3.0 (2.3, 3.8) per 100 patient-years forabatacept-treated patients and 2.3 (1.5, 3.3) per 100 patient-years for placebo-treated patients in thedouble-blind studies.

In the cumulative period in clinical trials in 7,044 patients treated with abatacept during20,510 patient-years, the incidence rate of serious infections was 2.4 per 100 patient-years, and theannualised incidence rate remained stable.

In placebo-controlled clinical trials, malignancies were reported in 1.2% (31/2,653)of abatacept-treated patients and in 0.9% (14/1,485) of placebo-treated patients. The incidence ratesfor malignancies was 1.3 (0.9, 1.9) per 100 patient-years for abatacept-treated patients and 1.1 (0.6,1.9) per 100 patient-years for placebo-treated patients.

In the cumulative period 7,044 patients treated with abatacept during 21,011 patient-years (of whichover 1,000 were treated with abatacept for over 5 years), the incidence rate of malignancy was1.2 (1.1, 1.4) per 100 patient-years, and the annualised incidence rates remained stable.

The most frequently reported malignancy in the placebo-controlled clinical trials was non-melanomaskin cancer; 0.6 (0.3, 1.0) per 100 patient-years for abatacept-treated patients and 0.4 (0.1, 0.9) per100 patient-years for placebo-treated patients and 0.5 (0.4, 0.6) per 100 patient-years in the cumulativeperiod.

The most frequently reported organ cancer in the placebo-controlled clinical trials was lung cancer0.17 (0.05, 0.43) per 100 patient-years for abatacept-treated patients, 0 for placebo-treated patients and0.12 (0.08, 0.17) per 100 patient-years in the cumulative period. The most common hematologicmalignancy was lymphoma 0.04 (0, 0.24) per 100 patient-years for abatacept-treated patients, 0 forplacebo-treated patients and 0.06 (0.03, 0.1) per 100 patient-years in the cumulative period.

Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) inseven pooled intravenous studies (for studies II, III, IV and V see section 5.1) were more common inthe abatacept-treated patients than the placebo-treated patients (5.2% for abatacept, 3.7% for placebo).

The most frequently reported event with abatacept (1-2%) was dizziness.

Acute infusion-related events that were reported in > 0.1% and ≤ 1% of patients treated with abataceptincluded cardiopulmonary symptoms such as hypotension, decreased blood pressure, tachycardia,bronchospasm, and dyspnoea; other symptoms included myalgia, nausea, erythema, flushing, urticaria,hypersensitivity, pruritus, throat tightness, chest discomfort, chills, infusion site extravasation, infusionsite pain, infusion site swelling, infusion related reaction, and rash. Most of these reactions were mildto moderate.

The occurrence of anaphylaxis remained rare during the double blind and the cumulative period.

Hypersensitivity was reported uncommonly. Other reactions potentially associated withhypersensitivity to the medicinal product, such as hypotension, urticaria, and dyspnoea, that occurredwithin 24 hours of ORENCIA infusion, were uncommon.

Discontinuation due to an acute infusion-related reaction occurred in 0.3% of patients receivingabatacept and in 0.1% of placebo-treated patients.

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

In study IV, there were 37 patients with COPD treated with intravenous abatacept and 17 treated withplacebo. The COPD patients treated with abatacept developed adverse reactions more frequently thanthose treated with placebo (51.4% vs. 47.1%, respectively). Respiratory disorders occurred morefrequently in abatacept-treated patients than in placebo-treated patients (10.8% vs. 5.9%, respectively);these included COPD exacerbation, and dyspnoea. A greater percentage of abatacept- thanplacebo-treated patients with COPD developed a serious adverse reaction (5.4% vs. 0%), including

COPD exacerbation (1 of 37 patients [2.7%]) and bronchitis (1 of 37 patients [2.7%]).

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 in abatacept-treated patients during the double-blindperiod was 8.8 (7.6, 10.1) per 100 person-years of exposure and for placebo-treated patients was9.6 (7.9, 11.5) per 100 person-years of exposure. The incidence rate in abatacept-treated patients was3.8 per 100 person-years in the cumulative period. The most frequently reported autoimmune-relateddisorders other than the indication being studied during the cumulative period were psoriasis,rheumatoid nodule, and Sjogren's syndrome.

Antibodies directed against the abatacept molecule were assessed by ELISA assays in3,985 rheumatoid arthritis patients treated for up to 8 years with abatacept. One hundred andeighty seven of 3,877 (4.8%) patients developed anti-abatacept antibodies while on treatment. Inpatients assessed for anti-abatacept antibodies after discontinuation of abatacept (> 42 days after lastdose), 103 of 1,888 (5.5%) were seropositive.

Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizingantibodies. Twenty-two of 48 evaluable patients showed significant neutralizing activity. The potentialclinical relevance of neutralizing antibody formation is not known.

Overall, there was no apparent correlation of antibody development to clinical response or adverseevents. However, the number of patients that developed antibodies was too limited to make adefinitive assessment. Because immunogenicity analyses are product-specific, comparison of antibodyrates with those from other products is not appropriate.

Safety information related to the pharmacological class

Abatacept is the first selective co-stimulation modulator. Information on the relative safety in aclinical trial versus infliximab is summarised in section 5.1.

Abatacept has been studied in patients with pJIA in two clinical trials (pJIA SC study and pJIA IVstudy). The pJIA SC study included 46 patients in the 2 to 5 year age cohort and 173 patients in the 6to 17 year age cohort. The pJIA IV study included 190 patients in the 6 to 17 year age cohort. Duringthe first 4-month open-label period, the overall safety profile in these 409 pJIA patients was similar tothat observed in the RA population with the following exceptions in the pJIA patients:

 Common adverse reactions: pyrexia Uncommon adverse reactions: haematuria, otitis (media and externa).

Infections were the most commonly reported adverse events in patients with pJIA. The types ofinfections were consistent with those commonly seen in outpatient paediatric populations. During thefirst 4-month treatment period of intravenous and subcutaneous abatacept in 409 patients with pJIA,the most common adverse reactions were nasopharyngitis (3.7% patients) and upper respiratory tractinfection (2.9% patients). Two serious infections (varicella and sepsis) were reported during the initial4 months of treatment with abatacept.

Of the 190 patients with pJIA treated with intravenous ORENCIA, one (0.5%) patient discontinueddue 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 4%, respectively,and were consistent with the types of reactions reported in adults.

Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept wereassessed by ELISA assays in patients with pJIA following repeated treatment with intravenous

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 12.8% (19/148) during Period C. Forpatients in Period B who were randomised to placebo (therefore withdrawn from therapy for up to6 months) the rate of seropositivity was 40.7% (22/54). Anti-abatacept antibodies were generallytransient and of low titer. The absence of concomitant methotrexate (MTX) did not appear to beassociated with a higher rate of seropositivity in Period B placebo recipients. The presence ofantibodies was not associated with adverse reactions or infusion reactions, or with changes in efficacyor 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.

Long-term extension period

During the extension period of the pJIA studies (20 months in the pJIA SC study and 5 years in thepJIA IV study), the safety profile in the pJIA patients aged 6 to 17 years was comparable to that seenin adult patients. One patient was diagnosed with multiple sclerosis while in the extension period ofthe pJIA IV study. One serious adverse reaction of infection (limb abscess) was reported in the 2 to5 year age cohort during the 20-month extension period of the pJIA SC study.

Long-term safety data in 2 to 5 year age cohort with pJIA was limited, but the existing evidence didnot reveal any new safety concern in this younger paediatric population. During the 24-monthcumulative period of the pJIA SC study (4-month short term period plus 20-month extension period), ahigher frequency of infections was reported in the 2 to 5 year age cohort (87.0%) compared to thatreported in the 6 to 17 year age cohort (68.2%). This was mostly due to non-serious upper respiratorytract infections in the 2 to 5 year age cohort.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Doses up to 50 mg/kg have been administered without apparent toxic effect. In case of overdose, it isrecommended that the patient be monitored for any signs or symptoms of adverse reactions andappropriate symptomatic treatment instituted.

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code:

L04AA24

Abatacept is a fusion protein that consists of the extracellular domain of human cytotoxic

T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc portion of humanimmunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in Chinesehamster ovary cells.

Abatacept selectively modulates a key costimulatory signal required for full activation of Tlymphocytes expressing CD28. Full activation of T lymphocytes requires two signals provided byantigen 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 abataceptthan memory T lymphocyte responses.

Studies in vitro and in animal models demonstrate that abatacept modulates T lymphocyte-dependentantibody responses and inflammation. In vitro, abatacept attenuates human T lymphocyte activation asmeasured by decreased proliferation and cytokine production. Abatacept decreases antigen specific

TNFα, interferon-γ, and interleukin-2 production by T lymphocytes.

Dose-dependent reductions were observed with abatacept in serum levels of soluble interleukin-2 receptor, a marker of T lymphocyte activation; serum interleukin-6, a product of activated synovialmacrophages and fibroblast-like synoviocytes in rheumatoid arthritis; rheumatoid factor, anautoantibody produced by plasma cells; and C-reactive protein, an acute phase reactant ofinflammation. In addition, serum levels of matrix metalloproteinase-3, which produces cartilagedestruction and tissue remodelling, were decreased. Reductions in serum TNFα were also observed.

Clinical efficacy and safety in adult rheumatoid arthritis

The efficacy and safety of intravenous abatacept were assessed in randomised, double-blind, placebo-controlled clinical trials in adult patients with active rheumatoid arthritis diagnosed according to

American College of Rheumatology (ACR) criteria. Studies I, II, III, V, and VI required patients tohave at least 12 tender and 10 swollen joints at randomisation. Study IV did not require any specificnumber of tender or swollen joints.

In studies I, II, and V the efficacy and safety of abatacept compared to placebo were assessed inpatients with an inadequate response to methotrexate and who continued on their stable dose ofmethotrexate. In addition, study V investigated the safety and efficacy of abatacept or infliximabrelative to placebo. In study III the efficacy and safety of abatacept were assessed in patients with aninadequate response to a TNF-inhibitor, with the TNF-inhibitor discontinued prior to randomisation;other DMARDs were permitted. Study IV primarily assessed safety in patients with active rheumatoidarthritis requiring additional intervention in spite of current therapy with non-biological and/orbiological DMARDs; all DMARDs used at enrollment were continued. In study VI, the efficacy andsafety 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 randomised to receive abatacept plus methotrexate ormethotrexate plus placebo. Study SC-II investigated the relative efficacy and safety of abatacept andadalimumab, 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 MTXtherapy. In study SC-III, abatacept subcutaneous was evaluated in combination with methotrexate(MTX), or as abatacept monotherapy, and compared to MTX monotherapy in induction of remissionfollowing 12 months of treatment, and the possible maintenance of drug-free remission after completedrug 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 forrapidly progressive disease (e.g., anti-citrullinated protein antibodies [ACPA+], as measured byanti-CCP2 assay, and/or RF+, baseline joint erosions).

Study I patients were randomised to receive abatacept 2 or 10 mg/kg or placebo for 12 months.

Study II, III, IV, and VI patients were randomised to receive a fixed dose approximating 10 mg/kg ofabatacept or placebo for 12 (studies II, IV, and VI) or 6 months (study III). The dose of abataceptwas 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and1,000 mg for patients weighing greater than 100 kg. Study V patients were randomised to receive thissame fixed dose of abatacept or 3 mg/kg infliximab or placebo for 6 months. Study V continued for anadditional 6 months with the abatacept and infliximab groups only.

Studies I, II, III, IV, V, VI, SC-II, and SC-III evaluated 339, 638, 389, 1441, 431, 509, 646, and351 adult patients, respectively.

The percent of abatacept-treated patients achieving ACR 20, 50, and 70 responses in study II (patientswith inadequate response to methotrexate), study III (patients with inadequate response to

TNF-inhibitor), and study VI (methotrexate-naive patients) are shown in Table 3.

In abatacept-treated patients in studies II and III, statistically significant improvement in the

ACR 20 response versus placebo was observed after administration of the first dose (day 15), and thisimprovement remained significant for the duration of the studies. In study VI, statistically significantimprovement in the ACR 20 response in abatacept plus methotrexate-treated patients versusmethotrexate plus placebo-treated patients was observed at 29 days, and was maintained through theduration of the study. In study II, 43% of the patients who had not achieved an ACR 20 responseat 6 months developed an ACR 20 response at 12 months.

Table 3: Clinical responses in controlled trials

Percent of patients

MTX-Naive Inadequate response to Inadequate response to

MTX TNF Inhibitor

Study VI Study II Study III

Abatacepta Placebo Abatacepta Placebo Abatacepta Placebo+MTX +MTX +MTX +MTX +DMARDsb +DMARDsb

Response Rate n = 256 n = 253 n = 424 n = 214 n = 256 n = 133

ACR 20

Day 15 24% 18% 23%* 14% 18%** 5%

Month 3 64%†† 53% 62%*** 37% 46%*** 18%

Month 6 75%† 62% 68%*** 40% 50%*** 20%

Month 12 76%‡ 62% 73%*** 40% NAd NAd

ACR 50

Month 3 40%‡ 23% 32%*** 8% 18%** 6%

Month 6 53%‡ 38% 40%*** 17% 20%*** 4%

Month 12 57%‡ 42% 48%*** 18% NAd NAd

ACR 70

Month 3 19%† 10% 13%*** 3% 6%†† 1%

Month 6 32%† 20% 20%*** 7% 10%** 2%

Month 12 43%‡ 27% 29%*** 6% NAd NAd

Major Clinical ‡

Responsec 27% 12% 14%*** 2% NAd NAd

DAS28-CRP

Remissione

Month 6 28%‡ 15% NA NA NA NA

Month 12 41%‡ 23% NA NA NA NA

* p < 0.05, abatacept vs. placebo.

** p < 0.01, abatacept vs. placebo.

*** p < 0.001, abatacept vs. placebo.† p < 0.01, abatacept plus MTX vs. MTX plus placebo‡ p < 0.001, abatacept plus MTX vs. MTX plus placebo†† p < 0.05, abatacept plus MTX vs. MTX plus placeboa Fixed dose approximating 10 mg/kg (see section 4.2).b Concurrent DMARDs included one or more of the following: methotrexate, chloroquine/hydroxychloroquine, sulfasalazine,leflunomide, azathioprine, gold, and anakinra.c Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period.d After 6 months, patients were given the opportunity to enter an open-label study.e DAS28-CRP Remission is defined as a DAS28-CRP score < 2.6

In the open-label extension of studies I, II, III, and VI durable and sustained ACR 20, 50,and 70 responses have been observed through 7 years, 5 years, 5 years, and 2 years, respectively, ofabatacept 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 responseswere assessed at 5 years in 270 patients with 84% ACR 20 responses, 61% ACR 50 responses, and40% 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 responseswere assessed at 2 years in 232 patients with 85% ACR 20 responses, 74% ACR 50 responses, and54% ACR 70 responses.

Greater improvements were seen with abatacept than with placebo in other measures of rheumatoidarthritis disease activity not included in the ACR response criteria, such as morning stiffness.

DAS28 response

Disease activity was also assessed using the Disease Activity Score 28. There was a significantimprovement of DAS in studies II, III, V, and VI as compared to placebo or comparator.

In study VI, which only included adults, a significantly higher proportion of patients in the abataceptplus methotrexate group (41%) achieved DAS28 (CRP)-defined remission (score < 2.6) versus themethotrexate plus placebo group (23%) at year 1. The response at year 1 in the abatacept group wasmaintained through year 2.

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

Study V: abatacept or infliximab versus placebo

A randomised, double-blind study was conducted to assess the safety and efficacy of abatacept orinfliximab versus placebo in patients with an inadequate response to methotrexate (study V). Theprimary outcome was the mean change in disease activity in abatacept-treated patients compared toplacebo-treated patients at 6 months with a subsequent double-blind assessment of safety and efficacyof abatacept and infliximab at 12 months. Greater improvement (p < 0.001) in DAS28 was observedwith abatacept and with infliximab compared to placebo at six months in the placebo-controlledportion of the trial; the results between the abatacept and infliximab groups were similar. The ACRresponses in study V were consistent with the DAS28 score. Further improvement was observed at12 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 incidenceof AE of infections were 59.6% (93), 68.5% (113), and the incidence of serious AE of infections were1.9% (3) and 8.5% (14) for abatacept and infliximab groups, respectively. The open label period of thestudy provided an assessment of the ability of abatacept to maintain efficacy for subjects originallyrandomised to abatacept and the efficacy response of those subjects who were switched to abataceptfollowing treatment with infliximab. The reduction from baseline in mean DAS28 score atday 365 (-3.06) was maintained through day 729 (-3.34) in those patients who continued withabatacept. In those patients who initially received infliximab and then switched to abatacept, thereduction in the mean DAS28 score from baseline was 3.29 at day 729 and 2.48 at day 365.

Study SC-II: abatacept versus adalimumab

A randomised, single (investigator)-blinded, non-inferiority study was conducted to assess the safetyand efficacy of weekly subcutaneous (SC) abatacept without an abatacept intravenous (IV) loadingdose versus every-other-weekly subcutaneous adalimumab, both with background MTX, in patientswith an inadequate response to methotrexate (study SC-II). The primary endpoint showednon-inferiority (predefined margin of 12%) of ACR 20 response after 12 months of treatment,64.8% (206/318) for the abatacept SC group and 63.4% (208/328) for the adalimumab SC group;treatment difference was 1.8% [95% confidence interval (CI): -5.6, 9.2], with comparable responsesthroughout the 24-month period. The respective values for ACR 20 at 24 months were59.7% (190/318) for the abatacept SC group and 60.1% (197/328) for the adalimumab SC group. Therespective values for ACR 50 and ACR 70 at 12 months and 24 months were consistent and similar forabatacept and adalimumab. The adjusted mean changes (standard error; SE) from baseline in

DAS28-CRP were -2.35 (SE 0.08) [95% CI: -2.51, -2.19] and -2.33 (SE 0.08) [95% CI: -2.50, -2.17]in the SC abatacept group and the adalimumab group, respectively, at 24 months, with similar changesover time. At 24 months, 50.6% (127/251) [95% CI: 44.4, 56.8] of patients in abatacept and53.3% (130/244) [95% CI: 47.0, 59.5] of patients in adalimumab groups achieved DAS 28 < 2.6.

Improvement from baseline as measured by HAQ-DI at 24 months and over time was also similarbetween abatacept SC and adalimumab SC.

Safety and structural damage assessments were conducted at one and two years. The overall safetyprofile with respect to adverse reactions was similar between the two groups over the 24-monthperiod. After 24 months, adverse reactions were reported in 41.5% (132/318) and 50% (164/328) ofabatacept and adalimumab-treated patients. Serious adverse reactions were reported in 3.5% (11/318)and 6.1% (20/328) of the respective group. At 24 months, 20.8% (66/318) of patients on abatacept and25.3% (83/328) on adalimumab had discontinued.

In SC-II, serious infections were reported in 3.8% (12/318) of patients treated with abatacept SCweekly, none of which led to discontinuation and in 5.8% (19/328) of patients treated withadalimumab SC every-other-week, leading to 9 discontinuations in the 24-month period.

The frequency of local injection site reactions was 3.8% (12/318) and 9.1% (30/328) at 12 months(p = 0.006) and 4.1% (13/318) and 10.4% (34/328) at 24 months for abatacept SC and adalimumab

SC, respectively. Over the 2 year study period, 3.8% (12/318) and 1.5% (5/328) patients treated withabatacept SC and adalimumab SC respectively reported autoimmune disorders mild to moderate inseverity (e.g., psoriasis, Raynaud’s phenomenon, erythema nodosum).

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

A randomised and double-blinded study evaluated abatacept SC in combination with methotrexate(abatacept + MTX), abatacept SC monotherapy, or methotrexate monotherapy (MTX group) ininduction of remission following 12 months of treatment, and maintenance of drug-free remission aftercomplete drug withdrawal in MTX-naive adult patients with highly active early rheumatoid arthritiswith poor prognostic factors. Complete drug withdrawal led to loss of remission (return to diseaseactivity) in all three treatment arms (abatacept with methotrexate, abatacept or methotrexate alone) in amajority of patients (Table 4).

Table 4: Remission rates at end of drug treatment and drug withdrawal phases in study

SC-III

Abatacept SC+ MTX MTX Abatacept SC

Number of patients n = 119 n = 116 n = 116

Proportion of randomised patients with induction of remission after 12 months of treatment

DAS28-Remissiona 60.9% 45.2% 42.5%

Odds Ratio (95% CI) vs. MTX 2.01 (1.18, 3.43) N/A 0.92 (0.55, 1.57)

P value 0.010 N/A N/A

SDAI Clinical Remissionb 42.0% 25.0% 29.3%

Estimate of Difference (95% CI) 17.02 (4.30, 29.73) N/A 4.31 (-7.98, 16.61)vs. MTX

Boolean Clinical Remission 37.0% 22.4% 26.7%

Estimate of Difference (95% CI) 14.56 (2.19, 26.94) N/A 4.31 (-7.62, 16.24)vs. MTX

Abatacept SC+ MTX MTX Abatacept SC

Number of patients n = 119 n = 116 n = 116

Proportion of randomised patients in remission at 12 months and at 18 months(6 months of complete drug withdrawal)

DAS28-Remission a 14.8% 7.8% 12.4%

Odds Ratio (95% CI) vs. MTX 2.51 (1.02, 6.18) N/A 2.04 (0.81, 5.14)

P value 0.045 N/A N/Aa 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 werereported in 44.5% (53/119), 41.4% (48/116), and 44.0% (51/116) and serious adverse reactions werereported in 2.5% (3/119), 2.6% (3/116) and 0.9% (1/116) of patients treated in the three treatmentgroups, respectively. Serious infections were reported in 0.8% (1/119), 3.4% (4/116) and 0% (0/116)patients.

Structural joint damage was assessed radiographically over a two-year period in studies II, and VI.

The results were measured using the Genant-modified total Sharp score (TSS) and its components, theerosion score and joint space narrowing (JSN) score.

In study II, the baseline median TSS was 31.7 in abatacept-treated patients and 33.4 in placebo-treatedpatients. Abatacept/methotrexate reduced the rate of progression of structural damage compared toplacebo/methotrexate after 12 months of treatment as shown in Table 5. The rate of progression ofstructural damage in year 2 was significantly lower than that in year 1 for patients randomised toabatacept (p < 0.0001). Subjects entering the long term extension after 1 year of double blindtreatment all received abatacept treatment and radiographic progression was investigated throughyear 5. Data were analysed in an as-observed analysis using mean change in total score from theprevious annual visit. The mean change was, 0.41 and 0.74 from year 1 to year 2 (n = 290, 130), 0.37and 0.68 from year 2 to year 3 (n = 293, 130), 0.34 and 0.43 from year 3 to year 4 (n = 290, 128) andthe change was 0.26 and 0.29 (n = 233, 114) from year 4 to year 5 for patients originally randomisedto abatacept plus MTX and placebo plus MTX respectively.

Table 5: Mean radiographic changes over 12 months in study II

Abatacept/MTX Placebo/MTX

Parameter n = 391 n = 195 P-valuea

Total Sharp score 1.21 2.32 0.012

Erosion score 0.63 1.14 0.029

JSN score 0.58 1.18 0.009a Based on non-parametric analysis.

In study VI, the mean change in TSS at 12 months was significantly lower in patients treated withabatacept plus methotrexate compared to those treated with methotrexate plus placebo. At 12 months61% (148/242) of the patients treated with abatacept plus methotrexate and 53% (128/242) of thepatients treated with methotrexate plus placebo had no progression (TSS ≤ 0). The progression ofstructural 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 whoentered the open-label 12-month period, 59% (125/213) of patients receiving continuous abataceptplus methotrexate treatment and 48% (92/192) of patients who initially received methotrexate andswitched to combination with abatacept had no progression.

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

Table 6: Structural and inflammatory MRI assessment in study SC-III

Mean Treatment Difference between Abatacept SC+MTX vs. MTX at 12 Months (95% CI)*

MRI Erosion Score -1.22 (-2.20, -0.25)

MRI Osteitis/Bone Oedema Score -1.43 (-2.68, -0.18)

MRI Synovitis Score -1.60 (-2.42, -0.78)

* n = 119 for Abatacept SC + MTX; n = 116 for MTX

Physical function response

Improvement in physical function was measured by the Health Assessment Questionnaire Disability

Index (HAQ-DI) in studies II, III, IV, V, and VI and the modified HAQ-DI in study I. The results fromstudies II, III, and VI are shown in Table 7.

Table 7: Improvement in physical function in controlled trials

Methotrexate-Naive Inadequate response to Inadequate response to

Methotrexate TNF Inhibitor

Study VI Study II Study III

HAQc Disability Abatacepta Placebo Abatacepta Placebo Abatacepta Placebo

Index +MTX +MTX +MTX +MTX +DMARDsb +DMARDsb

Baseline (Mean) 1.7 1.7 1.69 1.69 1.83 1.82(n = 254) (n = 251) (n = 422) (n = 212) (n = 249) (n = 130)

Mean Improvementfrom Baseline0.85 0.68 0.59*** 0.40 0.45*** 0.11

Month 6(n = 250) (n = 249) (n = 420) (n = 211) (n = 249) (n = 130)0.96 0.76 0.66*** 0.37

Month 12 NAe NAe(n = 254) (n = 251) (n = 422) (n = 212)

Proportion of patientswith a clinicallymeaningfulimprovementd

Month 6 72%† 63% 61%*** 45% 47%*** 23%

Month 12 72%† 62% 64%*** 39% NAe NAe

*** p < 0.001, abatacept vs. placebo.† p < 0.05, abatacept plus MTX vs MTX plus placeboa Fixed dose approximating 10 mg/kg (see section 4.2).b Concurrent DMARDs included one or more of the following: methotrexate, chloroquine/hydroxychloroquine, sulfasalazine,leflunomide, azathioprine, gold, and anakinra.

c Health Assessment Questionnaire; 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating,walking, hygiene, reach, grip, and activities.d Reduction in HAQ-DI of ≥ 0.3 units from baseline.e After 6 months, patients were given the opportunity to enter into an open-label study.

In study II, among patients with clinically meaningful improvement at month 12, 88% retained theresponse at month 18, and 85% retained the response at month 24. During the open-label periods ofstudies I, II, III, and VI the improvement in physical function has been maintained through 7 years,5 years, 5 years, and 2 years, respectively.

In study SC-III, the proportion of subjects with a HAQ response as a measure of clinically meaningfulimprovement in physical function (reduction from baseline in HAQ-D1 score of ≥ 0.3) was greater forthe abatacept + MTX group vs. the MTX group at month 12 (65.5% vs 44.0%, respectively; treatmentdifference vs. MTX group of 21.6% [95% CI: 8.3, 34.9]).

Health-related outcomes and quality of life

Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in studies I, II, and

III and at 12 months in studies I and II. In these studies, clinically and statistically significantimprovement was observed in the abatacept group as compared with the placebo group inall 8 domains of the SF-36 (4 physical domains: physical function, role physical, bodily pain, generalhealth; and 4 mental domains: vitality, social function, role emotional, mental health), as well as the

Physical Component Summary (PCS) and the Mental Component Summary (MCS). In study VI,improvement was observed at 12 months in abatacept plus methotrexate group as compared with themethotrexate plus placebo group in both PCS and MCS, and was maintained through 2 years.

Study VII: Safety of abatacept in patients with or without washout of previous TNF-inhibitor therapy

A study of open-label abatacept on a background of nonbiologic DMARDs was conducted in patientswith active RA who had an inadequate response to previous (washout for at least 2 months; n = 449)or current (no washout period; n = 597) TNF-inhibitor therapy (study VII). The primary outcome,incidence of AEs, SAEs, and discontinuations due to AEs during 6 months of treatment, was similarbetween those who were previous and current TNF-inhibitor users at enrollment, as was the frequencyof serious infections.

Clinical efficacy and safety in adult psoriatic arthritis

The efficacy and safety of abatacept were assessed in two randomised, double-blind,placebo-controlled trials (studies PsA-I and PsA-II) in adult patients, age 18 years and older. Patientshad active PsA (≥ 3 swollen joints and ≥ 3 tender joints) despite prior treatment with DMARD therapyand had one qualifying psoriatic skin lesion of at least 2 cm in diameter.

In study PsA-I, 170 patients received placebo or abatacept intravenously on day 1, 15, 29, and thenevery 28 days thereafter in a double blind manner for 24 weeks, followed by open-label abatacept10 mg/kg intravenously every 28 days. Patients were randomised to receive placebo or abatacept3 mg/kg, 10 mg/kg, or two doses of 30 mg/kg followed by 10 mg/kg, without escape for 24 weeks,followed by open label abatacept 10 mg/kg monthly intravenous every month. Patients were allowedto receive stable doses of concomitant methotrexate, low dose corticosteroids (equivalent to ≤ 10 mgof prednisone) and/or NSAIDs during the trial.

In study PsA-II, 424 patients were randomised 1:1 to receive in a double-blind manner weekly dosesof subcutaneous placebo or abatacept 125 mg without a loading dose for 24 weeks, followed byopen-label abatacept 125 mg subcutaneous weekly. Patients were allowed to receive stable doses ofconcomitant methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids(equivalent to ≤ 10 mg of prednisone) and/or NSAIDs during the trial. Patients who had not achievedat least a 20% improvement from baseline in their swollen and tender joint counts by week 16 escapedto open-label abatacept 125 mg subcutaneous weekly.

The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20response at Week 24 (day 169).

Clinical Response

Signs and symptoms

The percent of patients achieving ACR 20, 50, or 70 responses at the recommended abatacept dose instudies PsA-I (10 mg/kg intravenous) and PsA-II (125 mg subcutaneous) are presented in Table 8below.

Table 8: Proportion of patients with ACR responses at week 24 in studies PsA-I and

PsA-II

PsA-Ia PsA-IIb,c

Abatacept Placebo Estimate of Abatacept Placebo Estimate of10 mg/kg N = 42 difference 125 mg N = 211 difference

IV (95% CI) SC (95% CI)

N = 40 N = 213

ACR 20 47.5%* 19.0% 28.7 (9.4, 48.0) 39.4%* 22.3% 17.2 (8.7, 25.6)

ACR 50 25.0% 2.4% 22.7 (8.6, 36.9) 19.2% 12.3% 6.9 (0.1, 13.7)

ACR 70 12.5% 0% 12.5 (2.3, 22.7) 10.3% 6.6% 3.7 (-1.5, 8.9)

* p < 0.05 vs placebo, p values not assessed for ACR 50 and ACR 70.a 37% of patients were previously treated with TNF inhibitor.b 61% of patients were previously treated with TNF inhibitor.c Patients who had less than 20% improvement in tender or swollen joint counts at Week 16 met escape criteria and wereconsidered non-responders.

A significantly higher proportion of patients achieved an ACR 20 response after treatment withabatacept 10 mg/kg intravenous in PsA-I or 125 mg subcutaneous in PsA-II compared to placebo at

Week 24 in the overall study populations. Higher ACR 20 responses were observed with abatacept vsplacebo regardless of prior TNF-inhibitor treatment in both studies. In the smaller study PsA-I, the

ACR 20 responses with abatacept 10 mg/kg intravenous vs placebo in patients who were TNFinhibitor-naive were 55.6% vs 20.0%, respectively, and in patients who were TNFinhibitor-experienced were 30.8% vs 16.7%, respectively. In study PsA-II, the ACR 20 responses withabatacept 125 mg subcutaneous vs placebo in patients who were TNF inhibitor-naive were 44.0% vs22.2%, respectively (21.9 [8.3, 35.6], estimate of difference [95% CI]), and in patients who were TNFinhibitor-experienced were 36.4% vs 22.3%, respectively (14.0 [3.3, 24.8], estimate of difference[95% CI]).

Higher ACR 20 responses in study PsA-II were seen with abatacept 125 mg subcutaneous vs. placeboirrespective of concomitant nonbiological DMARD treatment. The ACR 20 responses with abatacept125 mg subcutaneous vs placebo in patients who did not use nonbiological DMARDs were 27.3% vs12.1%, respectively, (15.15 [1.83, 28.47], estimate of difference [95% CI]), and in patients who hadused non-biological DMARDs were 44.9% vs 26.9%, respectively, (18.00 [7.20, 28.81], estimate ofdifference [95% CI]). Clinical responses were maintained or continued to improve up to one year instudies PsA-I and PsA-II.

Structural response

In study PsA-II, the proportion of radiographic non-progressors (≤ 0 change from baseline) in total

PsA-modified SHS on x-rays at Week 24 was greater with abatacept 125 mg subcutaneous (42.7%)than placebo (32.7%) (10.0 [1.0, 19.1] estimate of difference [95% CI]).

Physical Function Response

In study PsA-I, the proportion of patients with ≥ 0.30 decrease from baseline in HAQ-DI score was45.0% with intravenous abatacept vs 19.0% with placebo (26.1 [6.8, 45.5], estimate of difference[95% CI]) at Week 24. In study PsA-II, the proportion of patients with at least ≥ 0.35 decrease frombaseline in HAQ-DI was 31.0% with abatacept vs. 23.7% with placebo (7.2 [-1.1, 15.6], estimate ofdifference [95% CI]). Improvement in HAQ-DI scores was maintained or improved for up to 1 yearwith continuing abatacept treatment in both PsA-I and PsA-II studies.

No significant changes in PASI scores with abatacept treatment were seen over the 24-weekdouble-blind period. Patients entering the two PsA studies had mild to moderate psoriasis with median

PASI scores of 8.6 in PsA-I and 4.5 in PsA-II. In study PsA-I, the proportions of patients achieving

PASI 50 response was 28.6% with abatacept vs. 14.3% with placebo (14.3 [-15.3, 43.9], estimate ofdifference [95% CI]), and the proportion of patients who achieved PASI 75 response was 14.3% withabatacept vs. 4.8% with placebo (9.5 [-13.0, 32.0], estimate of difference [95% CI]). In study PsA-II,the proportion of patients who achieved PASI 50 response was 26.7% with abatacept vs. 19.6% withplacebo (7.3 [-2.2, 16.7], estimate of difference [95% CI]), and the proportion of patients whoachieved PASI 75 response was 16.4% with abatacept vs. 10.1% with placebo (6.4 [-1.3, 14.1],estimate of difference [95% CI]).

Paediatric population in polyarticular juvenile idiopathic arthritis

Children and adolescents with moderate to severe active pJIA, ages 6 to 17 years with an inadequateresponse or intolerance to at least one DMARD, which may have included biologic agents, wereenrolled. The safety and efficacy of intravenous abatacept were assessed in a three-part study.

Period A was a 4-month open-label lead-in designed to induce an ACR Pedi 30 response. Patientsachieving at least a ACR Pedi 30 response at the end of Period A were randomised into adouble-blind, withdrawal phase (Period B), and received either abatacept or placebo for 6 months oruntil pJIA disease flare as defined in the study. Unless they had discontinued due to safety reasons, allpatients who completed, or had a flare during Period B or were non-responders in Period A wereoffered 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 assessedon day 113. During period A, 74% were taking methotrexate (mean dose at study entry,13.2 mg/m2/week) thus, 26% of patients received abatacept monotherapy in Period A. Of the190 patients entering the study, 57 (30%) had previously been treated with TNF-inhibitor therapy.

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

Flare was defined as: ≥ 30% worsening in at least 3 of the 6 pJIA core set variables ≥ 30% improvement in not more than 1 of the 6 pJIA 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 withlimited 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 of4.4 years. They had active disease, with baseline mean active joint count of 16 and a mean number ofjoints 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 pJIA 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 30response, and 122 were randomised to Period B. Responses were similar in all subtypes of pJIAstudied and for patients with or without methotrexate use. Of the 133 (70%) patients with no prior

TNF-inhibitor therapy, 101 (76%) achieved at least an ACR Pedi 30 response; of the 57 patients whohad received prior TNF-inhibitor therapy, 22 (39%) achieved at least an ACR Pedi 30 response.

During Period B, the time to disease flare for the patients randomised to placebo was significantlyshorter than for those randomised to abatacept (primary endpoint, p = 0.0002; log-rank test).

Significantly more placebo recipients flared during Period B (33/62; 53%) than those maintained onabatacept (12/60; 20%; chi-square p < 0.001). The risk of disease flare for patients continuing onabatacept was less than one third that for placebo-treated patients (hazard ratio estimate = 0.31;95% CI 0.16, 0.59).

Most randomised 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 5 years exposure in Period Care summarised in Table 9:

Table 9: Proportion (%) of polyarticular JIA patients with ACR responses or inactivedisease

End of End of Period Ba Period Cb

Period A (day 169) (day 1765)(day 113)

Abatacept Abatacept Placebo Abatacept group Placebo group Non-responder inin Period B in Period B Period An = 190 n = 58 n = 59 n = 33 n = 30 n = 13

ACR30 65 85 68 97 87 69

ACR50 50 79 53 94 80 69

ACR70 28 55 31 79 63 54

ACR90 13 41 15 67 40 39

Inactive Not 31 10 52 33 31disease assesseda day 169 Last Observation Carried Forward (LOCF) for patients treated in Period Cb As observed

Participants in Period C at day 1765 included 33 of the 58 Period B abatacept recipients, 30 of the 59

Period B placebo recipients, and 13 of the 36 Period A non-responders. The median duration ofabatacept treatment in Period C was 1815 days (range 57-2,415 days; nearly 61 months). One hundredand two (67%) of the subjects had received at least 1,080 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.

Abatacept in pJIA patients has also been studied with the subcutaneous formulation in children andadolescents with moderate to severe active pJIA, ages 2 to 17 years with an inadequate response orintolerance to at least one DMARD, which may have included biologic agents. The safety and efficacyof abatacept in the ongoing SC study were consistent with the results seen with abatacept in the IVstudy (see section 5.1 of the ORENCIA solution for injection in pre-filled syringe SmPC for completestudy description and results).

Adult rheumatoid arthritis

After multiple intravenous infusions (days 1, 15, 30, and every 4 weeks thereafter), thepharmacokinetics of abatacept in rheumatoid arthritis patients showed dose-proportional increases of

Cmax and AUC over the dose range of 2 mg/kg to 10 mg/kg. At 10 mg/kg, the mean terminal half-lifewas 13.1 days, ranging from 8 to 25 days. The mean distribution volume (Vss) was 0.07 L/kg andranged from 0.02 to 0.13 L/kg. The systemic clearance was approximately 0.22 mL/h/kg. Meansteady-state trough concentrations were approximately 25 mcg/mL, and mean Cmax concentrationswere approximately 290 mcg/mL. No systemic accumulation of abatacept occurred upon continuedrepeated treatment with 10 mg/kg at monthly intervals in rheumatoid arthritis patients.

Population pharmacokinetic analyses revealed that there was a trend toward higher clearance ofabatacept with increasing body weight. Age and gender (when corrected for body weight) did notaffect clearance. Methotrexate, NSAIDs, corticosteroids, and TNF-inhibitors were not found toinfluence abatacept clearance. No studies were conducted to examine the effects of either renal orhepatic impairment on the pharmacokinetics of abatacept.

In PsA-I, patients were randomised to receive intravenous placebo or abatacept 3 mg/kg (3/3 mg/kg),10 mg/kg (10/10 mg/kg), or two doses of 30 mg/kg followed by 10 mg/kg (30/10 mg/kg), on day 1,15, 29, and then every 28 days thereafter. In this study, the steady-state concentrations of abataceptwere dose-related. The geometric mean (CV%) cmin at day 169 were 7.8 mcg/mL (56.3%) for the3/3 mg/kg, 24.3 mcg/mL (40.8%) for 10/10 mg/kg, and 26.6 mcg/mL (39.0%) for the 30/10 mg/kgregimens.

In study PsA-II following weekly subcutaneous administration of abatacept at 125 mg, steady-state ofabatacept was reached at day 57 with the geometric mean (CV%) cmin ranging from 22.3 (54.2%) to25.6 (47.7%) mcg/mL on days 57 to 169, respectively.

Consistent with the results observed earlier in RA patients, population pharmacokinetic analyses forabatacept in PsA patients revealed that there was a trend toward higher clearance (L/h) of abataceptwith increasing body weight.

Population pharmacokinetic analysis of abatacept serum concentration data from patients with pJIA 6to 17 years of age following administration of intravenous abatacept 10 mg/kg revealed that theestimated clearance of abatacept, when normalised for baseline body weight, was higher in pJIApatients (0.4 mL/h/kg for a child weighing 40 kg) versus adult rheumatoid arthritis patients. Typicalestimates 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 ofdistribution in pJIA patients, the predicted and observed systemic exposures of abatacept were lowerthan that observed in adults, such that the observed mean (range) peak and trough concentrations were204 (66 to 595) mcg/mL and 10.6 (0.15 to 44.2) mcg/mL, respectively, in patients weighing less than40 kg, and 229 (58 to 700) mcg/mL and 13.1 (0.34 to 44.6) mcg/mL, respectively, in patientsweighing 40 kg or greater.

No mutagenicity or clastogenicity was observed with abatacept in a battery of in vitro studies. In amouse carcinogenicity study, increases in the incidence of malignant lymphomas and mammary glandtumours (in females) occurred. The increased incidence of lymphomas and mammary tumoursobserved in mice treated with abatacept may have been associated with decreased control of murineleukaemia virus and mouse mammary tumour virus, respectively, in the presence of long-termimmunomodulation. In a one-year toxicity study in cynomolgus monkeys, abatacept was notassociated with any significant toxicity. Reversible pharmacological effects consisted of minimaltransient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centres in thespleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphological changes wasobserved, despite the presence of a virus, lymphocryptovirus, which is known to cause such lesions inimmunosuppressed monkeys within the time frame of this study. The relevance of these findings to theclinical use of abatacept is unknown.

In rats, abatacept had no undesirable effects on male or female fertility. Embryo-foetal developmentstudies were conducted with abatacept in mice, rats, and rabbits at doses up to 20 to 30 times ahuman 10 mg/kg dose and no undesirable effects were observed in the offspring. In rats and rabbits,abatacept exposure was up to 29-fold a human 10 mg/kg exposure based on AUC. Abatacept wasshown to cross the placenta in rats and rabbits. In a pre- and postnatal development study withabatacept in rats, no undesirable effects were observed in pups of dams given abatacept at doses upto 45 mg/kg, representing 3-fold a human 10 mg/kg exposure based on AUC. At a dose of 200 mg/kg,representing 11-fold a human exposure at 10 mg/kg based on AUC, limited changes in immunefunction (a 9-fold increase in the mean T-cell-dependent antibody response in female pups andinflammation 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 lowincidence of infections leading to death (juvenile rats). In addition, inflammation of the thyroid andpancreas was frequently seen in both juvenile and adult rats exposed to abatacept. Juvenile rats seemedto be more sensitive to lymphocytic inflammation of thyroid. Studies in adult mice and monkeys havenot demonstrated similar findings. It is likely that the increased susceptibility to opportunisticinfections observed in juvenile rats is associated with the exposure to abatacept before development ofmemory responses. The relevance of these results to humans is unknown.

Maltose

Sodium dihydrogen phosphate monohydrate

Sodium chloride

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

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

Unopened vial3 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C. From amicrobiological point of view, the reconstituted solution should be diluted immediately.

When the reconstituted solution is diluted immediately, the chemical and physical in-use stability ofthe diluted infusion solution has been demonstrated for 24 hours at 2°C - 8°C. From a microbiologicalpoint of view, the product should be used immediately.

Store in a refrigerator (2°C - 8°C).

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

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

Vial (15 mL Type 1 glass) with a stopper (halobutyl-rubber) and flip off seal (aluminium).

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

Not all pack-sizes may be marketed.

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

Reconstitution1. 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 thesilicone-free disposable syringe provided with each vial (see section 6.2) and an 18-21 gaugeneedle.

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

- Insert the syringe needle into the vial through the centre of the rubber stopper and directthe 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 injectedinto the vial.

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

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

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

Dilution3. Immediately after reconstitution, the concentrate must be further diluted to 100 mL with sodiumchloride 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 orbottle using the same silicone-free disposable syringe provided with each vial.

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

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

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

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

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

EU/1/07/389/001-003

Date of first authorisation: 21 May 2007

Date of latest renewal: 15 March 2012

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.