Orencia - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

ORENCIA 250 mg powder for concentrate for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 250 mg of abatacept.

Each mL contains 25 mg of abatacept, after reconstitution.

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

Excipient with known effect

sodium: 0.375 mmol (8.625 mg) per vial

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for concentrate for solution for infusion.

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

4. CLINICAL PARTICULARS4.1 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.

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

Psoriatic arthritis

ORENCIA, alone or in combination with methotrexate (MTX), is indicated for the treatment of active psoriatic 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 not required.

Polyarticular juvenile idiopathic arthritis

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

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

4.2 Posology and method of administration

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

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

Posology

Rheumatoid arthritis

Adults

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

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

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

Psoriatic arthritis

Adults

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

Paediatric population

Polyarticular juvenile idiopathic arthritis

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

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

ORENCIA solution for injection in pre-filled syringe for subcutaneous administration is available for paediatric 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).

Special populations

Elderly patients

No dose adjustment is required (see section 4.4).

Renal and hepatic impairment

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

Method of administration

For intravenous use.

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 |im). For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

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).

4.4 Special warnings and precautions for use

Combination with TNF-inhibitors

There is limited experience with use of abatacept in combination with TNF-inhibitors (see section 5.1). In placebo-controlled clinical trials, in comparison with patients treated with TNF-inhibitors and placebo, patients who received combination TNF-inhibitors with abatacept experienced an increase in overall infections and serious infections (see section 4.5). Abatacept is not recommended for use in combination with TNF-inhibitors.

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

Allergic reactions

Allergic reactions have been reported uncommonly with abatacept administration in clinical trials, where patients were not required to be pretreated to prevent allergic reactions (see section 4.8). Anaphylaxis or anaphylactoid reactions can occur after the first infusion and can be life-threatening. In postmarketing experience, a case of fatal anaphylaxis following the first infusion of ORENCIA has been reported. If any serious allergic or anaphylactic reaction occurs, intravenous or subcutaneous ORENCIA therapy should be discontinued immediately and appropriate therapy initiated, and the use of ORENCIA should be permanently discontinued.

Effects on the immune system

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

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

Infections

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

No increase of tuberculosis was observed in the pivotal placebo-controlled studies; however, all ORENCIA patients were screened for tuberculosis. The safety of ORENCIA in individuals with latent tuberculosis is unknown. There have been reports of tuberculosis in patients receiving ORENCIA (see section 4.8). Patients should be screened for latent tuberculosis prior to initiating ORENCIA. The available medical guidelines should also be taken into account.

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

Treatment with immunosuppressive therapy, such as ORENCIA, may be associated with progressive multifocal leukoencephalopathy (PML). If neurological symptoms suggestive of PML occur during ORENCIA therapy, treatment with ORENCIA should be discontinued and appropriate diagnostic measures initiated.

Malignancies

In the placebo-controlled clinical trials, the frequencies of malignancies in abatacept- and placebo-treated patients were 1.2% and 0.9%, respectively (see section 4.8). Patients with known malignancies were not included in these clinical trials. In carcinogenicity studies in mice, an increase in lymphomas and mammary tumours were noted. The clinical significance of this observation is unknown (see section 5.3). The potential role of abatacept in the development of malignancies, including lymphoma, in humans is unknown. 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, particularly those with risk factors for skin cancer.

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.

It is recommended that patients with juvenile idiopathic arthritis be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ORENCIA therapy (see section 4.5).

Elderly patients

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

Autoimmune processes

There is a theoretical concern that treatment with abatacept might increase the risk for autoimmune processes in adults and children, for example deterioration of multiple sclerosis. In the placebo-controlled clinical trials, abatacept treatment did not lead to increased autoantibody formation, such as antinuclear and anti-dsDNA antibodies, relative to placebo treatment (see sections 4.8 and 5.3).

Blood glucose testing

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

Patients on controlled sodium diet

This medicinal product contains 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 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.

4.5 Interaction with other medicinal products and other forms of interaction

Combination with TNF-inhibitors

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

Combination with other medicinal products

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

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

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

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

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 abatacept. Medicinal products that affect the immune system, including abatacept, may blunt the effectiveness of some immunisations (see sections 4.4 and 4.6).

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 23valent 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.

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 during pregnancy unless the clinical condition of the woman requires treatment with abatacept. Women of childbearing potential have to use effective contraception during treatment 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 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.

Breast-feeding

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 after the last dose of abatacept treatment.

Fertility

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).

4.7 Effects on ability to drive and use machines

Based on its mechanism of action, abatacept is expected to have no or negligible influence on the ability to drive and use machines. However, dizziness and reduced visual acuity have been reported as common 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.

4.8 Undesirable effects

Summary of the safety profile in rheumatoid arthritis

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

In placebo-controlled clinical trials with abatacept, adverse reactions (ARs) were reported in 49.4% of abatacept-treated patients and 45.8% of placebo-treated patients. The most frequently reported adverse reactions (> 5%) among abatacept-treated patients were headache, nausea, and upper respiratory tract infections (including sinusitis). The proportion of patients who discontinued treatment due to ARs was 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 clinical trials (341 patients with abatacept, 253 patients with placebo) (see section 5.1). During the 24-week placebo-controlled period in the larger study PsA-II, the proportion of patients with adverse reactions was similar in the abatacept and placebo treatment groups (15.5% and 11.4%, respectively). There were no adverse reactions that occurred at > 2% in either treatment group during the 24-week placebo-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).

Tabulated list of adverse reactions

Listed in Table 2 are adverse reactions observed in clinical trials and post-marketing experience presented by system organ class and frequency, using the following categories: very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 2:                    Ad­verse reactions

Infections and infestations	Very Common Common Uncommon Rare	Upper respiratory tract infection (including tracheitis, nasopharyngitis, and sinusitis) Lower respiratory tract infection (including bronchitis), urinary tract infection, herpes infections (including herpes simplex, oral herpes, and herpes zoster), pneumonia, influenza Tooth infection, onychomycosis, sepsis, muskuloskeletal infections, skin abscess, pyelonephritis, rhinitis, ear infection Tuberculosis, bacteraemia, gastrointestinal infection, pelvic inflammatory disease
Neoplasms benign, malignant	Uncommon	Basal cell carcinoma, skin papilloma
and unspecified (incl. cysts and polyps)	Rare	Lymphoma, lung neoplasm malignant, squamous cell carcinoma
Blood and lymphatic system disorders	Uncommon	Thrombocytopenia, leukopenia
Immune system disorders	Uncommon	Hypersensitivity
Psychiatric disorders	Uncommon	Depression, anxiety, sleep disorder (including insomnia)
Nervous system disorders	Common Uncommon	Headache, dizziness 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 Uncommon	Hypertension, blood pressure increased Hypotension, hot flush, flushing, vasculitis, blood pressure decreased
Respiratory, thoracic and mediastinal disorders	Common Uncommon	Cough Chronic obstructive pulmonary disease exacerbated, bronchospasm, wheezing, dyspnea, throat tightness
Gastrointestinal disorders	Common Uncommon	Abdominal pain, diarrhoea, nausea, dyspepsia, mouth ulceration, aphthous stomatitis, vomiting Gastritis
Hepatobiliary disorders	Common	Liver function test abnormal (including transaminases increased)
Skin and subcutaneous tissue disorders	Common Uncommon	Rash (including dermatitis) Increased tendency to bruise, dry skin, alopecia, pruritus, urticaria, psoriasis, acne, erythema, hyperhidrosis
Musculoskeletal and connective tissue disorders	Uncommon	Arthralgia, pain in extremity
Reproductive system and breast disorders	Uncommon	Amenorrhea, menorrhagia
General disorders and administration site conditions	Common Uncommon	Fatigue, asthenia Influenza like illness, weight increased

Description of selected adverse reactions

Infections

In the placebo-controlled clinical trials with abatacept, infections at least possibly related to treatment were 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-treated patients and 1.1% of placebo-treated patients. The type of serious infections was similar between the abatacept 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 for abatacept-treated patients and 2.3 (1.5, 3.3) per 100 patient-years for placebo-treated patients in the double-blind studies.

In the cumulative period in clinical trials in 7,044 patients treated with abatacept during 20,510 patient-years, the incidence rate of serious infections was 2.4 per 100 patient-years, and the annualised incidence rate remained stable.

Malignancies

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 rates for 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 which over 1,000 were treated with abatacept for over 5 years), the incidence rate of malignancy was 1.2 (1.1, 1.4) per 100 patient-years, and the annualized incidence rates remained stable.

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

The most frequently reported organ cancer in the placebo-controlled clinical trials was lung cancer 0.17 (0.05, 0.43) per 100 patient-years for abatacept-treated patients, 0 for placebo-treated patients and 0.12 (0.08, 0.17) per 100 patient-years in the cumulative period. The most common hematologic malignancy was lymphoma 0.04 (0, 0.24) per 100 patient-years for abatacept-treated patients, 0 for placebo-treated patients and 0.06 (0.03, 0.1) per 100 patient-years in the cumulative period.

Infusion-related reactions

Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in seven pooled intravenous studies (for studies II, III, IV and V see section 5.1) were more common in the 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 abatacept included cardiopulmonary symptoms such as hypotension, decreased blood pressure, tachycardia, bronchospasm, and dyspnea; other symptoms included myalgia, nausea, erythema, flushing, urticaria, hypersensitivity, pruritus, throat tightness, chest discomfort, chills, infusion site extravasation, infusion site pain, infusion site swelling, infusion related reaction, and rash. Most of these reactions were mild to moderate.

The occurrence of anaphylaxis remained rare during the double blind and the cumulative period. Hypersensitivity was reported uncommonly. Other reactions potentially associated with hypersensitivity to the medicinal product, such as hypotension, urticaria, and dyspnea, that occurred within 24 hours of ORENCIA infusion, were uncommon.

Discontinuation due to an acute infusion-related reaction occurred in 0.3% of patients receiving abatacept and in 0.1% 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 with placebo. The COPD patients treated with abatacept developed adverse reactions more frequently than those treated with placebo (51.4% vs. 47.1%, respectively). Respiratory disorders occurred more frequently in abatacept-treated patients than in placebo-treated patients (10.8% vs. 5.9%, respectively); these included COPD exacerbation, and dyspnea. A greater percentage of abatacept- than placebo-treated patients with COPD developed a serious adverse reaction (5.4% vs. 0%), including COPD exacerbation (1 of 37 patients [2.7%]) and bronchitis (1 of 37 patients [2.7%]).

Autoimmune processes

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

The incidence rate of autoimmune disorders in abatacept-treated patients during the double-blind period was 8.8 (7.6, 10.1) per 100 person-years of exposure and for placebo-treated patients was 9.6 (7.9, 11.5) per 100 person-years of exposure. The incidence rate in abatacept-treated patients was 3.8 per 100 person-years in the cumulative period. The most frequently reported autoimmune-related disorders other than the indication being studied during the cumulative period were psoriasis, rheumatoid nodule, and Sjogren's syndrome.

Immunogenicity

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

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

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

Safety information related to the pharmacological class

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

Paediatric population

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

Description of selected adverse reactions

Infections

Infections were the most commonly reported adverse events in patients with pJIA. The types of infections were consistent with those commonly seen in outpatient paediatric populations. During the first 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 tract infection (2.9% patients). Two serious infections (varicella and sepsis) were reported during the initial 4 months of treatment with abatacept.

Infusion-related reactions

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

Immunogenicity

Antibodies directed against the entire abatacept molecule or to the CTLA-4 portion of abatacept were assessed by ELISA assays in patients with 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. For patients in Period B who were randomised to placebo (therefore withdrawn from therapy for up to 6 months) the rate of seropositivity was 40.7% (22/54). Anti-abatacept antibodies were generally transient and of low titer. The absence of concomitant methotrexate (MTX) did not appear to be associated with a higher rate of seropositivity in Period B placebo recipients. The presence of antibodies was not associated with adverse reactions or infusion reactions, or with changes in efficacy or serum abatacept concentrations. Of the 54 patients withdrawn from ORENCIA during the doubleblind 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 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 cohort 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.9 Overdose

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

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

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 human immunoglobulin G1 (IgG1). Abatacept is produced by recombinant DNA technology in Chinese hamster ovary cells.

Mechanism of action

Abatacept selectively modulates a key costimulatory signal required for full activation of T lymphocytes expressing CD28. Full activation of T lymphocytes requires two signals provided by antigen presenting cells: recognition of a specific antigen by a T cell receptor (signal 1) and a second, costimulatory signal. A major costimulatory pathway involves the binding of CD80 and

CD86 molecules on the surface of antigen presenting cells to the CD28 receptor on T lymphocytes (signal 2). Abatacept selectively inhibits this costimulatory pathway by specifically binding to CD80 and CD86. Studies indicate that naive T lymphocyte responses are more affected by abatacept than memory T lymphocyte responses.

Studies in vitro and in animal models demonstrate that abatacept modulates T lymphocyte-dependent antibody responses and inflammation. In vitro , abatacept attenuates human T lymphocyte activation as measured by decreased proliferation and cytokine production. Abatacept decreases antigen specific TNFa, interferon-Y, and interleukin-2 production by T lymphocytes.

Pharmacodynamic effects

Dose-dependent reductions were observed with abatacept in serum levels of soluble interleukin-2 receptor, a marker of T lymphocyte activation; serum interleukin-6, a product of activated synovial macrophages and fibroblast-like synoviocytes in rheumatoid arthritis; rheumatoid factor, an autoantibody produced by plasma cells; and C-reactive protein, an acute phase reactant of inflammation. In addition, serum levels of matrix metalloproteinase-3, which produces cartilage destruction and tissue remodelling, were decreased. Reductions in serum TNFa 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 to have at least 12 tender and 10 swollen joints at randomisation. Study IV did not require any specific number of tender or swollen joints.

In studies I, II, and V the efficacy and safety of abatacept compared to placebo were assessed in patients with an inadequate response to methotrexate and who continued on their stable dose of methotrexate. In addition, study V investigated the safety and efficacy of abatacept or infliximab relative to placebo. In study III the efficacy and safety of abatacept were assessed in patients with an inadequate response to a TNF-inhibitor, with the TNF-inhibitor discontinued prior to randomisation; 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 randomised 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 subcutaneous 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).

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 of abatacept or placebo for 12 (studies II, IV, and VI) or 6 months (study III). The dose of abatacept was 500 mg for patients weighing less than 60 kg, 750 mg for patients weighing 60 to 100 kg, and 1,000 mg for patients weighing greater than 100 kg. Study V patients were randomised to receive this same fixed dose of abatacept or 3 mg/kg infliximab or placebo for 6 months. Study V continued for an additional 6 months with the abatacept and infliximab groups only.

Studies I, II, III, IV, V, VI, SC-II, and SC-III evaluated 339, 638, 389, 1441, 431, 509, 646, and 351 adult patients, respectively.

Clinical response

ACR response

The percent of abatacept-treated patients achieving ACR 20, 50, and 70 responses in study II (patients with inadequate response to methotrexate), study III (patients with inadequate response to TNF-inhibitor), and study VI (methotrexate-naive patients) are shown in Table 3.

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

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%tt	53%	62%	37%	46%	18%
Month 6	75%t	62%	68%	40%	50%	20%
Month 12	76%i	62%	73%	40%	NAd	NAd
ACR 50
Month 3	40%i	23%	32%	8%	18%	6%
Month 6	53%i	38%	40%	17%	20%	4%
Month 12	57%i	42%	48%	18%	NAd	NAd
ACR 70
Month 3	19%/'	10%	13%	3%	6%ft	1%
Month 6	32%t	20%	20%	7%	10%	2%
Month 12	43%i	27%	29%	6%	NAd	NAd
Major Clinical Response6	27%i	12%	14%	2%	NAd	NAd
DAS28-CRP Remission6
Month 6	28%i	15%	NA	NA	NA	NA
Month 12	41%i	23%	NA	NA	NA	NA

* p < 0.05, abatacept vs. placebo.

p < 0.01, abatacept vs. placebo.

p < 0.001, abatacept vs. placebo.

t p < 0.01, abatacept plus MTX vs. MTX plus placebo

t p < 0.001, abatacept plus MTX vs. MTX plus placebo

tt p < 0.05, abatacept plus MTX vs. MTX plus placebo

a Fixed dose approximating 10 mg/kg (see section 4.2).

b Concurrent DMARDs included one or more of the following: methotrexate, chloroquine/hy­droxychloroqu­ine, sulfasalazine, leflunomide, azathioprine, gold, and anakinra.

c Major clinical response is defined as achieving an ACR 70 response for a continuous 6-month period.

d After 6 months, patients were given the opportunity to enter an open-label study.

e DAS28-CRP Remission is defined as a DAS28-CRP score < 2.6

In the open-label extension of studies I, II, III, and VI durable and sustained ACR 20, 50, and 70 responses have been observed through 7 years, 5 years, 5 years, and 2 years, respectively, of abatacept treatment. In study I, ACR responses were assessed at 7 years in 43 patients with 72% ACR 20 responses, 58% ACR 50 responses, and 44% ACR 70 responses. In study II, ACR responses were assessed at 5 years in 270 patients with 84% ACR 20 responses, 61% ACR 50 responses, and 40% ACR 70 responses. In study III, ACR responses were assessed at 5 years in 91 patients with 74% ACR 20 responses, 51% ACR 50 responses, and 23% ACR 70 responses. In study VI, ACR responses were assessed at 2 years in 232 patients with 85% ACR 20 responses, 74% ACR 50 responses, and 54% ACR 70 responses.

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

DAS28 response

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

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

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

Study V: abatacept or infliximab versus placebo

A randomised, double-blind study was conducted to assess the safety and efficacy of abatacept or infliximab versus placebo in patients with an inadequate response to methotrexate (study V). The primary outcome was the mean change in disease activity in abatacept-treated patients compared to placebo-treated patients at 6 months with a subsequent double-blind assessment of safety and efficacy of abatacept and infliximab at 12 months. Greater improvement (p < 0.001) in DAS28 was observed with abatacept and with infliximab compared to placebo at six months in the placebo-controlled portion of the trial; the results between the abatacept and infliximab groups were similar. The ACR responses in study V were consistent with the DAS28 score. Further improvement was observed at 12 months with abatacept. At 6 months, the incidence of AE of infections were 48.1% (75), 52.1% (86), and 51.8% (57) and the incidence of serious AE of infections were 1.3% (2), 4.2% (7), and 2.7% (3) for abatacept, infliximab and placebo groups, respectively. At 12 months, the incidence of AE of infections were 59.6% (93), 68.5% (113), and the incidence of serious AE of infections were 1.9% (3) and 8.5% (14) for abatacept and infliximab groups, respectively. The open label period of the study provided an assessment of the ability of abatacept to maintain efficacy for subjects originally randomised 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 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 safety and efficacy of weekly subcutaneous (SC) abatacept without an abatacept intravenous (IV) loading dose versus every-other-weekly subcutaneous adalimumab, both with background MTX, in patients with an inadequate response to methotrexate (study SC-II). The primary endpoint showed noninferiority (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 responses throughout the 24-month period. The respective values for ACR 20 at 24 months were 59.7% (190/318) for the abatacept SC group and 60.1% (197/328) for the adalimumab SC group. The respective values for ACR 50 and ACR 70 at 12 months and 24 months were consistent and similar for abatacept 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 changes over time. At 24 months, 50.6% (127/251) [95% CI: 44.4, 56.8] of patients in abatacept and 53.3% (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 similar between abatacept SC and adalimumab SC.

Safety and structural damage assessments were conducted at one and two years. The overall safety profile with respect to adverse reactions was similar between the two groups over the 24-month period. After 24 months, adverse reactions were reported in 41.5% (132/318) and 50% (164/328) of abatacept 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 and 25.3 % (83/328) on adalimumab had discontinued.

In SC-II, serious infections were reported in 3.8 % (12/318) of patients treated with abatacept SC weekly, none of which led to discontinuation and in 5.8 % (19/328) of patients treated with adalimumab 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 with abatacept SC and adalimumab SC respectively reported autoimmune disorders mild to moderate in severity (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) 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).

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

study SC-III

Number of patients	Abatacept SC+ MTX n = 119	MTX n = 116	Abatacept SC 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) vs. MTX	17.02 (4.30, 29.73)	N/A	4.31 (-7.98, 16.61)
Boolean Clinical Remission	37.0%	22.4%	26.7%
Estimate of Difference (95% CI) vs. MTX	14.56 (2.19, 26.94)	N/A	4.31 (-7.62, 16.24)
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/A

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.

Radiographic response

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

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

In study II, the baseline median TSS was 31.7 in abatacept-treated patients and 33.4 in placebo-treated patients. Abatacept/met­hotrexate reduced the rate of progression of structural damage compared to placebo/metho­trexate after 12 months of treatment as shown in Table 5. The rate of progression of structural damage in year 2 was significantly lower than that in year 1 for patients randomised to abatacept (p < 0.0001). Subjects entering the long term extension after 1 year of double blind treatment all received abatacept treatment and radiographic progression was investigated through year 5. Data were analysed 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 from year 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 randomised to abatacept plus MTX and placebo plus MTX respectively.

Table 5:	Mean radiographic changes over 12 months in study II
Parameter	Abatacept/MTX n = 391	Placebo/MTX 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	0.009
a Based on non-parametric analysis.

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

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).

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 from studies II, III, and VI are shown in Table 7.

Table 7:         Improvement in physical function in controlled trials

	Methotrexate-N aive		Inadequate response to Methotrexate		Inadequate response to TNF Inhibitor
	Study VI		Study II		Study III
HAQc Disability Index	Abatacepta +MTX	Placebo +MTX	Abatacepta +MTX	Placebo +MTX	Abatacepta +DMARDsb	Placebo +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 Improvement from Baseline
Month 6	0.85	0.68	0.59	0.40	0.45	0.11
	(n=250)	(n=249)	(n=420)	(n=211)	(n=249)	(n=130)
Month 12	0.96	0.76	0.66	0.37	NAe	NAe
	(n=254)	(n=251)	(n=422)	(n=212)
Proportion of patients with a clinically meaningful d improvementd
Month 6	72%/'	63%	61%	45%	47%	23%
Month 12	72%/'	62%	64%	39%	NAe	NAe

*** p < 0.001, abatacept vs. placebo.

t p < 0.05, abatacept plus MTX vs MTX plus placebo

a Fixed dose approximating 10 mg/kg (see section 4.2).

b Concurrent DMARDs included one or more of the following: methotrexate, chloroquine/hy­droxychloroqu­ine, sulfasalazine, leflunomide, azathioprine, gold, and anakinra.

c Health Assessment Questionnaire; 0 = best, 3 = worst; 20 questions; 8 categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities.

d Reduction in HAQ-DI of > 0.3 units from baseline.

e After 6 months, patients were given the opportunity to enter into an open-label study.

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

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]).

Health-related outcomes and quality of life

Health-related quality of life was assessed by the SF-36 questionnaire at 6 months in studies I, II, and III and at 12 months in studies I and II. In these studies, clinically and statistically significant improvement was observed in the abatacept group as compared with the placebo group in all 8 domains of the SF-36 (4 physical domains: physical function, role physical, bodily pain, general health; and 4 mental domains: vitality, social function, role emotional, mental health), as well as the Physical Component Summary (PCS) and the Mental Component Summary (MCS). In study VI, improvement was observed at 12 months in abatacept plus methotrexate group as compared with the methotrexate plus placebo group in both PCS and MCS, and was maintained through 2 years.

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

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

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. Patients had active PsA (> 3 swollen joints and > 3 tender joints) despite prior treatment with DMARD therapy and 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 then every 28 days thereafter in a double blind manner for 24 weeks, followed by open-label abatacept 10 mg/kg intravenously every 28 days. Patients were randomised to receive placebo or abatacept 3 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 allowed to receive stable doses of concomitant methotrexate, low dose corticosteroids (equivalent to < 10 mg of 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 doses of subcutaneous placebo or abatacept 125 mg without a loading dose for 24 weeks, followed by openlabel abatacept 125 mg subcutaneous weekly. Patients were allowed to receive stable doses of concomitant methotrexate, sulfasalazine, leflunomide, hydroxychloroquine, low dose corticosteroids (equivalent to < 10 mg of prednisone) and/or NSAIDs during the trial. Patients who had not achieved at least a 20% improvement from baseline in their swollen and tender joint counts by week 16 escaped to open-label abatacept 125 mg subcutaneous weekly.

The primary endpoint for both PsA-I and PsA-II was the proportion of patients achieving ACR 20 response 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 in studies PsA-I (10 mg/kg intravenous ) and PsA-II (125 mg subcutaneous ) are presented in Table 8 below.

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

and PsA-II

	PsA-Ia			PsA-n b,c
	Abatacept 10 mg/kg IV N=40	Placebo N=42	Estimate of difference (95% CI)	Abatacept 125 mg SC N=213	Placebo N=211	Estimate of difference (95% CI)
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.

a37% of patients were previously treated with TNF inhibitor.

b61% of patients were previously treated with TNF inhibitor.

cPatients who had less than 20% improvement in tender or swollen joint counts at Week 16 met escape criteria and were considered non-responders.

A significantly higher proportion of patients achieved an ACR 20 response after treatment with abatacept 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 vs placebo 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 TNF inhibitor-naive were 55.6% vs 20.0%, respectively, and in patients who were TNF inhibitor-experienced were 30.8% vs 16.7%, respectively. In study PsA-II, the ACR 20 responses with abatacept 125 mg subcutaneous vs placebo in patients who were TNF inhibitor-naive were 44.0% vs 22.2%, respectively (21.9 [8.3, 35.6], estimate of difference [95% CI]), and in patients who were TNF inhibitor-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. placebo irrespective of concomitant nonbiological DMARD treatment. The ACR 20 responses with abatacept 125 mg subcutaneous vs placebo in patients who did not use nonbiological DMARDs were 27.3% vs 12.1%, respectively, (15.15 [1.83, 28.47], estimate of difference [95% CI]), and in patients who had used non-biological DMARDs were 44.9% vs 26.9%, respectively, (18.00 [7.20, 28.81], estimate of difference [95% CI]). Clinical responses were maintained or continued to improve up to one year in studies 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 was 45.0% 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 from baseline in HAQ-DI was 31.0% with abatacept vs. 23.7% with placebo (7.2 [-1.1, 15.6], estimate of difference [95% CI]). Improvement in HAQ-DI scores was maintained or improved for up to 1 year with 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-week doubleblind 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 of difference [95% CI]), and the proportion of patients who achieved PASI 75 response was 14.3% with abatacept 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% with placebo (7.3 [-2.2, 16.7], estimate of difference [95% CI]), and the proportion of patients who achieved 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 inadequate response or intolerance to at least one DMARD, which may have included biologic agents, were enrolled. 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. Patients achieving at least a ACR Pedi 30 response at the end of Period A were randomised into a double-blind, withdrawal phase (Period B), and received either abatacept or placebo for 6 months or until pJIA disease flare as defined in the study. Unless they had discontinued due to safety reasons, all patients who completed, or had a flare during Period B or were non-responders in Period A were offered entry into Period C, the open-label extension, which assessed long-term safety and efficacy.

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

ACR Pedi 30 responders at the end of Period A were 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 with limited range of motion was used to define flare

The patients entered in the trial were a mean of 12.4 years of age with mean disease duration of 4.4 years. They had active disease, with baseline mean active joint count of 16 and a mean number of joints with loss of motion of 16; and elevated C-reactive protein (CRP) levels (mean, 3.2 mg/dl) and ESRs (mean, 32 mm/h). Their 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 30 response, and 122 were randomised to Period B. Responses were similar in all subtypes of pJIA studied and for patients with or without methotrexate use. Of the 133 (70%) patients with no prior TNF-inhibitor therapy, 101 (76%) achieved at least an ACR Pedi 30 response; of the 57 patients who had received prior TNF-inhibitor therapy, 22 (39%) achieved at least an ACR Pedi 30 response.

During Period B, the time to disease flare for the patients randomised to placebo was significantly shorter 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 on abatacept (12/60; 20%; chi-square p<0.001). The risk of disease flare for patients continuing on abatacept was less than one third that for placebo-treated patients (hazard ratio estimate=0.31; 95% CI 0.16, 0.59).

Most 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 C are summarized in Table 9:

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

inactive disease

	End of Period A (day 113)	End of Period Ba (day 169)		Period Cb (day 1765)
	Abatacept	Abatacept	Placebo	Abatacept group in Period B	Placebo group in Period B	Non-responder in Period A
	n= 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 disease	Not assessed	31	10	52	33	31

a day 169 Last Observation Carried Forward (LOCF) for patients treated in Period C b 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 of abatacept treatment in Period C was 1815 days (range 57–2,415 days; nearly 61 months). One hundred and 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 and adolescents with moderate to severe active pJIA, ages 2 to 17 years with an inadequate response or intolerance to at least one DMARD, which may have included biologic agents. The safety and efficacy of abatacept in the ongoing SC study were consistent with the results seen with abatacept in the IV study (see section 5.1 of the ORENCIA solution for injection in pre-filled syringe SmPC for complete study description and results).

5.2 Pharmacokinetic properties

Adult rheumatoid arthritis

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

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

Adult psoriatic arthritis

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 abatacept were dose-related. The geometric mean (CV%) cmin at day 169 were 7.8 mcg/mL (56.3%) for the 3/3 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/kg regimens.

In study PsA-II following weekly subcutaneous administration of abatacept at 125 mg, steady-state of abatacept was reached at day 57 with the geometric mean (CV%) cmin ranging from 22.3 (54.2%) to 25.6 (47.7%) mcg/mL on days 57 to 169, respectively.

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

Paediatric population

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

5.3 Preclinical safety data

No mutagenicity or clastogenicity was observed with abatacept in a battery of in vitro studies. In a mouse carcinogenicity study, increases in the incidence of malignant lymphomas and mammary gland tumours (in females) occurred. The increased incidence of lymphomas and mammary tumours observed in mice treated with abatacept may have been associated with decreased control of murine leukaemia virus and mouse mammary tumour virus, respectively, in the presence of long-term immunomodulation. In a one-year toxicity study in cynomolgus monkeys, abatacept was not associated with any significant toxicity. Reversible pharmacological effects consisted of minimal transient decreases in serum IgG and minimal to severe lymphoid depletion of germinal centres in the spleen and/or lymph nodes. No evidence of lymphomas or preneoplastic morphological changes was observed, despite the presence of a virus, lymphocryptovirus, which is known to cause such lesions in immunosuppressed monkeys within the time frame of this study. The relevance of these findings to the clinical use of abatacept is unknown.

In rats, abatacept had no undesirable effects on male or female fertility. Embryo-foetal development studies were conducted with abatacept in mice, rats, and rabbits at doses up to 20 to 30 times a human 10 mg/kg dose and no undesirable effects were observed in the offspring. In rats and rabbits, abatacept exposure was up to 29-fold a human 10 mg/kg exposure based on AUC. Abatacept was shown to cross the placenta in rats and rabbits. In a pre- and postnatal development study with abatacept in rats, no undesirable effects were observed in pups of dams given abatacept at doses up to 45 mg/kg, representing 3-fold a human 10 mg/kg exposure based on AUC. At a dose of 200 mg/kg, representing 11-fold a human exposure at 10 mg/kg based on AUC, limited changes in immune function (a 9-fold increase in the mean T-cell-dependent antibody response in female pups and inflammation of the thyroid of 1 female pup out of 10 male and 10 female pups evaluated at this dose) were observed.

Non-clinical studies relevant for use in the paediatric population

Studies in rats exposed to abatacept have shown immune system abnormalities including a low incidence of infections leading to death (juvenile rats). In addition, inflammation of the thyroid and pancreas was frequently seen in both juvenile and adult rats exposed to abatacept. Juvenile rats seemed to be more sensitive to lymphocytic inflammation of thyroid. Studies in adult mice and monkeys have not demonstrated similar findings. It is likely that the increased susceptibility to opportunistic infections observed in juvenile rats is associated with the exposure to abatacept before development of memory responses. The relevance of these results to humans is unknown.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Maltose

Sodium dihydrogen phosphate monohydrate

Sodium chloride

6.2 Incompatibilities

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

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

6.3 Shelf life

Unopened vial

3 years

After reconstitution

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

After dilution

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

6.4 Special precautions for storage

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.

6.5 Nature and contents of container

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.

6.6 Special precautions for disposal and other handling

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

Reconstitution

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

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

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

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

• – Do not use the vial if the vacuum is not present.

• – Remove the syringe and needle after 10 mL of water for injections have been injected into the vial.

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

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

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

Dilution

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

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

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

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

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

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

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

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

7. MARKETING AUTHORISATION HOLDER

Bristol-Myers Squibb Pharma EEIG

Plaza 254

Blanchardstown Corporate Park 2

Dublin 15, D15 T867

Ireland

8. MARKETING AUTHORISATION NUMBERS

EU/1/07/389/001–003

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 May 2007

Date of latest renewal: 21 May 2012