abatacept: prescribing information – dosing, contraindications, interactions, side effects

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.

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 2 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.

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.

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 ORENCIAa

Body Weight of Patient
Dose
Number of Vialsb
< 60 kg
500 mg
≥ 60 kg to ≤ 100 kg
750 mg
> 100 kg
1,000 mg 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 μm). For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.

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

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

Posology

Rheumatoid arthritis

Adults
ORENCIA subcutaneous (SC) may be initiated with or without an intravenous (IV) loading dose.
ORENCIA SC should be administered weekly at a dose of 125 mg abatacept by subcutaneous injection regardless of weight (see section 5.1). If a single IV infusion is given to initiate treatment (IV loading dose before SC administration), the first 125 mg abatacept SC should be administered within a day of the IV infusion, followed by the weekly 125 mg abatacept SC injections (for the posology of the intravenous loading dose, please refer to section 4.2 of ORENCIA 250 mg powder for concentrate for solution for infusion).

Patients switching from abatacept intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

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

Psoriatic arthritis

Adults
ORENCIA should be administered weekly at a dose of 125 mg by subcutaneous (SC) injection without the need for an intravenous (IV) loading dose.

Patients switching from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Paediatric population

Polyarticular juvenile idiopathic arthritis

The recommended weekly dose of ORENCIA solution for injection in pre-filled syringe for patients 2 to 17 years of age with polyarticular juvenile idiopathic arthritis should be initiated without an intravenous loading dose and administered utilizing the weight range-based dosing as specified in the table below:

Table 1:
Weekly dose of ORENCIA

Body weight of patient
Dose
10 kg to less than 25 kg
50 mg
25 kg to less than 50 kg
87.5 mg
50 kg or more
125 mg

Patients switching from abatacept intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

ORENCIA powder for concentrate for solution for infusion for intravenous administration is available for paediatric patients 6 years of age and older for the treatment of pJIA (see Summary of Product Characteristics for ORENCIA powder for concentrate for solution for infusion).

Missed dose
If a patient misses an injection of abatacept and is within three days of the planned date, he/she should be instructed to take the missed dose immediately and remain on the original weekly schedule. If the dose is missed by more than three days, the patient should be instructed when to take the next dose based on medical judgment (condition of the patient, status of disease activity, etc).

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.

Paediatric population
The safety and efficacy of ORENCIA in children below 2 years of age have not been established. No data are available.

There is no relevant use of ORENCIA in children under two years old.

Method of administration

For subcutaneous use.

ORENCIA is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous injection technique, a patient or caregiver may inject with ORENCIA if a physician/healthcare professional determines that it is appropriate.

The total content of the pre-filled syringe should be administered as a subcutaneous injection only.
Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard.

Comprehensive instructions for the preparation and administration of ORENCIA in a pre-filled syringe are given in the package leaflet and “Important instructions for use”.

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

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

Posology

Rheumatoid arthritis

Adults
ORENCIA subcutaneous (SC) may be initiated with or without an intravenous (IV) loading dose.
ORENCIA SC should be administered weekly at a dose of 125 mg by subcutaneous injection regardless of weight (see section 5.1). If a single IV infusion is given to initiate treatment (IV loading dose before SC administration), the first 125 mg abatacept SC should be administered within a day of the IV infusion, followed by the weekly 125 mg abatacept SC injections (for the posology of the intravenous loading dose, please refer to section 4.2 of ORENCIA 250 mg powder for concentrate for solution for infusion).

Patients switching from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

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

Psoriatic arthritis

Adults
ORENCIA should be administered weekly at a dose of 125 mg by subcutaneous (SC) injection without the need for an intravenous (IV) loading dose.
Patients switching from ORENCIA intravenous therapy to subcutaneous administration should administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Missed dose
If a patient misses an injection of ORENCIA and is within three days of the planned date, he/she should be instructed to take the missed dose immediately and remain on the original weekly schedule.
If the dose is missed by more than three days, the patient should be instructed when to take the next dose based on medical judgment (condition of the patient, status of disease activity, etc).

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.

Paediatric population
The safety and efficacy of ORENCIA solution for injection in pre-filled pen for subcutaneous administration in children below 18 years of age have not been established. No data are available.

ORENCIA powder for concentrate for solution for infusion is available for paediatric patients 6 years of age and older for the treatment of pJIA (see Summary of Product Characteristics for ORENCIA powder for concentrate for solution for infusion).

ORENCIA solution for injection 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 pre-filled syringe).

Method of administration

For subcutaneous use.

ORENCIA is intended for use under the guidance of a healthcare professional. After proper training in subcutaneous injection technique, a patient may self-inject with ORENCIA if a physician/healthcare professional determines that it is appropriate.

The total content (1 mL) of the pre-filled pen should be administered as a subcutaneous injection only.
Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red, or hard.

Comprehensive instructions for the preparation and administration of ORENCIA in a pre-filled pen are given in the package leaflet and "Important instructions for use". For instructions on preparation of the medicinal product before administration, 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).

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 Upper respiratory tract infection (including tracheitis, nasopharyngitis, and sinusitis)

Common
Lower respiratory tract infection (including bronchitis), urinary tract infection, herpes infections (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, gastrointestinal infection, pelvic inflammatory disease

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
Uncommon
Basal cell carcinoma, skin papilloma
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
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, blood pressure decreased

Respiratory, thoracic and mediastinal disorders
Common
Cough
Uncommon
Chronic obstructive pulmonary disease exacerbated, 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 (including transaminases increased)

Skin and subcutaneous tissue disorders
Common
Rash (including dermatitis)
Uncommon
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
Fatigue, asthenia
Uncommon
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 annualised 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.

Registry studies in Denmark and Sweden have reported a higher risk of non-melanoma skin cancer in rheumatoid arthritis patients treated with abatacept compared to other DMARDs. In Denmark, standardised incidence rates (IR) for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in abatacept-treated patients (n = 1,280) were 0.86/100 patient-years (95% CI 0.66-1.11) and 0.21/100 patient-years (95% CI 0.12-0.36), and age, sex and medical history adjusted hazard ratios (HR) for BCC and SCC in abatacept-treated patients were 1.49 (95% CI 1.07-2.09) and 2.49 (1.26-4.91) when compared to targeted DMARDs (n = 9,256). In Swedish data, IRs in abatacept- treated patients (n = 5,052) were 1.13/100 patient-years (95% CI 1.01-1.26) and 0.38/100 patient-years (95% CI 0.32-0.46) for BCC and SCC, and corresponding adjusted HRs were 1.11 (95% CI 0.98-1.25)

and 1.61 (95% CI 1.29-1.99) in abatacept-treated patients when compared to biological/targeted DMARD-treated patients (n = 43,096). Abatacept-treated patients tended to have more severe rheumatoid arthritis and a higher co-morbidity burden at baseline. No increased risk of other malignancies was observed in these registry data.

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 dyspnoea; 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 dyspnoea, 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 dyspnoea. 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 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 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.

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.

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 Upper respiratory tract infection (including tracheitis, nasopharyngitis, and sinusitis)

Common
Lower respiratory tract infection (including bronchitis), urinary tract infection, herpes infections (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, gastrointestinal infection, pelvic inflammatory disease

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
Uncommon
Basal cell carcinoma, skin papilloma
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
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, blood pressure decreased

Respiratory, thoracic and mediastinal disorders
Common
Cough
Uncommon
Chronic obstructive pulmonary disease exacerbated, 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 (including transaminases increased)

Skin and subcutaneous tissue disorders
Common
Rash (including dermatitis)
Uncommon
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
Fatigue, asthenia, local injection site reactions, systemic injection reactions* Uncommon Influenza like illness, weight increased

*(e.g. pruritus, throat tightness, dyspnoea)

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 annualised 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.

Registry studies in Denmark and Sweden have reported a higher risk of non-melanoma skin cancer in rheumatoid arthritis patients treated with abatacept compared to other DMARDs. In Denmark, standardised incidence rates (IR) for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in abatacept-treated patients (n = 1,280) were 0.86/100 patient-years (95% CI 0.66-1.11) and 0.21/100 patient-years (95% CI 0.12-0.36), and age, sex and medical history adjusted hazard ratios (HR) for BCC and SCC in abatacept-treated patients were 1.49 (95% CI 1.07-2.09) and 2.49 (1.26-4.91) when compared to targeted DMARDs (n = 9,256). In Swedish data, IRs in abatacept- treated patients (n = 5,052) were 1.13/100 patient-years (95% CI 1.01-1.26) and 0.38/100 patient-years (95% CI 0.32-0.46) for BCC and SCC, and corresponding adjusted HRs were 1.11 (95% CI 0.98-1.25) and 1.61 (95% CI 1.29-1.99) in abatacept-treated patients when compared to biological/targeted DMARD-treated patients (n = 43,096). Abatacept-treated patients tended to have more severe rheumatoid arthritis and a higher co-morbidity burden at baseline. No increased risk of other malignancies was observed in these registry data.

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 dyspnoea. 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 in adults treated with intravenous abatacept
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.

Immunogenicity in adults treated with subcutaneous abatacept
Study SC-I compared the immunogenicity to abatacept following subcutaneous or intravenous administration as assessed by ELISA assay. During the initial double blind 6 months period (short-term period), the overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no effect of immunogenicity on pharmacokinetics, safety, or efficacy.

Immunogenicity to abatacept following long-term subcutaneous administration was assessed by a new electrochemiluminescence (ECL) assay. Comparison of incidence rates across different assays is not appropriate, as the ECL assay was developed to be more sensitive and drug tolerant than the previous ELISA assay. The cumulative immunogenicity frequency to abatacept by the ECL assay with at least one positive sample in the short-term and long-term periods combined was 15.7% (215/1369) while on abatacept, with a mean duration of exposure of 48.8 months, and 17.3% (194/1121) after discontinuation (> 21 days up to 168 days after last dose). The exposure adjusted incidence rate (expressed per 100 person-years) remained stable over the treatment duration.

Consistent with previous experience, titers and persistence of antibody responses were generally low and did not increase upon continued dosing (6.8% subjects were seropositive on 2 consecutive visits), and there was no apparent correlation of antibody development to clinical response, adverse events, or pharmacokinetics.

In study SC-III, similar immunogenicity rates were seen in patients on treatment for the abatacept+MTX, and abatacept monotherapy groups (2.9% (3/103) and 5.0% (5/101), respectively) during the double-blind 12-month period. As in study SC-I, there was no effect of immunogenicity on safety or efficacy.

Immunogenicity and safety of abatacept upon withdrawal and restart of treatment
A study in the subcutaneous programme was conducted to investigate the effect of withdrawal (three months) and restart of abatacept subcutaneous treatment on immunogenicity. Upon withdrawal of abatacept subcutaneous treatment, the increased rate of immunogenicity was consistent with that seen upon discontinuation of abatacept administered intravenously. Upon reinitiating therapy, there were no injection reactions and no other safety concerns in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in the treatment arm that reinitiated therapy without an intravenous loading dose was also consistent with that observed in the other studies.

In SC-III, increased rates of immunogenicity were observed in subjects tested during 6 months of complete drug withdrawal in the abatacept+MTX and abatacept monotherapy groups (37.7% [29/77] and 44.1% [27/59], respectively) with generally low titer antibody responses. No clinical impact of

these antibody responses was detected, and no safety concerns were observed upon reinitiation of abatacept therapy.

Injection Reactions in adult patients treated with subcutaneous abatacept
Study SC-I compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the subcutaneous placebo group (intravenous abatacept), respectively. All injection site reactions were described as mild to moderate (hematoma, pruritus, or erythema) and generally did not necessitate drug discontinuation. During the cumulative study period when all subjects treated with abatacept in 7 SC studies were included, the frequency of injection site reactions was 4.6% (116/2,538) with an incidence rate of 1.32 per 100 person-years.

Postmarketing reports of systemic injection reactions (e.g. pruritus, throat tightness, dyspnoea) have been received following the use of subcutaneous ORENCIA.

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.

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).

Paediatric population

Abatacept has been studied in patients with pJIA in 2 clinical trials (ongoing 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.

Injection reactions
Of the 219 patients with pJIA treated with subcutaneous abatacept during the first 4-month abatacept treatment, the frequency of local injection reactions was 4.6% (10/219); injection site pain and injection site erythema were the most frequently reported local injection reactions. No systemic hypersensitivity reactions were reported.

Immunogenicity in patients with pJIA treated with subcutaneous abatacept
Antibodies directed against the whole abatacept molecule or to the CTLA-4 portion of abatacept were assessed by an ECL assay in patients with pJIA following repeated treatment with subcutaneous abatacept. Overall, 6.9% (15/218) of subjects (cohorts combined) had a positive immunogenicity response relative to baseline during the cumulative period, including the 4-month short-term treatment period, 20-month extension treatment period and the 6-month post abatacept follow-up period. In the 6 to 17 year age cohort, the overall rate of seropositivity during the cumulative period including post abatacept follow-up was 4.7% (8/172): 2.3% (4/172) on treatment and 13.6% (6/44) after discontinuation of abatacept (≥ 28 days after the last dose). In the 2 to 5 year age cohort, the overall rate of seropositivity during the cumulative period including post abatacept follow-up was 15.2% (7/46): 10.9% (5/46) on treatment and 37.5% (3/8) after discontinuation of abatacept (≥ 28 days after the last dose).

Overall antibodies against abatacept were generally transient and of low titer. The absence of concomitant methotrexate did not appear to be associated with a higher rate of seropositivity. The significance of the higher incidence in the 2 to 5 year age cohort is unknown, taking into account the difference in sample size. The presence of antibodies was not associated with adverse reactions, or with changes in efficacy or serum abatacept concentrations, in either cohort.

Long-term extension period
During the extension period of the pJIA studies (20 months in the pJIA ongoing 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.

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.

Tabulated list of adverse reactions

Listed in Table 1 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 1:
Adverse reactions

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

Common
Lower respiratory tract infection (including bronchitis), urinary tract infection, herpes infections (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, gastrointestinal infection, pelvic inflammatory disease

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)
Uncommon
Basal cell carcinoma, skin papilloma

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
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, blood pressure decreased

Respiratory, thoracic and mediastinal disorders
Common
Cough
Uncommon
Chronic obstructive pulmonary disease exacerbated, 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 (including transaminases increased)

Skin and subcutaneous tissue disorders
Common
Rash (including dermatitis)
Uncommon
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
Fatigue, asthenia, local injection site reactions, systemic injection reactions* Uncommon Influenza like illness, weight increased

*(e.g. pruritus, throat tightness, dyspnoea)

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 annualised 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.

Registry studies in Denmark and Sweden have reported a higher risk of non-melanoma skin cancer in rheumatoid arthritis patients treated with abatacept compared to other DMARDs. In Denmark, standardised incidence rates (IR) for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in abatacept-treated patients (n = 1,280) were 0.86/100 patient-years (95% CI 0.66-1.11) and 0.21/100 patient-years (95% CI 0.12-0.36), and age, sex and medical history adjusted hazard ratios (HR) for BCC and SCC in abatacept-treated patients were 1.49 (95% CI 1.07-2.09) and 2.49 (1.26-4.91) when compared to targeted DMARDs (n = 9,256). In Swedish data, IRs in abatacept- treated patients (n = 5,052) were 1.13/100 patient-years (95% CI 1.01-1.26) and 0.38/100 patient-years (95% CI 0.32-0.46) for BCC and SCC, and corresponding adjusted HRs were 1.11 (95% CI 0.98-1.25) and 1.61 (95% CI 1.29-1.99) in abatacept-treated patients when compared to biological/targeted DMARD-treated patients (n = 43,096). Abatacept-treated patients tended to have more severe rheumatoid arthritis and a higher co-morbidity burden at baseline. No increased risk of other malignancies was observed in these registry data.

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 dyspnoea. 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 in adults treated with intravenous abatacept
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.

Immunogenicity in adults treated with subcutaneous abatacept
Study SC-I compared the immunogenicity to abatacept following subcutaneous or intravenous administration as assessed by ELISA assay. During the initial double blind 6 months period (short-term period), the overall immunogenicity frequency to abatacept was 1.1% (8/725) and 2.3% (16/710) for the subcutaneous and intravenous groups, respectively. The rate is consistent with previous experience, and there was no effect of immunogenicity on pharmacokinetics, safety, or efficacy.

Immunogenicity to abatacept following long-term subcutaneous administration was assessed by a new electrochemiluminescence (ECL) assay. Comparison of incidence rates across different assays is not appropriate, as the ECL assay was developed to be more sensitive and drug tolerant than the previous ELISA assay. The cumulative immunogenicity frequency to abatacept by the ECL assay with at least one positive sample in the short-term and long-term periods combined was 15.7% (215/1369) while on abatacept, with a mean duration of exposure of 48.8 months, and 17.3% (194/1121) after discontinuation (> 21 days up to 168 days after last dose). The exposure adjusted incidence rate (expressed per 100 person-years) remained stable over the treatment duration.

Consistent with previous experience, titers and persistence of antibody responses were generally low and did not increase upon continued dosing (6.8% subjects were seropositive on 2 consecutive visits), and there was no apparent correlation of antibody development to clinical response, adverse events, or pharmacokinetics.

In study SC-III, similar immunogenicity rates were seen in patients on treatment for the abatacept+MTX, and abatacept monotherapy groups (2.9% (3/103) and 5.0% (5/101), respectively) during the double-blind 12-month period. As in study SC-I, there was no effect of immunogenicity on safety or efficacy.

Immunogenicity and safety of abatacept upon withdrawal and restart of treatment
A study in the subcutaneous programme was conducted to investigate the effect of withdrawal (three months) and restart of abatacept subcutaneous treatment on immunogenicity. Upon withdrawal of abatacept subcutaneous treatment, the increased rate of immunogenicity was consistent with that seen upon discontinuation of abatacept administered intravenously. Upon reinitiating therapy, there were no injection reactions and no other safety concerns in patients who were withdrawn from subcutaneous therapy for up to 3 months relative to those who remained on subcutaneous therapy, whether therapy was reintroduced with or without an intravenous loading dose. The safety observed in the treatment arm that reinitiated therapy without an intravenous loading dose was also consistent with that observed in the other studies.

In SC-III, increased rates of immunogenicity were observed in subjects tested during 6 months of complete drug withdrawal in the abatacept+MTX and abatacept monotherapy groups (37.7% [29/77] and 44.1% [27/59], respectively) with generally low titer antibody responses. No clinical impact of

these antibody responses was detected, and no safety concerns were observed upon reinitiation of abatacept therapy.

Injection Reactions in adult patients treated with subcutaneous abatacept
Study SC-I compared the safety of abatacept including injection site reactions following subcutaneous or intravenous administration. The overall frequency of injection site reactions was 2.6% (19/736) and 2.5% (18/721) for the subcutaneous abatacept group and the subcutaneous placebo group (intravenous abatacept), respectively. All injection site reactions were described as mild to moderate (hematoma, pruritus, or erythema) and generally did not necessitate drug discontinuation. During the cumulative study period when all subjects treated with abatacept in 7 SC studies were included the frequency of injection site reactions was 4.6% (116/2,538) with an incidence rate of 1.32 per 100 person-years.
Postmarketing reports of systemic injection reactions (e.g. pruritus, throat tightness, dyspnoea) have been received following the use of subcutaneous ORENCIA.

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.

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 1).

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.

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.

Progressive multifocal leukoencephalopathy (PML)
Cases of PML have been reported in patients receiving abatacept mostly in combination with other immunosuppressive medication. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological, psychiatric and cognitive symptoms. If 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 immunisations in agreement with current immunisation 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 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 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.

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 (see section 4.8).

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.

Progressive multifocal leukoencephalopathy (PML)
Cases of PML have been reported in patients receiving abatacept mostly in combination with other immunosuppressive medication. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological, psychiatric and

cognitive symptoms. If 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 (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 intravenous abatacept in placebo-controlled clinical trials. A total of 270 patients 65 years of age and older, including 46 patients 75 years and older, received subcutaneous abatacept in controlled clinical trials. The frequencies of serious infection and malignancy relative to placebo among intravenous abatacept-treated patients over age 65 were higher than among those under age 65. Similarly, the frequencies of serious infection and malignancy among subcutaneous 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, 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).

Patients on controlled sodium diet

This medicinal product contains less than 1 mmol sodium (23 mg) per pre-filled syringe, that is to say essentially ‘sodium-free’.

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.

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 post-marketing 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 (see section 4.8).

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.

Progressive multifocal leukoencephalopathy (PML)
Cases of PML have been reported in patients receiving abatacept mostly in combination with other immunosuppressive medication. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological, psychiatric and cognitive symptoms. If 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 (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 intravenous abatacept in placebo-controlled clinical trials. A total of 270 patients 65 years of age and older, including 46 patients 75 years and older, received subcutaneous abatacept in controlled clinical trials. The frequencies of serious infection and malignancy relative to placebo among intravenous abatacept-treated patients over age 65 were higher than among those under age 65. Similarly, the frequencies of serious infection and malignancy among subcutaneous 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, 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).

Patients on controlled sodium diet

This medicinal product contains 0.014 mmol sodium (0.322 mg) per pre-filled pen, that is to say essentially ‘sodium- free’.

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.

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 23-valent pneumococcal vaccine. After pneumococcal vaccination, 62 of 112 abatacept-treated patients were able to mount an adequate immune response of at least a 2-fold increase in antibody titers to pneumococcal polysaccharide vaccine.

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

Pregnancy and women of childbearing potential

There are no adequate data from use of abatacept in pregnant women. In pre-clinical embryo-foetal 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).

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.

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 PROPERTIES

Doses up to 50 mg/kg have been administered intravenously 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 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 TNFα, interferon-γ, 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 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 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.

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 TNFα, interferon-γ, 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 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 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. Study SC-I was a randomised, double-blind, double-dummy non- inferiority study administered to patients stratified by body weight (< 60 kg, 60 to 100 kg, > 100 kg) that compared the efficacy and safety of abatacept administered subcutaneously and intravenously in subjects with rheumatoid arthritis (RA), receiving background methotrexate (MTX), and experiencing an inadequate response to MTX (MTX-IR).

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.

Adult rheumatoid arthritis

The geometric mean estimate (90% confidence interval) for the bioavailability of abatacept following subcutaneous administration relative to intravenous administration is 78.6% (64.7%, 95.6%). The mean (range) for cmin and cmax at steady state observed after 85 days of treatment was 32.5 mcg/mL (6.6 to 113.8 mcg/mL) and 48.1 mcg/mL (9.8 to 132.4 mcg/mL), respectively. Mean estimates for systemic clearance (0.28 mL/h/kg), volume of distribution (0.11 L/kg), and terminal half- life (14.3 days) were comparable between subcutaneous and intravenous administration.

A single study was conducted to determine the effect of monotherapy use of abatacept on immunogenicity following subcutaneous administration without an intravenous load. When the intravenous loading dose was not administered, a mean trough concentration of 12.6 mcg/mL was achieved after 2 weeks of dosing. The efficacy response over time in this study appeared consistent with studies that included an intravenous loading dose, however, the effect of no intravenous load on the onset of efficacy has not been formally studied.

Consistent with the intravenous data, population pharmacokinetic analyses for subcutaneous abatacept in RA patients 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 apparent clearance.
Concomitant MTX, NSAIDs, corticosteroids, and TNF-inhibitors did not influence abatacept apparent clearance.

Adult psoriatic arthritis