ORENCIA 250 mg powder for concentrate for solution for infusion.

Each vial contains 250 mg of abatacept.

Each ml contains 25 mg of abatacept, after reconstitution.

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

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

For the full list of excipients, see section 6.1.

Powder for concentrate for solution for infusion.

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

Rheumatoid arthritis

ORENCIA in combination with methotrexate is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who responded inadequately to previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) or a tumour necrosis factor (TNF)-alpha inhibitor.

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

Polyarticular juvenile idiopathic arthritis

ORENCIA in combination with methotrexate is indicated for the treatment of moderate to severe active polyarticular juvenile idiopathic arthritis (JIA) in paediatric patients 6 years of age and older who have had an insufficient response to other DMARDs including at least one TNF inhibitor.

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

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.

^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.

Juvenile Idiopathic Arthritis

Paediatric population

The recommended dose of ORENCIA for patients 6 to 17 years of age with juvenile idiopathic arthritis who weigh less than 75 kg is 10 mg/kg calculated based on the 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 ORENCIA in children below 6 years of age have not been studied and therefore, ORENCIA is not recommended for use in children under six years old.

Special population

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

The entire, fully diluted ORENCIA solution should be administered over a period of 30 minutes and must be administered with an infusion set and a sterile, non-pyrogenic, low-protein-binding filter (pore size of 0.2 to 1.2 μm). See section 6.6 for information on reconstitution and dilution.

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

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

Combination with TNF-inhibitors

There is limited experience with use of abatacept in combination with TNF-inhibitors (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, ORENCIA therapy should be discontinued immediately and appropriate therapy initiated, and the use of ORENCIA should be permanently discontinued.

Effects on the immune system

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

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

Infections

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

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

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

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

Malignancies

In the placebo-controlled clinical trials, the frequencies of malignancies in abatacept- and placebo-treated patients were 1.4% and 1.1%, 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 for 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 ORENCIA, may blunt the effectiveness of some immunisations.

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

Elderly patients

A total of 323 patients 65 years of age and older, including 53 patients 75 years and older, received abatacept in placebo-controlled clinical trials. Similar efficacy was observed in these patients and in younger patients. The frequencies of serious infection and malignancy relative to placebo among abatacept-treated patients over age 65 were higher than among those under age 65. Because there is a higher incidence of infections and malignancies in the elderly in general, caution should be used when treating the elderly (see section 4.8).

Autoimmune processes

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

Blood glucose testing

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

Patients on controlled sodium diet

This medicinal product contains 1.5 mmol (or 34.5 mg) sodium per maximum dose of 4 vials (0.375 mmol or 8.625 mg sodium per vial). To be taken into consideration when treating patients on a controlled sodium diet.

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 ORENCIA 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 ORENCIA 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 ORENCIA 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 ORENCIA. Medicinal products that affect the immune system, including ORENCIA, may blunt the effectiveness of some immunisations (see section 4.4).

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

Abatacept was eva luated 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 eva luated 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-fetal development studies no undesirable effects were observed at doses up to 29-fold a human 10 mg/kg dose based on AUC. In a pre- and postnatal development study in rats limited changes in immune function were observed at 11-fold a human 10 mg/kg dose based on AUC (see section 5.3). ORENCIA should not be used in pregnant women unless clearly necessary. Women of child-bearing potential should use effective contraception during treatment with ORENCIA and up to 14 weeks after the last dose of abatacept treatment.

Breast-feeding

Abatacept has been shown to be present in rat milk. It is not known whether abatacept is excreted in human milk. Women should not breastfeed while treated 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.

Adverse reactions in adults

Summary of the safety profile

Abatacept has been studied in patients with active rheumatoid arthritis in placebo-controlled clinical trials (2,111 patients with abatacept, 1,099 with placebo).

In placebo-controlled clinical trials with abatacept, adverse reactions (ARs) were reported in 51.8% of abatacept-treated patients and 46.4% of placebo-treated patients. The most frequently reported adverse reactions (≥ 5%) among abatacept-treated patients were headache, nausea, and upper respiratory tract infections. The proportion of patients who discontinued treatment due to ARs was 3.3% 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

Description of selected adverse reactions

Infections

In the placebo-controlled clinical trials, infections at least possibly related to treatment were reported in 23.1% of abatacept-treated patients and 20.7% of placebo-treated patients.

Serious infections at least possibly related to treatment were reported in 1.8% of abatacept-treated patients and 1.1% of placebo-treated patients. Serious infections reported in at least one patient treated with abatacept (0.05% of patients) included the following: pneumonia, cellulitis, localised infection, urinary tract infection, bronchitis, diverticulitis, pyelonephritis acute, sepsis, abscess, arthritis bacterial, bacteraemia, bronchopneumonia, bronchopulmonary aspergillosis, bursitis infective, cellulitis staphylococcal, empyema, gastrointestinal infection, hepatitis E, infected skin ulcer, peridiverticular abscess, pneumonia bacterial, pneumonia haemophilus, pneumonia influenzal, sinusitis, streptococcal sepsis, tuberculosis, urosepsis (see section 4.4).

In double blind and open-label clinical trials in 4,149 patients treated with abatacept during 11,584 patient-years, the incidence rate of serious infections was 2.87 per 100 patient -years, and the annualized incidence rate remained stable.

Malignancies

In placebo-controlled clinical trials, malignancies were reported in 29 of 2,111 abatacept-treated patients observed during 1,829 patient-years, and in 12 of 1,099 placebo-treated patients observed during 849 patient-years.

In double blind and open-label clinical trials in 4,149 patients treated with abatacept during 11,932 patient-years (of which over 1,000 were treated with abatacept for over 5 years), the incidence rate of malignancy was 1.42 per 100 patient-years, and the annualized incidence rate remained stable. The incidence rates per 100 patient-years were 0.73 for non-melanomatous skin cancer, 0.59 for solid malignancies and 0.13 for hematologic malignancies. The most frequently reported organ cancer was lung cancer (0.15 per 100 patient-years), and the most common hematologic malignancy was lymphoma (0.07 per 100 patient-years). The incidence rate did not increase for malignancies overall, by major type (non-melanomatous skin cancer, solid tumors, and hematologic malignancies), or for individual tumor types in the double blind and open label period compared to the double-blind experience. The type and pattern of malignancies reported during the open-label period of the trials were similar to those reported for the double-blind experience.

The incidence rate of observed malignancies was consistent with that expected in an age- and gender-matched rheumatoid arthritis population (see section 4.4).

Infusion-related reactions

Acute infusion-related events (adverse reactions occurring within 1 hour of the start of the infusion) in Studies II, III, IV and V (see section 5.1) were more common in the abatacept-treated patients than the placebo-treated patients (9.4% for abatacept, 7.2% for placebo). The most frequently reported events with abatacept (1-2%) were dizziness, headache, and hypertension.

Acute infusion-related events that were reported in > 0.1% and ≤ 1% of patients treated with abatacept included cardiopulmonary symptoms such as hypotension, increased blood pressure, decreased blood pressure, and dyspnea; other symptoms included nausea, flushing, urticaria, cough, hypersensitivity, pruritus, rash, and wheezing. Most of these reactions were mild to moderate.

The occurrence of anaphylaxis remained rare between the double blind and long-term open-label experience. Hypersensitivity was reported uncommonly. Other reactions potentially associated with hypersensitivity to the medicinal product, such as hypotension, urticaria, and dyspnea, that occurred within 24 hours of ORENCIA infusion, were uncommon.

Discontinuation due to an acute infusion-related reaction occurred in 0.3% of patients receiving abatacept and in 0.2% 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 abatacept and 17 treated with placebo. The COPD patients treated with abatacept developed adverse reactions more frequently than those treated with placebo (51.4% vs. 47.1%, respectively). Respiratory disorders occurred more frequently in abatacept-treated patients than in placebo-treated patients (10.8% vs. 5.9%, respectively); these included COPD exacerbation, and dyspnea. A greater percentage of abatacept- than placebo-treated patients with COPD developed a serious adverse reaction (5.4% vs. 0%), including COPD exacerbation (1 of 37 patients [2.7%]) and bronchitis (1 of 37 patients [2.7%]).

Autoimmune processes

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

The incidence rate of autoimmune disorders remained stable during open-label experience (1.95 per 100 patient -years) compared to the double blind experience (2.36 per 100 patient -years).The most frequently reported autoimmune-related disorders during the open-label experience were psoriasis, vasculitis, and Sjogren's syndrome.

Immunogenicity

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

Samples with confirmed binding activity to CTLA-4 were assessed for the presence of neutralizing antibodies. Twenty-two of 48 eva luable 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 summarized in section 5.1.

Adverse reactions in paediatric patients with polyarticular juvenile idiopathic arthritis

ORENCIA has been studied in 190 paediatric patients, 6 to 17 years of age, with polyarticular JIA (see section 5.1). Adverse reactions occurring in the 4 month, lead-in, open-label period of the study were similar in type and frequency to those seen in adults (Table 2) with the following exceptions:

Common: upper respiratory tract infection (including sinusitis, nasopharyngitis and rhinitis), otitis (media and externa), haematuria, pyrexia.

Description of selected adverse reactions

Infections

The types of infections were consistent with those commonly seen in outpatient paediatric populations. The infections resolved without sequelae. One serious infection (varicella) was reported during the initial 4 months of treatment with ORENCIA.

Infusion-related reactions

Of the 190 patients with JIA treated with ORENCIA in this study, 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 polyarticular JIA following repeated treatment with 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 randomized 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