Orencia · 4.1 Therapeutic indications · 3

HOS-094418 · has-adverse-reaction-information · PDF-Seite 8

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

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HOS-094424 · has-adverse-reaction-information · PDF-Seite 34

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. 34 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 Uncommon Basal cell carcinoma, skin papilloma and unspecified (incl. cysts and Rare Lymphoma, lung neoplasm malignant, squamous polyps)

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HOS-094430 · has-adverse-reaction-information · PDF-Seite 61

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. 61 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 Uncommon Basal cell carcinoma, skin papilloma and unspecified (incl. cysts and polyps) Rare Lymphoma, lung neoplasm malignant,

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HOS-094414 · has-contraindication-information · PDF-Seite 4

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).

HOS-094420 · has-contraindication-information · PDF-Seite 30

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). 30

HOS-094426 · has-contraindication-information · PDF-Seite 58

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).

HOS-094419 · has-indication-information · PDF-Seite 28

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. 28 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.

HOS-094425 · has-indication-information · PDF-Seite 56

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.

HOS-094413 · has-indication-information · PDF-Seite 2

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

HOS-094422 · has-interaction-information · PDF-Seite 32

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. 32 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 patient

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HOS-094428 · has-interaction-information · PDF-Seite 60

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 va

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HOS-094416 · has-interaction-information · PDF-Seite 6

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). 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

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HOS-094429 · has-pregnancy-information · PDF-Seite 61

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).

HOS-094417 · has-pregnancy-information · PDF-Seite 7

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).

HOS-094423 · has-pregnancy-information · PDF-Seite 33

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. 33 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).

HOS-094427 · has-warning-information · PDF-Seite 58

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 58 undergoing treatment with ORENCIA should be monitored closely. Administra

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HOS-094415 · has-warning-information · PDF-Seite 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, 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). 4 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 sho

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HOS-094421 · has-warning-information · PDF-Seite 31

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 develo

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