Benlysta · 4.3 Contraindications · 2

HOS-095770 · has-adverse-reaction-information · PDF-Seite 55

Summary of the safety profile in adults The safety of belimumab in patients with SLE has been evaluated in three pre-registration placebo-controlled intravenous studies and one subsequent regional placebo-controlled intravenous study, one placebo-controlled subcutaneous study, and two post-marketing placebo-controlled intravenous studies; the safety in patients with active lupus nephritis has been evaluated in one placebo-controlled intravenous study. 55 The data presented in the table below reflect exposure in 674 patients from the three pre-registration clinical studies and 470 patients in the subsequent placebo-controlled study with SLE administered Benlysta intravenously (10 mg/kg body weight over a 1-hour period on Days 0, 14, 28, and then every 28 days for up to 52 weeks), and 556 patients with SLE exposed to Benlysta subcutaneously (200 mg once weekly up to 52 weeks). The safety data presented include data beyond Week 52 in some patients with SLE. The data reflect additional exposure in 224 patients with active lupus nephritis who received Benlysta intravenously (10 mg/kg body weight for up to 104 weeks). Data from post-marketing reports are also included. The majority of patients were also receiving one or more of the following concomitant treatments for SLE: corticosteroids, immunomodulatory medicinal products, anti-malarials, non-steroidal anti-inflammatory medicinal products. Adverse reactions were reported in 84 % of Benlysta-treated patients and 87 % of placebo-treated patients. The most frequently reported adverse reaction (≥ 5 % of patients with SLE treated with Benlysta plus standard of care and at a rate ≥ 1 % greater than placebo) was nasopharyngitis. The proportion of patients who discontinued treatment due to adverse reactions was 7 % for Benlysta-treated patients and 8 % for placebo-treated patients. The most frequently reported adverse reactions (> 5 % of patients with active lupus nephritis treated with Benlysta plus standard of care) were upper respiratory tract infection, urinary tract infection, and herpes zoster. The proportion of patients who discontinued treatment due to adverse reactions was 12.9 % for Benlysta-treated patients and 12.9 % for placebo-treated patients. Severe cutaneous adverse reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with Benlysta treatment (see section 4.4). Tabulated list o

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HOS-095758 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The safety of belimumab in patients with SLE has been evaluated in three pre-registration placebo-controlled intravenous studies and one subsequent regional placebo-controlled intravenous study, one placebo- controlled subcutaneous study, and two post-marketing placebo-controlled intravenous studies; the safety in patients with active lupus nephritis has been evaluated in one placebo-controlled intravenous study. The data presented in the table below reflect exposure in 674 patients with SLE from the three pre- registration clinical studies and 470 patients in the subsequent placebo-controlled study administered Benlysta intravenously (10 mg/kg body weight over a 1-hour period on Days 0, 14, 28, and then every 28 days for up to 52 weeks), and 556 patients with SLE exposed to Benlysta subcutaneously (200 mg once weekly up to 52 weeks). The safety data presented include data beyond Week 52 in some patients with SLE. The data reflect additional exposure in 224 patients with active lupus nephritis who received Benlysta intravenously (10 mg/kg body weight for up to 104 weeks). Data from post-marketing reports are also included. 7 The majority of patients were also receiving one or more of the following concomitant treatments for SLE: corticosteroids, immunomodulatory medicinal products, anti-malarials, non-steroidal anti-inflammatory medicinal products. Adverse reactions were reported in 84 % of Benlysta-treated patients and 87 % of placebo-treated patients. The most frequently reported adverse reaction (≥ 5 % of patients with SLE treated with Benlysta plus standard of care and at a rate ≥ 1 % greater than placebo) was nasopharyngitis. The proportion of patients who discontinued treatment due to adverse reactions was 7 % for Benlysta-treated patients and 8 % for placebo-treated patients. The most frequently reported adverse reactions (> 5 % of patients with active lupus nephritis treated with Benlysta plus standard of care) were upper respiratory tract infection, urinary tract infection, and herpes zoster. The proportion of patients who discontinued treatment due to adverse reactions was 12.9 % for Benlysta-treated patients and 12.9 % for placebo-treated patients. Severe cutaneous adverse reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with Benlysta treatment (see section 4.4). Tabulated list of adverse

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HOS-095764 · has-adverse-reaction-information · PDF-Seite 31

Summary of the safety profile The safety of belimumab in patients with SLE has been evaluated in three pre-registration placebo-controlled intravenous studies and one subsequent regional placebo-controlled intravenous study, one placebo- controlled subcutaneous study, and two post-marketing placebo-controlled intravenous studies; the safety in patients with active lupus nephritis has been evaluated in one placebo-controlled intravenous study. The data presented in the table below reflect exposure in 674 patients with SLE from the three pre- registration clinical studies and 470 patients in the subsequent placebo-controlled study administered Benlysta intravenously (10 mg/kg body weight over a 1-hour period on Days 0, 14, 28, and then every 28 days for up to 52 weeks), and 556 patients with SLE exposed to Benlysta subcutaneously (200 mg once weekly up to 52 weeks). The safety data presented include data beyond Week 52 in some patients with SLE. The data reflect additional exposure in 224 patients with active lupus nephritis who received Benlysta intravenously (10 mg/kg body weight for up to 104 weeks). Data from post-marketing reports are also included. 31 The majority of patients were also receiving one or more of the following concomitant treatments for SLE: corticosteroids, immunomodulatory medicinal products, anti-malarials, non-steroidal anti-inflammatory medicinal products. Adverse reactions were reported in 84 % of Benlysta-treated patients and 87 % of placebo-treated patients. The most frequently reported adverse reaction (≥ 5 % of patients with SLE treated with Benlysta plus standard of care and at a rate ≥ 1 % greater than placebo) was nasopharyngitis. The proportion of patients who discontinued treatment due to adverse reactions was 7 % for Benlysta-treated patients and 8 % for placebo-treated patients. The most frequently reported adverse reactions (> 5 % of patients with active lupus nephritis treated with Benlysta plus standard of care) were upper respiratory tract infection, urinary tract infection, and herpes zoster. The proportion of patients who discontinued treatment due to adverse reactions was 12.9 % for Benlysta-treated patients and 12.9 % for placebo-treated patients. Severe cutaneous adverse reactions: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in association with Benlysta treatment (see section 4.4). Tabulated list of advers

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HOS-095760 · has-contraindication-information · PDF-Seite 28

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

HOS-095766 · has-contraindication-information · PDF-Seite 52

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

HOS-095754 · has-contraindication-information · PDF-Seite 4

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

HOS-095765 · has-indication-information · PDF-Seite 50

Benlysta is indicated as add-on therapy in patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g., positive anti-dsDNA and low complement) despite standard therapy (see section 5.1). Benlysta is indicated in combination with background immunosuppressive therapies for the treatment of adult patients with active lupus nephritis (see sections 4.2 and 5.1).

HOS-095759 · has-indication-information · PDF-Seite 26

Benlysta is indicated as add-on therapy in adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g., positive anti-dsDNA and low complement) despite standard therapy (see section 5.1). Benlysta is indicated in combination with background immunosuppressive therapies for the treatment of adult patients with active lupus nephritis (see sections 4.2 and 5.1).

HOS-095753 · has-indication-information · PDF-Seite 2

Benlysta is indicated as add-on therapy in patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g., positive anti-dsDNA and low complement) despite standard therapy (see section 5.1). Benlysta is indicated in combination with background immunosuppressive therapies for the treatment of adult patients with active lupus nephritis (see sections 4.2 and 5.1).

HOS-095768 · has-interaction-information · PDF-Seite 55

No in vivo interaction studies have been performed. The formation of some CYP450 enzymes is suppressed by increased levels of certain cytokines during chronic inflammation. It is not known if belimumab could be an indirect modulator of such cytokines. A risk for indirect reduction of CYP activity by belimumab cannot be excluded. On initiation or discontinuation of belimumab, therapeutic monitoring is to be considered for patients being treated with CYP substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g. warfarin).

HOS-095756 · has-interaction-information · PDF-Seite 6

No in vivo interaction studies have been performed. The formation of some CYP450 enzymes is suppressed by increased levels of certain cytokines during chronic inflammation. It is not known if belimumab could be an indirect modulator of such cytokines. A risk for indirect reduction of CYP activity by belimumab cannot be excluded. On initiation or discontinuation of belimumab, therapeutic monitoring is to be considered for patients being treated with CYP substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g. warfarin). 6

HOS-095762 · has-interaction-information · PDF-Seite 30

No in vivo interaction studies have been performed. The formation of some CYP450 enzymes is suppressed by increased levels of certain cytokines during chronic inflammation. It is not known if belimumab could be an indirect modulator of such cytokines. A risk for indirect reduction of CYP activity by belimumab cannot be excluded. On initiation or discontinuation of belimumab, therapeutic monitoring is to be considered for patients being treated with CYP substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g. warfarin). 30

HOS-095757 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential/Contraception in males and females Women of childbearing potential must use effective contraception during Benlysta treatment and for at least 4 months after the last treatment. Pregnancy There are a limited amount of data from the use of Benlysta in pregnant women. Besides an expected pharmacological effect i.e. reduction of B cells, animal studies in monkeys do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Benlysta should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus. Breast-feeding It is unknown whether Benlysta is excreted in human milk or is absorbed systemically after ingestion. However, belimumab was detected in the milk from female monkeys administered 150 mg/kg body weight every 2 weeks. Because maternal antibodies (IgG) are excreted in breast milk, it is recommended that a decision is made on whether to discontinue breast-feeding or to discontinue Benlysta therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data on the effects of belimumab on human fertility. Effects on male and female fertility have not been formally evaluated in animal studies (see section 5.3).

HOS-095769 · has-pregnancy-information · PDF-Seite 55

Women of childbearing potential/Contraception in males and females Women of childbearing potential must use effective contraception during Benlysta treatment and for at least 4 months after the last treatment. Pregnancy There are a limited amount of data from the use of Benlysta in pregnant women. Besides an expected pharmacological effect i.e. reduction of B cells, animal studies in monkeys do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Benlysta should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus. Breast-feeding It is unknown whether Benlysta is excreted in human milk or is absorbed systemically after ingestion. However, belimumab was detected in the milk from female monkeys administered 150 mg/kg body weight every 2 weeks. Because maternal antibodies (IgG) are excreted in breast milk, it is recommended that a decision is made on whether to discontinue breast-feeding or to discontinue Benlysta therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data on the effects of belimumab on human fertility. Effects on male and female fertility have not been formally evaluated in animal studies (see section 5.3).

HOS-095763 · has-pregnancy-information · PDF-Seite 31

Women of childbearing potential/Contraception in males and females Women of childbearing potential must use effective contraception during Benlysta treatment and for at least 4 months after the last treatment. Pregnancy There are a limited amount of data from the use of Benlysta in pregnant women. Besides an expected pharmacological effect i.e. reduction of B cells, animal studies in monkeys do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). Benlysta should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus. Breast-feeding It is unknown whether Benlysta is excreted in human milk or is absorbed systemically after ingestion. However, belimumab was detected in the milk from female monkeys administered 150 mg/kg body weight every 2 weeks. Because maternal antibodies (IgG) are excreted in breast milk, it is recommended that a decision is made on whether to discontinue breast-feeding or to discontinue Benlysta therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data on the effects of belimumab on human fertility. Effects on male and female fertility have not been formally evaluated in animal studies (see section 5.3).

HOS-095767 · has-warning-information · PDF-Seite 52

Traceability In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded. Benlysta has not been studied in the following adult and paediatric patient groups, and is not recommended in: • severe active central nervous system lupus (see section 5.1) • HIV • a history of, or current, hepatitis B or C • hypogammaglobulinaemia (IgG < 400 mg/dL) or IgA deficiency (IgA < 10 mg/dL) • a history of major organ transplant or hematopoietic stem cell /marrow transplant or renal transplant. 52 Concomitant use with B cell targeted therapy Available data do not support the co-administration of rituximab with Benlysta in patients with SLE (see section 5.1). Caution needs to be exercised if Benlysta is co-administered with other B cell targeted therapy. Infusion reactions and hypersensitivity Administration of Benlysta may result in hypersensitivity reactions and infusion reactions which can be severe, and fatal. In the event of a severe reaction, Benlysta administration must be interrupted and appropriate medical therapy administered (see section 4.2). The risk of hypersensitivity reactions is greatest with the first two infusions; however the risk must be considered for every infusion administered. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Premedication including an antihistamine, with or without an antipyretic, may be administered before the infusion of Benlysta. There is insufficient knowledge to determine whether premedication could diminish the frequency or severity of infusion reactions. In clinical studies, serious infusion and hypersensitivity reactions affected approximately 0.9 % of adult patients, and included anaphylactic reaction, bradycardia, hypotension, angioedema, and dyspnoea. Infusion reactions occurred more frequently during the first two infusions and tended to decrease with subsequent infusions (see section 4.8). Patients have been reported to develop symptoms of acute hypersensitivity several hours after the infusion has been administered. Recurrence of clinically significant reactions after initial appropriate treatment of symptoms has also been observed (see sections 4.2 and 4.8). Therefore, Benlysta must be administered in an environm

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HOS-095761 · has-warning-information · PDF-Seite 28

Traceability In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded. Benlysta has not been studied in the following patient groups and is not recommended in: • severe active central nervous system lupus • HIV • a history of, or current, hepatitis B or C • hypogammaglobulinaemia (IgG < 400 mg/dL) or IgA deficiency (IgA < 10 mg/dL) • a history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant. Concomitant use with B cell targeted therapy Available data do not support the co-administration of rituximab with Benlysta in patients with SLE (see section 5.1). Caution needs to be exercised if Benlysta is co-administered with other B cell targeted therapy. 28 Hypersensitivity Administration of subcutaneous or intravenous Benlysta may result in hypersensitivity reactions which can be severe, and fatal. In the event of a severe reaction, Benlysta administration must be interrupted and appropriate medical therapy administered (see section 4.2). The risk of hypersensitivity reactions is greatest with the first two doses; however, the risk must be considered for every administration. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Recurrence of clinically significant reactions after initial appropriate treatment of symptoms has also been observed (see sections 4.2 and 4.8). Patients must be advised that hypersensitivity reactions are possible, on the day of, or several days after administration, and be informed of potential signs and symptoms and the possibility of recurrence. Patients must be instructed to seek immediate medical attention if they experience any of these symptoms. The package leaflet must be available to the patient. Delayed-type, non-acute hypersensitivity reactions have also been observed and included symptoms such as rash, nausea, fatigue, myalgia, headache, and facial oedema. In intravenous clinical studies, serious infusion and hypersensitivity reactions included anaphylactic reaction, bradycardia, hypotension, angioedema, and dyspnoea. Please refer to the Summary of Product Characteristics for Benlysta powder for concentrate for solution for infusion (section 4.4). Infections The mechanism o

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HOS-095755 · has-warning-information · PDF-Seite 4

Traceability In order to improve traceability of biological medicinal products, the tradename and the batch number of the administered product should be clearly recorded. Benlysta has not been studied in the following patient groups and is not recommended in: • severe active central nervous system lupus • HIV • a history of, or current, hepatitis B or C • hypogammaglobulinaemia (IgG < 400 mg/dL) or IgA deficiency (IgA < 10 mg/dL) • a history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant. 4 Concomitant use with B cell targeted therapy Available data do not support the co-administration of rituximab with Benlysta in patients with SLE (see section 5.1). Caution needs to be exercised if Benlysta is co-administered with other B cell targeted therapy. Hypersensitivity Administration of subcutaneous or intravenous Benlysta may result in hypersensitivity reactions which can be severe, and fatal. In the event of a severe reaction, Benlysta administration must be interrupted and appropriate medical therapy administered (see section 4.2). The risk of hypersensitivity reactions is greatest with the first two doses; however, the risk must be considered for every administration. Patients with a history of multiple drug allergies or significant hypersensitivity may be at increased risk. Recurrence of clinically significant reactions after initial appropriate treatment of symptoms has also been observed (see sections 4.2 and 4.8). Patients must be advised that hypersensitivity reactions are possible, on the day of, or several days after administration, and be informed of potential signs and symptoms and the possibility of recurrence. Patients must be instructed to seek immediate medical attention if they experience any of these symptoms. The package leaflet must be available to the patient. Delayed-type, non-acute hypersensitivity reactions have also been observed and included symptoms such as rash, nausea, fatigue, myalgia, headache, and facial oedema. In intravenous clinical studies, serious infusion and hypersensitivity reactions included anaphylactic reaction, bradycardia, hypotension, angioedema, and dyspnoea. Please refer to the Summary of Product Characteristics for Benlysta powder for concentrate for solution for infusion (section 4.4). Infections The mechanism of a

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