Nucala · 4.6 Fertility, pregnancy and lactation · 1

HOS-097259 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Severe eosinophilic asthma In placebo-controlled studies in adult and adolescent patients with severe refractory eosinophilic asthma, the most commonly reported adverse reactions during treatment were headache (20%), injection site reactions (8%) and back pain (6%). CRSwNP In a placebo-controlled study in patients with CRSwNP, the most commonly reported adverse reactions during treatment were headache (18%) and back pain (7%). COPD In three placebo-controlled studies in patients with COPD, the most commonly reported adverse reactions during treatment were headache (10%), back pain (7%) and arthralgia (5%). EGPA In a placebo-controlled study in patients with EGPA, the most commonly reported adverse reactions during treatment were headache (32%), injection site reactions (15%) and back pain (13%). Systemic allergic/hypersensitivity reactions were reported by 4% of EGPA patients. HES In a placebo-controlled study in patients with HES, the most commonly reported adverse reactions during treatment were headache (13%), urinary tract infection (9%), injection site reactions and pyrexia (7% each). Tabulated list of adverse reactions The table below presents the adverse reactions from placebo-controlled severe eosinophilic asthma studies from patients receiving mepolizumab 100 mg subcutaneously (SC) (n=263), from a 8 randomised, double-blind placebo-controlled 52-week study in patients with CRSwNP receiving mepolizumab 100 mg SC (n=206), in three double-blind placebo-controlled 52- to 104-week studies in patients with COPD receiving mepolizumab 100 mg SC (n=1043), in patients with EGPA receiving mepolizumab 300 mg SC (n=68), in a double-blind placebo-controlled 32-week study in patients with HES receiving mepolizumab 300 mg SC (n= 54), and from spontaneous post-marketing reports. Safety data is also available from open-label extension studies in severe refractory eosinophilic asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years). The safety profile of mepolizumab in HES patients (n=102) enrolled in a 20-week open label extension study was similar to the safety profile of patients in the pivotal placebo-controlled study. The frequency of adverse reactions is defined using the following convention: 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); and not known

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HOS-097265 · has-adverse-reaction-information · PDF-Seite 37

Summary of the safety profile Severe eosinophilic asthma In placebo-controlled studies in adult and adolescent patients with severe refractory eosinophilic asthma, the most commonly reported adverse reactions during treatment were headache (20%), injection site reactions (8%) and back pain (6%). CRSwNP In a placebo-controlled study in patients with CRSwNP, the most commonly reported adverse reactions during treatment were headache (18%) and back pain (7%). 37 COPD In three placebo-controlled studies in patients with COPD, the most commonly reported adverse reactions during treatment were headache (10%), back pain (7%) and arthralgia (5%). EGPA In a placebo-controlled study in patients with EGPA, the most commonly reported adverse reactions during treatment were headache (32%), injection site reactions (15%) and back pain (13%). Systemic allergic/hypersensitivity reactions were reported by 4% of EGPA patients. HES In a placebo-controlled study in patients with HES, the most commonly reported adverse reactions during treatment were headache (13%), urinary tract infection (9%), injection site reactions and pyrexia (7% each). Tabulated list of adverse reactions The table below presents the adverse reactions from placebo-controlled severe eosinophilic asthma studies from patients receiving mepolizumab 100 mg subcutaneously (SC) (n= 263), from a randomised, double-blind placebo-controlled 52-week study in patients with CRSwNP receiving mepolizumab 100 mg SC (n=206), in three double-blind placebo-controlled 52- to 104-week studies in patients with COPD receiving mepolizumab 100 mg SC (n=1043), in patients with EGPA receiving mepolizumab 300 mg SC (n=68), in a double-blind placebo-controlled 32-week study in patients with HES receiving mepolizumab 300 mg SC (n= 54), and from spontaneous post-marketing reports. Safety data is also available from open-label extension studies in severe refractory eosinophilic asthma patients (n=998) treated for a median of 2.8 years (range 4 weeks to 4.5 years). The safety profile of mepolizumab in HES patients (n=102) enrolled in a 20-week open label extension study was similar to the safety profile of patients in the pivotal placebo-controlled study. The frequency of adverse reactions is defined using the following convention: 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); and not k

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HOS-097255 · has-contraindication-information · PDF-Seite 6

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

HOS-097261 · has-contraindication-information · PDF-Seite 35

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

HOS-097260 · has-indication-information · PDF-Seite 32

Severe eosinophilic asthma Nucala is indicated as an add-on treatment for severe refractory eosinophilic asthma in adults, adolescents and children aged 6 years and older (see section 5.1). Chronic rhinosinusitis with nasal polyps (CRSwNP) Nucala is indicated as an add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not provide adequate control. Chronic obstructive pulmonary disease (COPD) Nucala is indicated in adults as an add-on maintenance treatment for uncontrolled chronic obstructive pulmonary disease (COPD) characterised by raised blood eosinophils on a combination of an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) (see section 5.1). Eosinophilic granulomatosis with polyangiitis (EGPA) Nucala is indicated as an add-on treatment for patients aged 6 years and older with relapsing-remitting or refractory eosinophilic granulomatosis with polyangiitis (EGPA). 32 Hypereosinophilic syndrome (HES) Nucala is indicated as an add-on treatment for adult patients with inadequately controlled hypereosinophilic syndrome without an identifiable non-haematologic secondary cause (see section 5.1).

HOS-097254 · has-indication-information · PDF-Seite 2

Severe eosinophilic asthma Nucala is indicated as an add-on treatment for severe refractory eosinophilic asthma in adults, adolescents and children aged 6 years and older (see section 5.1). 2 Chronic rhinosinusitis with nasal polyps (CRSwNP) Nucala is indicated as an add-on therapy with intranasal corticosteroids for the treatment of adult patients with severe CRSwNP for whom therapy with systemic corticosteroids and/or surgery do not provide adequate disease control. Chronic obstructive pulmonary disease (COPD) Nucala is indicated in adults as an add-on maintenance treatment for uncontrolled chronic obstructive pulmonary disease (COPD) characterised by raised blood eosinophils on a combination of an inhaled corticosteroid (ICS), a long-acting beta2-agonist (LABA), and a long-acting muscarinic antagonist (LAMA) (see section 5.1). Eosinophilic granulomatosis with polyangiitis (EGPA) Nucala is indicated as an add-on treatment for patients aged 6 years and older with relapsing-remitting or refractory eosinophilic granulomatosis with polyangiitis (EGPA). Hypereosinophilic syndrome (HES) Nucala is indicated as an add-on treatment for adult patients with inadequately controlled hypereosinophilic syndrome without an identifiable non-haematologic secondary cause (see section 5.1).

HOS-097257 · has-interaction-information · PDF-Seite 7

No interaction studies have been performed. Cytochrome P450 enzymes, efflux pumps and protein-binding mechanisms are not involved in the clearance of mepolizumab. Increased levels of pro-inflammatory cytokines (e.g. IL-6), via interaction with their cognate receptors on hepatocytes, have been shown to suppress the formation of CYP450 enzymes and drug transporters, however, elevation of systemic pro-inflammatory markers in severe refractory eosinophilic asthma is minimal and there is no evidence of IL-5 receptor alpha expression on hepatocytes. The potential for interactions with mepolizumab is therefore considered low.

HOS-097263 · has-interaction-information · PDF-Seite 36

No interaction studies have been performed. Cytochrome P450 enzymes, efflux pumps and protein-binding mechanisms are not involved in the clearance of mepolizumab. Increased levels of pro-inflammatory cytokines (e.g. IL-6), via interaction with their cognate receptors on hepatocytes, have been shown to suppress the formation of CYP450 36 enzymes and drug transporters, however, elevation of systemic pro-inflammatory markers in severe refractory eosinophilic asthma is minimal and there is no evidence of IL-5 receptor alpha expression on hepatocytes. The potential for interactions with mepolizumab is therefore considered low.

HOS-097258 · has-pregnancy-information · PDF-Seite 7

Pregnancy There is a limited amount of data (less than 300 pregnancy outcomes) from the use of mepolizumab in pregnant women. Mepolizumab crosses the placental barrier in monkeys. Animal studies do not indicate reproductive toxicity (see section 5.3). The potential for harm to a human fetus is unknown. As a precautionary measure, it is preferable to avoid the use of Nucala during pregnancy. Administration of Nucala to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus. 7 Breast-feeding There are no data regarding the excretion of mepolizumab in human milk. However, mepolizumab was excreted into the milk of cynomolgus monkeys at concentrations of less than 0.5% of those detected in plasma. A decision must be made whether to discontinue breast-feeding or to discontinue Nucala therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no fertility data in humans. Animal studies showed no adverse effects of anti-IL5 treatment on fertility (see section 5.3).

HOS-097264 · has-pregnancy-information · PDF-Seite 37

Pregnancy There is a limited amount of data (less than 300 pregnancy outcomes) from the use of mepolizumab in pregnant women. Mepolizumab crosses the placental barrier in monkeys. Animal studies do not indicate reproductive toxicity (see section 5.3). The potential for harm to a human fetus is unknown. As a precautionary measure, it is preferable to avoid the use of Nucala during pregnancy. Administration of Nucala to pregnant women should only be considered if the expected benefit to the mother is greater than any possible risk to the fetus. Breast-feeding There are no data regarding the excretion of mepolizumab in human milk. However, mepolizumab was excreted into the milk of cynomolgus monkeys at concentrations of less than 0.5% of those detected in plasma. A decision must be made whether to discontinue breast-feeding or to discontinue Nucala therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no fertility data in humans. Animal studies showed no adverse effects of anti-IL5 treatment on fertility (see section 5.3).

HOS-097262 · has-warning-information · PDF-Seite 35

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. Asthma or COPD exacerbations Mepolizumab must not be used to treat acute asthma or COPD exacerbations. 35 Asthma-related or COPD-related adverse symptoms or exacerbations may occur during treatment. Patients must be instructed to seek medical advice if their asthma or COPD remains uncontrolled or worsens after initiation of treatment. Corticosteroids Abrupt discontinuation of corticosteroids after initiation of mepolizumab therapy is not recommended. Reduction in corticosteroid doses, if required, must be gradual and performed under the supervision of a physician. Hypersensitivity and administration-related reactions Acute and delayed systemic reactions, including hypersensitivity reactions (e.g. anaphylaxis, urticaria, angioedema, rash, bronchospasm, hypotension), have occurred following administration of mepolizumab. These reactions generally occur within hours of administration, but in some instances have a delayed onset (i.e., typically within several days). These reactions may occur for the first time after a long duration of treatment (see section 4.8). In the event of a hypersensitivity reaction, appropriate treatment as clinically indicated must be initiated. Parasitic infections Eosinophils may be involved in the immunological response to some helminth infections. Patients with pre-existing helminth infections should be treated before starting therapy. If patients become infected whilst receiving treatment with mepolizumab and do not respond to anti-helminth treatment, temporary discontinuation of therapy should be considered. COPD patients with low blood eosinophil counts Data do not support the use of Nucala in patients with COPD with blood eosinophil count <150 cells/mcL and no evidence of blood eosinophil count ≥300 cells/mcL in the previous 12 months. Organ threatening or life-threatening EGPA Nucala has not been studied in patients with organ threatening or life-threatening manifestations of EGPA (see section 4.2). Life-threatening HES Nucala has not been studied in patients with life-threatening manifestations of HES (see section 4.2). Excipients This medicinal product contains polysorbate 80 (see section 2), which may cause allergic reactions. This medicinal product contains less than 1 mmol sodium

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HOS-097256 · has-warning-information · PDF-Seite 6

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. Asthma or COPD exacerbations Mepolizumab must not be used to treat acute asthma or COPD exacerbations. Asthma-related or COPD-related adverse symptoms or exacerbations may occur during treatment. Patients must be instructed to seek medical advice if their asthma or COPD remains uncontrolled or worsens after initiation of treatment. Corticosteroids Abrupt discontinuation of corticosteroids after initiation of mepolizumab therapy is not recommended. Reduction in corticosteroid doses, if required, must be gradual and performed under the supervision of a physician. Hypersensitivity and administration-related reactions Acute and delayed systemic reactions, including hypersensitivity reactions (e.g. anaphylaxis, urticaria, angioedema, rash, bronchospasm, hypotension), have occurred following administration of mepolizumab. These reactions generally occur within hours of administration, but in some instances have a delayed onset (i.e., typically within several days). These reactions may occur for the first time after a long duration of treatment (see section 4.8). In the event of a hypersensitivity reaction, appropriate treatment as clinically indicated must be initiated. 6 Parasitic infections Eosinophils may be involved in the immunological response to some helminth infections. Patients with pre-existing helminth infections should be treated before starting therapy. If patients become infected whilst receiving treatment with mepolizumab and do not respond to anti-helminth treatment, temporary discontinuation of therapy should be considered. COPD patients with low blood eosinophil counts Data do not support the use of Nucala in patients with COPD with blood eosinophil count <150 cells/mcL and no evidence of blood eosinophil count ≥300 cells/mcL in the previous 12 months. Organ threatening or life-threatening EGPA Nucala has not been studied in patients with organ threatening or life-threatening manifestations of EGPA (see section 4.2). Life-threatening HES Nucala has not been studied in patients with life-threatening manifestations of HES (see section 4.2). Excipients This medicinal product contains polysorbate 80 (see section 2), which may cause allergic reactions. This medicinal product contains less than 1 mmol sodium (2

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