Flebogamma DIF (previously Flebogammadif) · 4.1 Therapeutic indications · 1

HOS-094726 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile Adverse reactions caused by human normal immunoglobulins (in decreasing frequency) encompass (see also Section 4.4): • chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain • reversible haemolytic reactions; especially in those patients with blood groups A, B, and AB and (rarely) haemolytic anaemia requiring transfusion • (rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration • (rarely) transient cutaneous reactions (including cutaneous lupus erythematosus - frequency unknown) • (very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses • cases of reversible aseptic meningitis • cases of increased serum creatinine level and/or occurrence of acute renal failure • cases of Transfusion Related Acute Lung Injury (TRALI) For safety information with respect to transmissible agents, see section 4.4. Tabulated list of adverse reactions The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). - 10 - Frequencies have been evaluated according to 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) - not known (cannot be estimated from the available data) Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Source of the safety database from clinical trials and post-authorisation safety studies in a total of 128 patients exposed to Flebogamma DIF 50 mg/ml (with a total of 1318 infusions) Frequency Frequency MedDRA System Organ Adverse reaction per per Class (SOC) patient infusion Infections and infestations Nasopharyngitis Uncommon Uncommon Immune system disorders Hypersensitivity Uncommon Rare Psychiatric disorders

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HOS-094732 · has-adverse-reaction-information · PDF-Seite 24

Summary of the safety profile Adverse reactions caused by human normal immunoglobulins (in decreasing frequency) encompass (see also Section 4.4): • chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain • reversible haemolytic reactions; especially in those patients with blood groups A, B, and AB and (rarely) haemolytic anaemia requiring transfusion - 24 - • (rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration • (rarely) transient cutaneous reactions (including cutaneous lupus erythematosus - frequency unknown) • (very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses • cases of reversible aseptic meningitis • cases of increased serum creatinine level and/or occurrence of acute renal failure • cases of Transfusion Related Acute Lung Injury (TRALI) For safety information with respect to transmissible agents, see section 4.4. Tabulated list of adverse reactions Increase in the frequency of adverse reactions through the clinical trials likely related to the increased infusion rate has been observed (see section 4.2). The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been evaluated according to 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) - not known (cannot be estimated from the available data) Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Source of the safety database from clinical trials and post-authorisation safety studies in a total of 160 patients exposed to Flebogamma DIF 100 mg/ml (with a total of 915 infusions) Frequency Frequency MedDRA System Organ Adverse reaction per per Class (SOC) patient infusion M

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HOS-094728 · has-contraindication-information · PDF-Seite 20

Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (see sections 4.4 and 6.1). Hereditary fructose intolerance (see section 4.4). In babies and young children (aged 0 - 2 years) hereditary fructose intolerance (HFI) may not yet be diagnosed and may be fatal, thus, they must not receive this medicinal product. Patients with selective IgA deficiency who developed antibodies to IgA, as administering an IgA-containing product can result in anaphylaxis.

HOS-094722 · has-contraindication-information · PDF-Seite 6

Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (see sections 4.4 and 6.1). Hereditary fructose intolerance (see section 4.4). In babies and young children (aged 0 - 2 years) hereditary fructose intolerance (HFI) may not yet be diagnosed and may be fatal, thus, they must not receive this medicinal product. Patients with selective IgA deficiency who developed antibodies to IgA, as administering an IgA-containing product can result in anaphylaxis.

HOS-094727 · has-indication-information · PDF-Seite 16

Replacement therapy in adults, children and adolescents (2 - 18 years) in: - Primary immunodeficiency syndromes (PID) with impaired antibody production - Secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF)* or serum IgG level of <4 g/l - 16 - * PSAF= failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines Measles pre-/post exposure prophylaxis for susceptible adults, children and adolescents (2 - 18 years) in whom active immunisation is contraindicated or not advised. Consideration should also be given to official recommendations on intravenous human immunoglobulin use in measles pre-/post exposure prophylaxis and active immunisation. Immunomodulation in adults, children and adolescents (2 - 18 years) in: - Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count - Guillain Barré syndrome - Kawasaki disease (in conjunction with acetylsalicylic acid; see 4.2) - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) - Multifocal motor neuropathy (MMN)

HOS-094721 · has-indication-information · PDF-Seite 2

Replacement therapy in adults, children and adolescents (2 - 18 years) in: - Primary immunodeficiency syndromes (PID) with impaired antibody production - Secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF)* or serum IgG level of <4 g/l -2- *PSAF= failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines Measles pre-/post exposure prophylaxis for susceptible adults, children and adolescents (2 - 18 years) in whom active immunisation is contraindicated or not advised. Consideration should also be given to official recommendations on intravenous human immunoglobulin use in measles pre-/post exposure prophylaxis and active immunisation. Immunomodulation in adults, children and adolescents (2 - 18 years) in: - Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count - Guillain Barré syndrome - Kawasaki disease (in conjunction with acetylsalicylic acid; see 4.2) - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) - Multifocal motor neuropathy (MMN)

HOS-094724 · has-interaction-information · PDF-Seite 9

Live attenuated virus vaccines Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this medicinal product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore, patients receiving measles vaccine should have their antibody status checked. Loop diuretics Avoidance of concomitant use of loop diuretics Paediatric population It is expected that the same interactions than those mentioned for the adults may be presented by the paediatric population. -9-

HOS-094730 · has-interaction-information · PDF-Seite 24

Live attenuated virus vaccines Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this medicinal product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore patients receiving measles vaccine should have their antibody status checked. Loop diuretics Avoidance of concomitant use of loop diuretics Paediatric population It is expected that the same interactions than those mentioned for the adults may be presented by the paediatric population.

HOS-094725 · has-pregnancy-information · PDF-Seite 10

Pregnancy The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women. IVIg products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are expected. Breast-feeding The safety of this medicinal product for use in breast-feeding mothers has not been established in controlled clinical trials and therefore should only be given with caution to breast-feeding mothers. Immunoglobulins are excreted into human milk. No negative effects on the breastfed newborns/infants are anticipated. Fertility Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.

HOS-094731 · has-pregnancy-information · PDF-Seite 24

Pregnancy The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women. IVIg products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are expected. Breast-feeding The safety of this medicinal product for use in breast-feeding mothers has not been established in controlled clinical trials and therefore should only be given with caution to breast-feeding mothers. Immunoglobulins are excreted into human milk. No negative effects on the breastfed newborns/infants are anticipated. Fertility Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.

HOS-094729 · has-warning-information · PDF-Seite 20

Sorbitol Patients with rare hereditary fructose intolerance (HFI) must not be given this medicine unless strictly necessary. Babies and young children (below 2 years of age) may not yet be diagnosed with hereditary fructose intolerance (HFI). Medicines (containing sorbitol/fructose) given intravenously may be life-threatening and should be contraindicated in this population unless there is an overwhelming clinical need and no alternatives are available. - 20 - A detailed history with regard to HFI symptoms has to be taken of each patient prior to being given this medicinal product. 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. Precautions for use Potential complications can often be avoided by ensuring that patients: - are not sensitive to human normal immunoglobulin by initially administering the product slowly (at an initial rate of 0.01 ml/kg/min) - are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative IVIg product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion in a controlled healthcare setting in order to detect potential adverse signs and to ensure that emergency treatment can be administered immediately should problems occur. All other patients should be observed for at least 20 minutes after administration In all patients, IVIg administration requires: - adequate hydration prior to the initiation of the IVIg infusion - monitoring of urine output - monitoring of serum creatinine levels - avoidance of concomitant use of loop diuretics (see 4.5) In case of adverse reaction, either infusion the rate must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the adverse reaction. Infusion-related reaction Certain adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension) may be related to the rate of infusion. The recommended infusion rate given under section 4.2 must be closely followed. Patients must be closely monitored and carefully observed for any symptoms t

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HOS-094723 · has-warning-information · PDF-Seite 6

Sorbitol Patients with rare hereditary fructose intolerance (HFI) must not be given this medicine unless strictly necessary. Babies and young children (below 2 years of age) may not yet be diagnosed with hereditary fructose intolerance (HFI). Medicines (containing sorbitol/fructose) given intravenously may be life-threatening and should be contraindicated in this population unless there is an overwhelming clinical need and no alternatives are available. A detailed history with regard to HFI symptoms has to be taken of each patient prior to being given this medicinal product. 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. -6- Precautions for use Potential complications can often be avoided by ensuring that patients: - are not sensitive to human normal immunoglobulin by initially administering the product slowly (at an initial rate of 0.01 - 0.02 ml/kg/min) - are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative IVIg product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion in a controlled healthcare setting in order to detect potential adverse signs and to ensure that emergency treatment can be administered immediately should problems occur. All other patients should be observed for at least 20 minutes after administration In all patients, IVIg administration requires: - adequate hydration prior to the initiation of the IVIg infusion - monitoring of urine output - monitoring of serum creatinine levels - avoidance of concomitant use of loop diuretics (see 4.5) In case of adverse reaction, either the infusion rate must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the adverse reaction. Infusion-related reaction Certain adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension) may be related to the rate of infusion. The recommended infusion rate given under section 4.2 must be closely followed. Patients must be closely monitored and carefully observed for any symp

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