Advate · 4.5 Interaction with other medicinal products and other forms of interaction · 2

HOS-093682 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock). Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions may be observed. Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with ADVATE (see section 5.1). If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. 6 Tabulated summary of adverse reactions Table 2 provides the frequency of adverse reactions in clinical trials and from spontaneous reporting, according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequency has 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. Table 2. Frequency of adverse reactions in clinical trials and from spontaneous reports MedDRA Standard System Organ Class Adverse reaction Frequencya Infections and infestations Influenza Uncommon Laryngitis Uncommon Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)b Very common (PUPs)b Lymphangitis Uncommon Immune syste

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HOS-093688 · has-adverse-reaction-information · PDF-Seite 19

Summary of the safety profile Clinical studies with ADVATE included 418 subjects with at least one exposure to ADVATE reporting in total 93 adverse drug reactions (ADRs). The ADRs that occurred in the highest frequency were development of neutralising antibodies to factor VIII (inhibitors), headache and fever. Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the infusion site, chills, flushing, generalised urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely and may in some cases progress to severe anaphylaxis (including shock). Development of antibodies to mouse and/or hamster protein with related hypersensitivity reactions may be observed. Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with ADVATE (see section 5.1). If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. 19 Tabulated summary of adverse reactions Table 2 provides the frequency of adverse reactions in clinical trials and from spontaneous reporting, according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequency has 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. Table 2. Frequency of adverse reactions in clinical trials and from spontaneous reports MedDRA Standard System Organ Class Adverse reaction Frequencya Infections and infestations Influenza Uncommon Laryngitis Uncommon Blood and lymphatic system disorders Factor VIII inhibition Uncommon (PTPs)b Very common (PUPs)b Lymphangitis Uncommon Immune

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HOS-093678 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Known allergic reaction to mouse or hamster protein.

HOS-093684 · has-contraindication-information · PDF-Seite 18

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Known allergic reaction to mouse or hamster protein.

HOS-093683 · has-indication-information · PDF-Seite 16

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). ADVATE is indicated in all age groups.

HOS-093677 · has-indication-information · PDF-Seite 3

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). ADVATE is indicated in all age groups.

HOS-093680 · has-interaction-information · PDF-Seite 6

No interactions of human coagulation factor VIII (rDNA) products with other medicinal products have been reported.

HOS-093686 · has-interaction-information · PDF-Seite 19

No interactions of human coagulation factor VIII (rDNA) products with other medicinal products have been reported.

HOS-093681 · has-pregnancy-information · PDF-Seite 6

Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and lactation only if clearly indicated.

HOS-093687 · has-pregnancy-information · PDF-Seite 19

Animal reproduction studies have not been conducted with factor VIII. Based on the rare occurrence of haemophilia A in women, experience regarding the use of factor VIII during pregnancy and breast-feeding is not available. Therefore, factor VIII should be used during pregnancy and lactation only if clearly indicated.

HOS-093685 · has-warning-information · PDF-Seite 18

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. Hypersensitivity Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. In case of shock, standard medical treatment for shock should be implemented. Due to the decrease in injection volume for ADVATE reconstituted in 2 ml sterilised water for injections, if hypersensitivity reactions occur there is less time to react by stopping the injection. Therefore, caution is advised during injection of ADVATE reconstituted in 2 ml sterilised water for injections, especially in children. Inhibitors The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 50 exposure days but continues throughout life although the risk is uncommon. The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre posing less of a risk of insufficient clinical response than high titre inhibitors. In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VI

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HOS-093679 · has-warning-information · PDF-Seite 5

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. Hypersensitivity Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with ADVATE. The product contains traces of mouse and hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. In case of shock, standard medical treatment for shock should be implemented. Inhibitors The formation of neutralising antibodies (inhibitors) to factor VIII is a known complication in the management of individuals with haemophilia A. These inhibitors are usually IgG immunoglobulins directed against the factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per ml of plasma using the modified assay. The risk of developing inhibitors is correlated to the severity of the disease as well as the exposure to factor VIII, this risk being highest within the first 50 exposure days but continues throughout life although the risk is uncommon. The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre posing less of a risk of insufficient clinical response than high titre inhibitors. In general, all patients treated with coagulation factor VIII products should be carefully monitored for the development of inhibitors by appropriate clinical observations and laboratory tests. If the expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with an appropriate dose, testing for factor VIII inhibitor presence should be performed. In patients with high levels of inhibitor, factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of haemophilia and factor VIII inhibitors. Cardiovascular events In patients with existing cardiovascular risk factors, substitution therapy with factor VIII may increase the cardiovascular risk. 5 Catheter-related complications If a central venous access device (CVAD) is required, risk of CVAD-related

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