ReFacto AF · 4.4 Special warnings and special precautions for use · 1

HOS-083898 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile 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 infrequently for ReFacto, and may in some cases progress to severe anaphylaxis including shock (see section 4.4). Trace amounts of hamster protein may be present in ReFacto AF. Very rarely, development of antibodies to hamster protein has been observed, but there were no clinical sequelae. In a study of ReFacto, twenty of 113 (18%) previously treated patients (PTPs) had an increase in anti-CHO antibody titre, without any apparent clinical effect. 7 Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with ReFacto AF. If such inhibitors occur, the condition may manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted. Tabulated list of adverse reactions 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) and uncommon (≥ 1/1,000 to < 1/100). The table lists adverse reactions reported in the clinical trials with ReFacto or ReFacto AF. The frequencies are based on all causality treatment emergent adverse events in pooled clinical trials with 765 subjects. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. System Organ Class Very common Common Uncommon ≥ 1/10 ≥ 1/100 ≥ 1/1,000 to to < 1/10 < 1/100 Blood and lymphatic FVIII inhibition FVIII inhibition system disorders (PUPs)* (PTPs)* Immune system Anaphylactic reaction disorders Metabolism and Decreased appetite nutrition disorders Nervous system Headach

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HOS-083894 · has-contraindication-information · PDF-Seite 6

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

HOS-083893 · has-indication-information · PDF-Seite 3

Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital factor VIII deficiency). ReFacto AF is appropriate for use in adults and children of all ages, including newborns. ReFacto AF does not contain von Willebrand factor, and hence is not indicated in von Willebrand’s disease.

HOS-083896 · has-interaction-information · PDF-Seite 7

No interactions of recombinant coagulation factor VIII products with other medicinal products have been reported.

HOS-083897 · has-pregnancy-information · PDF-Seite 7

Animal reproduction studies have not been conducted with factor VIII, therefore no data are available on fertility. Because of 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 breast-feeding only if clearly indicated.

HOS-083895 · has-warning-information · PDF-Seite 6

Traceability In order to improve traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Patients can affix one of the peel-off labels found on the vial or pre-filled syringe to document the batch number in their diary or for reporting any side effects. Hypersensitivity Allergic type hypersensitivity reactions have been observed with ReFacto AF. The medicinal product contains traces of hamster proteins. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of the medicinal 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 pro-coagulant 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. 6 Reports of lack of effect Reports of lack of effect, mainly in prophylaxis patients, have been received in

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