Jivi · 4.1 Therapeutic indications · 1

HOS-097557 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed and may in some cases progress to severe anaphylaxis (including shock). Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with Jivi (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 specialized haemophilia centre be contacted. The most frequently reported adverse reactions in clinical studies in PTPs were headache, cough and pyrexia. 8 Tabulated list of adverse reactions A total of 256 patients constituted the safety population from 4 pivotal Phase I and III studies (one phase I study and 3 phase III studies), 148 adolescents/adults and 108 paediatric patients < 12 years. The median number of exposure days to Jivi per patient was 195 (min-max: 1-698) for all patients in the clinical studies. Overall, in all studies 75 patients, 39 of them below 12 years of age, were observed for a treatment duration of more than 5 years. See section 5.1 for additional details on the clinical studies. 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 2: Frequency of adverse drug reactions in clinical studies MedDRA Standard Adverse reactions Frequency System Organ Class Blood and lymphatic system disorders FVIII inhibition uncommon (PTPs)a very common (PUPs)a Immune system disorders Hypersensitivity common Psychiatric disorders Insomnia common Nerv

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HOS-097553 · has-contraindication-information · PDF-Seite 6

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

HOS-097552 · has-indication-information · PDF-Seite 3

Treatment and prophylaxis of bleeding in patients ≥ 7 years of age with haemophilia A (congenital factor VIII deficiency).

HOS-097555 · has-interaction-information · PDF-Seite 8

Interactions of human coagulation factor VIII (rDNA) products with other medicinal products have not been reported.

HOS-097556 · has-pregnancy-information · PDF-Seite 8

Pregnancy and breast-feeding 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 breast-feeding only if clearly indicated. Fertility In the repeat dose systemic toxicity studies in rats and rabbits with Jivi, treatment related effects on male reproductive organs were not seen (see section 5.3). The effect on fertility in humans is unknown.

HOS-097554 · 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. Hypersensitivity Allergic type hypersensitivity reactions are possible with Jivi. The medicinal product may contain traces of mouse and hamster proteins. Hypersensitivity reactions could also be related to antibodies against PEG (see paragraph Immune response to polyethylene glycol (PEG)). If symptoms of hypersensitivity occur, patients should be advised to discontinue the use of the medicinal product immediately and contact their physician. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. Symptomatic treatment for hypersensitivity should be instituted as appropriate. In case of anaphylaxis or shock, the current medical standards for treatment 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 Bethesda 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 (ED) but continues throughout life although the risk is uncommon. Rarely, inhibitors may develop after the first 50 exposure days. 6 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

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