Alhemo · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-288799 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The overall safety profile of concizumab is based on data from clinical trials. The most serious adverse reactions in the clinical trials with concizumab were thromboembolic events (0.9%) and hypersensitivity (0.3%). Tabulated list of adverse reactions The following adverse reactions are based on data from post-marketing surveillance and pooled data from the clinical trials NN7415-4159 (phase 1b), NN7415-4310 (phase 2), NN7415-4255 (phase 2), NN7415-4311 (phase 3) and NN7415-4307 (phase 3), in which a total of 320 male patients with haemophilia A with and without inhibitors and haemophilia B with and without inhibitors received at least one dose of concizumab as routine prophylaxis. The patients were exposed for a total of 475 exposure years in clinical trials. Table 2 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). Table 2 Adverse reactions from pooled clinical trials with concizumab System Organ Class Adverse reaction Frequency Immune system disorders Hypersensitivity Common Vascular disorders Thromboembolic events Uncommon General disorders and Injection site reactions Very common administration site disorders Description of selected adverse reactions Injection site reactions Injection site reactions were reported across the multiple dose clinical trials. The most frequently reported symptoms were injection site erythema (5.9%), injection site bruising (4.4%) and injection site haematoma (4.1%). The majority were reported as mild. Paediatric population 78 of the clinical trial participants were adolescents (≥ 12 to < 18 years). The safety profile was similar between adolescent and adult patients and as expected for the age group. The safety and efficacy of concizumab in children aged below 12 years have not yet been established. No data are available. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the be

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HOS-288795 · has-contraindication-information · PDF-Seite 7

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 7

HOS-288794 · has-indication-information · PDF-Seite 3

Alhemo is indicated for routine prophylaxis of bleeding in patients 12 years of age or more with: • haemophilia A (congenital factor VIII deficiency) with FVIII inhibitors. • severe haemophilia A (congenital factor VIII deficiency, FVIII < 1%) without FVIII inhibitors. • haemophilia B (congenital factor IX deficiency) with FIX inhibitors. • moderate/severe haemophilia B (congenital factor IX deficiency, FIX ≤ 2%) without FIX inhibitors.

HOS-288797 · has-interaction-information · PDF-Seite 9

No drug-drug interaction clinical trials have been conducted. A drug-drug interaction toxicity study with rFVIIa in concizumab treated cynomolgus monkeys was conducted. No sign of thrombosis or other adverse findings were observed in normo-coagulant monkeys when adding three consecutive doses of up to 1 mg/kg rFVIIa on top of concizumab at steady state, see section 5.3. In vitro and ex vivo drug-drug interaction studies were performed with rFVIIa, aPCC, rFVIII or rFIX in blood from haemophilia patients who are on prophylactic treatment with concizumab. These studies did not suggest clinically relevant drug-drug interactions. Additive and sometimes synergistic increase in thrombin peak as quantified in the thrombin generation assay has been observed in plasma from haemophilia patients who were on prophylactic treatment with concizumab with concomitant presence of rFVIII, rFIX or bypassing agents including rFVIIa and aPCC. Depending on concentrations of concizumab and haemostatic agents, the impact on thrombin peak ranged from being additive with all haemostatic agents to an extra 40% effect with rFVIIa, an extra 33% effect with aPCC, an extra 22% with rFVIII and less than 13% with rFIX. Adding concizumab to plasma containing a sequence-identical analogue (SIA) of emicizumab resulted in an 33% synergistic effect, without reinforcing the known positive interaction between emicizumab- SIA and aPCC, or the negative interaction between emicizumab-SIA and rFVIII. Drug interaction between concizumab and rFVIIa persisted when combined with emicizumab-SIA. For guidance on the use of bypassing agents for treatment of breakthrough bleeding episodes in patients receiving concizumab prophylaxis, see section 4.2.

HOS-288798 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential/contraception in males and females Women of childbearing potential receiving concizumab should use highly effective contraception during treatment with concizumab and until 7 weeks after end of treatment. The benefits and thromboembolic risks of the type of contraceptives used should be evaluated by the treating physician. Pregnancy There are no available data on concizumab use in pregnant women. Animal reproduction studies have not been conducted with concizumab. It is not known whether concizumab can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Concizumab should only be used during pregnancy if the potential benefit for the mother outweighs the potential risk to the foetus. Breast-feeding It is unknown whether concizumab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. Afterwards, concizumab could be used during breast-feeding if clinically needed. Fertility Animal studies do not indicate direct or indirect harmful effects with respect to fertility, see section 5.3. No fertility data are available in humans. Thus, the effect of concizumab on male and female fertility is unknown.

HOS-288796 · has-warning-information · PDF-Seite 8

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 reactions Allergic type hypersensitivity reactions have occurred with concizumab within the initial weeks of treatment, including hospitalisation and permanent discontinuation of therapy. Patients should be informed of the signs of acute hypersensitivity reactions. If symptoms of hypersensitivity occur, the patient should be advised to discontinue the use of Alhemo and contact the physician who should ensure appropriate treatment. Immunogenicity Development of neutralising anti-concizumab antibodies, observed in some patients, has not led to loss of efficacy (see section 5.1). However, patients with clinical signs of loss of efficacy (e.g. increase in breakthrough bleeding events) should be evaluated to assess the etiology and other therapeutic options should be considered if neutralising anti-concizumab antibodies are suspected. Thromboembolic events Cases of non-fatal arterial and venous thromboembolic events have been reported in the concizumab clinical trials. These cases occurred in patients with multiple risk factors including high or frequent doses of breakthrough bleed treatment (see section 4.8). Patients treated with concizumab should be informed of and monitored for the occurrence of signs and symptoms of thromboembolic events. In case of suspicion of thromboembolic events, concizumab should be discontinued, and further investigations and appropriate medical treatment should be initiated. There should be careful consideration whether the potential benefit of concizumab treatment outweighs the potential risk in patients considered at high risk of thromboembolic events. This consideration should be re-evaluated periodically. In conditions in which tissue factor is overexpressed (e.g., advanced atherosclerotic disease, crush injury, cancer or septicaemia), there may be a risk of thromboembolic events or disseminated intravascular coagulation (DIC). In these situations, the potential benefit of treatment with concizumab should be weighed against the risk of these complications. Effects of concizumab on coagulation tests Concizumab therapy does not produce clinically meaningful changes in standard measures of coagulation including activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT). Excipients This medicinal product contains less than

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