Hemlibra · 4.1 Therapeutic indications · 1

HOS-098215 · has-adverse-reaction-information · PDF-Seite 10

Summary of the safety profile The overall safety profile of Hemlibra is based on data from clinical studies and post-marketing surveillance. The most serious adverse drug reactions (ADRs) reported from the clinical studies with Hemlibra were thrombotic microangiopathy (TMA) and thrombotic events, including cavernous sinus thrombosis (CST) and superficial vein thrombosis contemporaneous with skin necrosis (see below and section 4.4). The most common ADRs reported in ≥ 10% of patients treated with at least one dose of Hemlibra were: injection site reactions (19.4 %), arthralgia (14.2 %) and headache (14.0 %). In total three patients (0.7 %) in the clinical studies receiving Hemlibra prophylaxis withdrew from treatment due to ADRs, which were TMA, skin necrosis contemporaneous with superficial thrombophlebitis, and headache. Tabulated list of adverse drug reactions The following adverse drug reactions (ADRs) are based on data from post-marketing surveillance and pooled data from five phase III clinical studies (adult and adolescent studies [BH29884 - HAVEN 1, BH30071 – HAVEN 3, and BO39182 – HAVEN 4], an all-age group study [BO41423 – HAVEN 6], and a paediatric study [BH29992 - HAVEN 2]), in which a total of 444 patients with haemophilia A received at least one dose of Hemlibra as routine prophylaxis (see section 5.1). Three hundred and seven (69.1 %) of the clinical study participants were adults (of which two were female), 61 (13.7 %) were adolescents (≥ 12 to < 18 years), 71 (16.0 %) were children (≥ 2 to < 12 years) and five (1.1 %) were infants and toddlers (1 month to < 2 years). The median duration of exposure across the studies was 32 weeks (range: 0.1 to 94.3 weeks). ADRs from the phase III clinical studies and post-marketing surveillance are listed by MedDRA system organ class (Table 2). The corresponding frequency categories for each ADR are based on 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) and not known (cannot be estimated from the available data). 10 Table 2 Summary of adverse drug reactions from pooled HAVEN clinical studies and post- marketing surveillance with Hemlibra System Organ Class (SOC) Adverse reactions Frequency (preferred term, MedDRA) Blood and lymphat

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HOS-098211 · has-contraindication-information · PDF-Seite 6

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

HOS-098210 · has-indication-information · PDF-Seite 2

Hemlibra is indicated for routine prophylaxis of bleeding episodes in patients with haemophilia A (congenital factor VIII deficiency): ● with factor VIII inhibitors ● without factor VIII inhibitors who have: - severe disease (FVIII < 1%) - moderate disease (FVIII ≥ 1% and ≤ 5%) with severe bleeding phenotype. Hemlibra can be used in all age groups. 2

HOS-098213 · has-interaction-information · PDF-Seite 9

No adequate or well-controlled interaction studies have been conducted with emicizumab. Clinical experience indicates a medicinal product interaction exists with emicizumab and aPCC (see sections 4.4 and 4.8). There is a possibility for hypercoagulability with rFVIIa or FVIII with emicizumab based on preclinical experiments. Emicizumab increases coagulation potential, therefore the rFVIIa or FVIII dose required to achieve haemostasis may be lower than when used without Hemlibra prophylaxis. In case of thrombotic complication, the physician should consider discontinuing rFVIIa or FVIII and interrupt Hemlibra prophylaxis as clinically indicated. Further management should be tailored to the individual clinical circumstances. ● Decision about dose modifications should take into account the half-life of medicinal products; specifically, interruption of emicizumab may not have an immediate effect. ● Monitoring using a FVIII chromogenic assay may guide the administration of coagulation factors, and testing for thrombophilic traits may be considered. Experience with concomitant administration of anti-fibrinolytics with aPCC or rFVIIa in patients receiving Hemlibra prophylaxis is limited. However, the possibility of thrombotic events should be considered when systemic anti-fibrinolytics are used in combination with aPCC or rFVIIa in patients receiving emicizumab.

HOS-098214 · has-pregnancy-information · PDF-Seite 9

Women of childbearing potential/Contraception Women of childbearing potential receiving Hemlibra should use effective contraception during, and for at least 6 months after cessation of Hemlibra treatment (see section 5.2). Pregnancy There are no clinical studies of emicizumab use in pregnant women. Animal reproduction studies have not been conducted with Hemlibra. It is not known whether emicizumab can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Hemlibra should be used during pregnancy only if the potential benefit for the mother outweighs the potential risk to the fetus taking into account that, during pregnancy and after parturition, the risk for thrombosis is increased and that several pregnancy complications are linked to an increased risk for disseminated intravascular coagulation (DIC). Breast-feeding It is not known whether emicizumab is excreted in human milk. No studies have been conducted to assess the impact of emicizumab on milk production or its presence in breast milk. Human IgG is known to be present in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Hemlibra therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). No fertility data are available in humans. Thus, the effect of emicizumab on male and female fertility is unknown. 9

HOS-098212 · 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. Thrombotic microangiopathy associated with Hemlibra and aPCC Cases of thrombotic microangiopathy (TMA) were reported from a clinical study in patients receiving Hemlibra prophylaxis when on average a cumulative amount of >100U/kg/24 hours of aPCC for 24 hours or more was administered (see section 4.8). Treatment for the TMA events included supportive care with or without plasmapheresis and haemodialysis. Evidence of improvement was seen within one week following discontinuation of aPCC and interruption of Hemlibra. This rapid improvement is distinct from the usual clinical course observed in atypical hemolytic uremic syndrome and classic TMAs, such as thrombotic thrombocytopenic purpura (see section 4.8). One patient resumed Hemlibra following resolution of TMA and continued to be treated safely. Patients receiving Hemlibra prophylaxis should be monitored for the development of TMA when administering aPCC. The physician should immediately discontinue aPCC and interrupt Hemlibra therapy if clinical symptoms and/or laboratory findings consistent with TMA occur, and manage as clinically indicated. Physicians and patients/caregivers should weigh the benefits and risks of resuming Hemlibra prophylaxis following complete resolution of TMA on a case-by-case basis. In case a bypassing agent is indicated in a patient receiving Hemlibra prophylaxis, see below for dosing guidance on the use of bypassing agents. Caution should be used when treating patients who are at high risk for TMA (e.g. have a previous medical history or family history of TMA), or those who are receiving concomitant medicinal products known to be a risk factor for the development of TMA (e.g. ciclosporin, quinine, tacrolimus). Thromboembolism associated with Hemlibra and aPCC Serious thrombotic events were reported from a clinical study in patients receiving Hemlibra prophylaxis when on average a cumulative amount of >100U/kg/24 hours of aPCC for 24 hours or more was administered (see section 4.8). No cases required anticoagulation therapy. Following discontinuation of aPCC and interruption of Hemlibra, evidence of improvement or resolution was seen within one month (see section 4.8). One patient resumed Hemlibra following resolution of thrombotic event and continued to be treated safely.

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