Ondexxya · 4.1 Therapeutic indications · 1

HOS-097689 · has-adverse-reaction-information · PDF-Seite 6

Summary of the safety profile The most frequently observed adverse reactions in healthy volunteers were mild or moderate infusion-related reactions comprising symptoms such as flushing, feeling hot, cough, dysgeusia, and dyspnoea occurring within a few minutes to a few hours of the infusion. Among the healthy subjects studied, women experienced more adverse reactions (mainly infusion-related reactions) than men. In clinical studies including patients with acute major bleeding and who were under treatment with a FXa inhibitor (apixaban or rivaroxaban), the most frequently observed adverse reactions were pyrexia (8.8%), ischaemic stroke (6.7%), and myocardial infarction (4.6%). Tabulated list of adverse reactions Table 4 provides the list of adverse reactions from clinical studies in bleeding patients treated with andexanet alfa. The adverse reactions are classified by system organ class (SOC) and frequency, using 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); or not known (cannot be estimated from available data). Table 4: List of adverse reactions from clinical studies in bleeding patients System Organ Class Common Uncommon ≥ 1/100 to < 1/10 ≥ 1/1 000 to < 1/100 Nervous system disorders Ischaemic strokeb Transient ischaemic attack Cardiac disorders Myocardial infarctionc Cardiac arrest 6  System Organ Class Common Uncommon ≥ 1/100 to < 1/10 ≥ 1/1 000 to < 1/100 Vascular disorders Deep vein thrombosis Embolism arteriald Respiratory, thoracic and Pulmonary embolism mediastinal disorders General disorders and Pyrexia administrative site conditions Injury, poisoning and procedural Infusion related reactiona complications a Reported signs/symptoms (rigors, chills, hypertension, oxygen desaturation, agitation and confusion) were transient and mild to moderate in severity. b Ischaemic stroke includes, e.g. the preferred terms: cerebrovascular accident

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HOS-097685 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any other ingredients listed in section 6.1. Known allergic reaction to hamster proteins.

HOS-097684 · has-indication-information · PDF-Seite 2

For adult patients treated with a direct factor Xa (FXa) inhibitor (apixaban or rivaroxaban) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

HOS-097687 · has-interaction-information · PDF-Seite 6

No interaction studies with andexanet alfa have been performed. In vitro data suggest interaction of andexanet alfa with the heparin-anti-thrombin III (ATIII) complex and neutralisation of the anticoagulant effect of heparin. Off-label use of andexanet alfa pre-surgery, intra-operatively, or during procedures requiring heparinisation has been reported to cause unresponsiveness to heparin (see section 4.4). Use of andexanet alfa as an antidote for heparin or low-molecular weight heparin has not been evaluated and is not recommended.

HOS-097688 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no data from the use of andexanet alfa in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Andexanet alfa is not recommended during pregnancy or in women of childbearing potential not using contraception. Breast-feeding It is unknown whether andexanet alfa is excreted in human milk. A risk to newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with andexanet alfa. Fertility There are no data on the effects of andexanet alfa on human fertility.

HOS-097686 · has-warning-information · PDF-Seite 4

Limitations of use Clinical efficacy is based upon reversal of anti-FXa-activity in healthy volunteers and achievement of haemostatic efficacy in bleeding patients dosed with apixaban or rivaroxaban. Clinical benefit in terms of reduced morbidity or mortality has not been demonstrated (see section 5.1). Andexanet alfa is not suitable for pre-treatment of urgent surgery. Use for edoxaban or enoxaparin-reversal is not recommended due to lack of data. Andexanet alfa will not reverse the effects of non-FXa inhibitors (see section 5.1). Treatment monitoring should be based mainly on clinical parameters indicative of appropriate response (i.e. achievement of haemostasis), lack of efficacy (i.e. re-bleeding), and adverse events (i.e. thromboembolic events). Treatment monitoring of andexanet alfa should not be based on anti-FXa-activity. Commercial anti-FXa-activity assays are unsuitable for measuring anti-FXa activity following administration of andexanet alfa as these assays result in erroneously elevated anti-FXa activity levels, thereby causing a substantial underestimation of the reversal activity of andexanet alfa. Dosage recommendation is based upon data-modelling in healthy volunteers. Data from bleeding 4 patients are limited and validation has not been successful, yet. Data suggest higher risk of thrombosis for patients receiving the higher dose of andexanet alfa and patients on rivaroxaban. In clinical studies, intracranial haemorrhage (ICrH) patients (GCS > 7 and haematoma volume ≤ 60 mL) have been included. Treatment of patients with more severe ICrH with andexanet alfa has not been studied. Thrombotic events Serious arterial and venous thromboembolic events have been reported following treatment with andexanet alfa, including frequent reports of early manifestation (within 72 hours) after reversal. Patients with prior history of stroke, myocardial infarction or heart failure may be at higher risk of thrombotic events (see section 4.8 and 5.1). Patients being treated with FXa inhibitor therapy have underlying disease states that predispose them to thrombotic events. Reversing FXa inhibitor therapy exposes patients to the thrombotic risk of their underlying disease. In addition, independent pro-coagulant effect of andexanet alfa, mediated by inhibition of tissue factor pathway inhibitor (TFPI), has been demonstrated, which may pose an additional risk of developing thrombosis. The duration of this

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