Ondexxya

Restricted to hospital use only. Posology Andexanet alfa is administered as an intravenous bolus at a target rate of approximately 30 mg/min over 15 minutes (low dose) or 30 minutes (high dose), followed by administration of a continuous infusion of 4 mg/min (low dose) or 8 mg/min (high dose) for 120 minutes (see Table 1).

2). 3 Table 1: Dosing regimens Initial intravenous bolus Continuous intravenous infusion Total number of 200 mg vials needed Low dose 400 mg at a target rate of 30 mg/min 4 mg/min for 120 minutes (480 mg) 5 High dose 800 mg at a target rate of 30 mg/min 8 mg/min for 120 minutes (960 mg) 9 Reversal of apixaban The recommended dose regimen of Ondexxya is based on the dose of apixaban the patient is taking at the time of anticoagulation reversal, as well as on the time since the patient’s last dose of apixaban (see Table 2).

If the strength of the last dose of anticoagulant or the interval between the last dosage and the bleeding episode are unknown, no dose recommendation is available. Measurement of baseline anti-FXa-level should support the clinical decision of starting treatment (if level is available in an acceptable timely frame).

Table 2:

Summary of dosing for reversal of apixaban FXa inhibitor Last dose Timing of last dose before Ondexxya initiation < 8 hours ≥ 8 hours Apixaban ≤ 5 mg Low dose Low dose > 5 mg High dose Reversal of rivaroxaban The recommended dose regimen of Ondexxya is based on the dose of rivaroxaban the patient is taking at the time of anticoagulation reversal, as well as on the time since the patient’s last dose of rivaroxaban (see Table 3).

If the strength of the last dose of anticoagulant or the interval between the last dosage and the bleeding episode are unknown, no dose recommendation is available. Measurement of baseline anti-FXa-level should support the clinical decision of starting treatment (if level is available in an acceptable timely frame).

Table 3:

Summary of dosing for reversal of rivaroxaban FXa inhibitor Last dose Timing of last dose before Ondexxya initiation < 8 hours ≥ 8 hours Rivaroxaban ≤ 10 mg Low dose Low dose > 10 mg High dose Restarting antithrombotic therapy Following administration of Ondexxya and cessation of a major bleed, re-anticoagulation should be considered to prevent thrombotic events due to the patient’s underlying medical condition.

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. 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 ≥ 1/100 to < 1/10 Uncommon ≥ 1/1 000 to < 1/100 Nervous system disorders Ischaemic strokeb Transient ischaemic attack Cardiac disorders Myocardial infarctionc Cardiac arrest 7 System Organ Class Common ≥ 1/100 to < 1/10 Uncommon ≥ 1/1 000 to < 1/100 Vascular disorders Deep vein thrombosis Embolism arteriald Respiratory, thoracic and mediastinal disorders Pulmonary embolism General disorders and administrative site conditions Pyrexia Injury, poisoning and procedural complications Infusion related reactiona a Reported signs/symptoms (rigors, chills, hypertension, oxygen desaturation, agitation and confusion) were transient and mild to moderate in severity.

g. the preferred terms: cerebrovascular accident, cerebellar stroke and cerebral infarction. g. the preferred term: acute myocardial infarction. g. the preferred terms: iliac artery occlusion, renal infarct and femoral artery embolism. 1).

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. 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. 1). e. e. 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 5 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.

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.

1. Known allergic reaction to hamster proteins.