4.1. Therapeutic indications

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.

4.2. Posology and method of administration

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).

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 could support the clinical decision of starting treatment (if level is available in an acceptable timeframe).

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 could support the clinical decision of starting treatment (if level is available in an acceptable time 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.

Antithrombotic therapy can be re-initiated as soon as medically indicated following treatment if the patient is clinically stable and adequate haemostasis has been achieved. A normal degree of anticoagulation from FXa inhibitors (i.e. apixaban, rivaroxaban) or low molecular weight heparin (i.e. enoxaparin) can be expected after 4 hours following end of infusion of Ondexxya based on PK/PD modelling (see section 5.1). Medical judgement should balance the benefits of anticoagulation with the risks of re-bleeding (see section 4.4).

Special populations

Elderly patients (aged 65 years and over): No dose adjustment is required in elderly patients (see section 5.2).

Renal impairment: The effect of renal impairment on andexanet alfa exposure levels has not been evaluated. Based on the existing data on clearance, no dose adjustment is recommended.

Hepatic impairment: Based on the existing data on clearance of andexanet alfa, no dose adjustment is recommended. The safety and efficacy have not been studied in patients with hepatic impairment (see section 5.2).

Paediatric population: The safety and efficacy of andexanet alfa in children and adolescents have not been established. No data are available.

Method of administration

Intravenous use

After an appropriate number of vials of Ondexxya has been reconstituted, the reconstituted solution (10 mg/mL) without further dilution is transferred to sterile large volume syringes in case a syringe pump is used for administration or to suitable empty intravenous bags comprised of polyolefin (PO) or polyvinyl chloride (PVC) material (see section 6.6). Prior to administration by IV infusion a 0.2 or 0.22 micron inline polyethersulfone (PES) or equivalent low protein-binding filter should be used.

Ondexxya is administered as an IV 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 (low dose) or 8 mg (high dose) per minute for 120 minutes (see Table 1).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any other ingredients listed in section 6.1.

Known allergic reaction to hamster proteins.

4.4. Special warnings and precautions for use

Limitations of use

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.

Thrombotic events

Thrombotic events have been reported following treatment with andexanet alfa. Patients being treated with FXa inhibitor therapy have underlying disease states that predispose them to thrombotic events. Patients with prior history of stroke, myocardial infarction or heart failure may be at higher risk of thrombotic events (see section 4.8). 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 a risk of developing thrombosis. Duration of this effect in subjects with bleeds is not known. Laboratory parameters as anti‑FXa activity, endogenous thrombotic potential (ETP), or markers of thrombosis might not be reliable for guidance. To reduce this risk, resumption of anticoagulant therapy should be considered as soon as medically appropriate after completion of treatment (see section 4.2).

In healthy volunteers, dose-dependent increases in coagulation markers F1+2, TAT, and D-dimer, and dose-dependent decreases in TFPI, after administration of andexanet alfa were observed, but no thromboembolic events were reported. These markers were not measured in patients enrolled in study 14‑505 and 18‑513, but thromboembolic events have been observed (see section 4.8 and 5.1). Monitoring for signs and symptoms of thrombosis is therefore strongly recommended.

Use of andexanet alfa in conjunction with other supportive measures

Andexanet alfa can be used in conjunction with standard haemostatic supportive measures, which should be considered as medically appropriate.

The safety of andexanet alfa has not been evaluated in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood within seven days prior to the bleeding event, as they were excluded from clinical studies. Pro-coagulant factor treatments (e.g. 3- or 4-factor prothrombin complex concentrate (PCC)/activated PCC, recombinant factor VIIa, fresh frozen plasma) and whole blood should be avoided unless absolutely required, due to lack of data in combination with these treatments.

Interaction with heparin

Use of andexanet alfa prior to heparinisation e.g. during surgeries or procedures should be avoided as andexanet alfa causes unresponsiveness to heparin. Use of andexanet alfa as an antidote for heparin or low-molecular weight heparin has not been evaluated and is not recommended (see section 4.5).

Infusion-related reactions

In case of mild or moderate infusion reactions, careful observation may be sufficient. For moderate symptoms, consideration may be given to a brief interruption or slowing of the infusion with resumption of the infusion after symptoms subside. Diphenhydramine may be administered.

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.

4.5. Interaction with other medicinal products and other forms of interaction

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). Based on PK/PD modelling, the anticoagulant activity of low molecular weight heparin may be affected up to 4 hours following end of infusion with andexanet alfa (see section 5.1). Use of andexanet alfa as an antidote for heparin or low-molecular weight heparin has not been evaluated and is not recommended.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

Andexanet alfa has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The safety of andexanet alfa has been evaluated in clinical studies including 417 healthy subjects administered an FXa inhibitor, as well as in the Phase IIIb/IV study 14‑505 (ANNEXA‑4) including 419 patients who had acute major bleeding and were under treatment with an FXa inhibitor (apixaban and rivaroxaban), and in the Phase IV study 18‑513 (ANNEXA‑I) including 262 andexanet alfa‑treated patients presenting with acute intracranial haemorrhage (ICrH) and under treatment with apixaban, rivaroxaban or edoxaban (see section 5.1).

In clinical studies in healthy subjects who were administered a FXa inhibitor and then received andexanet alfa, the frequency of adverse reactions was similar in the andexanet alfa-treated group (16.8%) and in the placebo treated group (12.2%). The most frequently observed adverse reactions 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 ANNEXA‑4, the most commonly reported adverse reactions were pyrexia, deep vein thrombosis, and ischaemic stroke. In ANNEXA‑I, the most commonly reported adverse reactions were pyrexia and ischaemic stroke. The safety profile of andexanet alfa was overall consistent across the studies.

In the healthy subject studies, elevations > 2 x ULN in D‑dimer and prothrombin fragments F1+2 were frequently observed. These elevations were maintained between several hours to a few days following administration, but no thrombotic events were reported.

In patients with major bleedings, thrombosis‑markers have not been investigated since bleeding can interfere with the thrombosis marker results. Thromboses and thromboembolic events have commonly been documented.

Tabulated list of adverse reactions

Table 4 provides the list of adverse reactions from clinical studies in subjects with bleeds 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 subjects with bleeds

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

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

aReported signs/symptoms (rigors, chills, hypertension, oxygen desaturation, agitation and confusion) were transient and mild to moderate in severity.

b Ischaemic strokes includes, e.g. the preferred terms: cerebrovascular accident, cerebellar stroke and cerebral infarction.

c Myocardial infarction includes, e.g. the preferred term: acute myocardial infarction.

d Embolism arterial includes, e.g. the preferred terms: iliac artery occlusion, renal infarct and femoral artery embolism.

Description of selected adverse reactions

Thrombotic events

Study 14‑505 (ANNEXA‑4)

In study 14‑505, 45/419 (11%) patients experienced one or more of the following thromboembolic events: cerebrovascular accident (CVA) (19/45; 42%), deep venous thrombosis (11/45; 24%), myocardial infarction (MI) including acute myocardial infarction and myocardial ischaemia (9/45; 20%), pulmonary embolism (PE) (5/45; 11%), and transient ischaemic attack (TIA) (1/45; 2%). The median time to first thromboembolic event was 10 days. A total of 38% of patients with thromboembolic events (17/45) experienced the thromboembolic event during the first three days. Of the 419 subjects who received andexanet alfa, 266 received at least one anticoagulation dose within 30 days after treatment as a prophylactic measure. Of these 266 subjects, 14 subjects (5%) had a thrombotic event after resumption of anticoagulation; while of the 153 subjects who did not receive anticoagulation as a prophylactic, 31 (20.3%) had a thrombotic event (see section 4.4).

Study 18‑513 (ANNEXA‑I)

In the ANNEXA‑I study, adjudicated thrombotic events through 30 days post‑randomisation were reported in 27 patients (10.3%) in the andexanet alfa group and 15 patients (5.7%) in the usual care group. The difference in rate of thrombotic events between the treatment groups across the pre‑defined patient subgroups was generally consistent with the overall population.

When considering underlying disease history, patients in the andexanet alfa group with a prior history of stroke or myocardial infarction, or history of heart failure, were found to have a numerically higher rate of thrombotic events, compared with patients without a history of these underlying diseases. Of the 78 patients who had a prior history of stroke or myocardial infarction, 10 patients (12.8%) had a thrombotic event, compared with 17 of 184 patients (9.2%) without this medical history. In the 46 patients who had a history of heart failure, 8 patients (17.4%) had a thrombotic event, compared with 19 of 216 patients (8.8%) without this medical history (see section 4.4).

Patients in the andexanet alfa group and usual care group experienced one or more of the following adjudicated thrombotic events, respectively: ischaemic stroke (6.5% versus 1.5%), myocardial infarction (4.2% versus 1.5%), pulmonary embolism (0.4% versus 2.3%), arterial systemic embolism (1.1% versus 0.8%) and deep vein thrombosis (0.4% versus 0.8%). The median time to thrombotic event was 3 and 14 days in the andexanet alfa and usual care group, respectively. In the andexanet alfa group, 14 patients had a thrombotic event during the first 3 days, compared with 1 patient in the usual care group. None of these patients had received any dose of anticoagulant prior to the thrombotic event. Adjudicated thrombotic events leading to death were reported in 6 patients (2.3%) in the andexanet alfa group and 2 patients (0.8%) in the usual care group.

Overall, 199 patients (76.0%) in the andexanet alfa group and 192 patients (72.5%) in the usual care group were restarted with any anticoagulant within 30 days post randomisation. Of those, 183 patients (92.0%) in the andexanet alfa group and 187 patients (97.4%) in the usual care group received at least one dose of any anticoagulant as a prophylactic measure. In this population, a similar rate of thrombotic events (4.9% and 4.8%) was observed in the andexanet alfa and usual care group, respectively. In the 79 patients in the andexanet alfa group who did not receive any anticoagulation as a prophylactic measure, 18 patients (22.8%) had a thrombotic event, compared with 6 of 78 patients (7.7%) in the usual care group (see section 4.4).

Infusion related reactions

Based on data from 419 patients from the Phase IIIb/IV study 14‑505 (ANNEXA‑4) treated with apixaban and rivaroxaban and experiencing an acute major bleeding episode, two patients (0.5%) experienced an infusion-related reaction neither of which was assessed as severe (1 moderate; 1 mild). In study 18‑513 (ANNEXA‑I), no events of infusion related reactions were reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no clinical experience with overdose of andexanet alfa. No dose‑limiting toxicities have been observed during clinical studies.