Contents of the package leaflet for the medicine ONDEXXYA 200mg powder for solution for infusion

1. NAME OF THE MEDICINAL PRODUCT

Ondexxya 200 mg powder for solution for infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 200 mg of andexanet alfa*.

After reconstitution, each mL of solution contains 10 mg of andexanet alfa.

* Andexanet alfa is produced by recombinant DNA technology in Chinese Hamster Ovary (CHO)cells.

Excipient with known effect

Each vial of Ondexxya contains 2 mg of polysorbate 80.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for solution for infusion

White to off-white lyophilised powder

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

For adult patients treated with a direct factor Xa (FXa) inhibitor (apixaban or rivaroxaban) whenreversal 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/minover 15 minutes (low dose) or 30 minutes (high dose), followed by administration of a continuousinfusion of 4 mg/min (low dose) or 8 mg/min (high dose) for 120 minutes (see Table 1). Posology ofandexanet alfa is based upon PK/PD-modelling and simulation exercises (see sections 5.1 and 5.2).

Table 1: Dosing regimens

Total number of

Continuous intravenous

Initial intravenous bolus 200 mg vialsinfusionneeded400 mg at a target rate of 4 mg/min for 120 minutes

Low dose 530 mg/min (480 mg)800 mg at a target rate of 8 mg/min for 120 minutes

High dose 930 mg/min (960 mg)

Reversal of apixaban

The recommended dose regimen of Ondexxya is based on the dose of apixaban the patient is taking atthe 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 dosageand the bleeding episode are unknown, no dose recommendation is available. Measurement of baselineanti-FXa-level should support the clinical decision of starting treatment (if level is available in anacceptable timely frame).

Table 2: Summary of dosing for reversal of apixaban

Timing of last dose before Ondexxya initiation

FXa inhibitor Last dose< 8 hours ≥ 8 hours≤ 5 mg Low dose

Apixaban Low dose> 5 mg High dose

Reversal of rivaroxaban

The recommended dose regimen of Ondexxya is based on the dose of rivaroxaban the patient istaking at the time of anticoagulation reversal, as well as on the time since the patient’s last dose ofrivaroxaban (see Table 3). If the strength of the last dose of anticoagulant or the interval betweenthe 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

Timing of last dose before Ondexxya initiation

FXa inhibitor Last dose< 8 hours ≥ 8 hours≤ 10 mg Low dose

Rivaroxaban Low dose> 10 mg High dose

Restarting antithrombotic therapy

Following administration of Ondexxya and cessation of a major bleed, re-anticoagulation should beconsidered 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 thepatient is clinically stable and adequate haemostasis has been achieved. The time to when a normaldegree of anticoagulation from antithrombotic therapy can be expected has not yet been established.

Medical judgement should balance the benefits of anticoagulation with the risks of re-bleeding (seesection 4.4).

Special populations

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

Renal impairment: The effect of renal impairment on andexanet alfa exposure levels has not beenevaluated. 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 adjustmentis 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 havenot 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 syringepump is used for administration or to suitable empty intravenous bags comprised of polyolefin (PO) orpolyvinyl chloride (PVC) material (see section 6.6). Prior to administration by IV infusion a 0.2 or0.22 micron in-line 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

Clinical efficacy is based upon reversal of anti-FXa-activity in healthy volunteers and achievement ofhaemostatic efficacy in bleeding patients dosed with apixaban or rivaroxaban. Clinical benefit in termsof reduced morbidity or mortality has not been demonstrated (see section 5.1). Andexanet alfa is notsuitable for pre-treatment of urgent surgery. Use for edoxaban or enoxaparin-reversal is notrecommended 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 appropriateresponse (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 onanti-FXa-activity. Commercial anti-FXa-activity assays are unsuitable for measuring anti-FXaactivity following administration of andexanet alfa as these assays result in erroneously elevatedanti-FXa activity levels, thereby causing a substantial underestimation of the reversal activity ofandexanet alfa.

Dosage recommendation is based upon data-modelling in healthy volunteers. Data from bleedingpatients are limited and validation has not been successful, yet. Data suggest higher risk ofthrombosis 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 hasnot been studied.

Thrombotic events

Serious arterial and venous thromboembolic events have been reported following treatment withandexanet 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 ofthrombotic events (see section 4.8 and 5.1). Patients being treated with FXa inhibitor therapy haveunderlying disease states that predispose them to thrombotic events. Reversing FXa inhibitor therapyexposes patients to the thrombotic risk of their underlying disease. In addition, independentpro-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. Theduration of this effect in bleeding patients is not known. Laboratory parameters as anti-FXa activity,endogenous thrombotic potential (ETP), or markers of thrombosis might not be reliable forguidance. To reduce this risk, resumption of anticoagulant therapy should be considered as soon asmedically appropriate after completion of treatment (see section 4.2).

In healthy volunteers, while no thrombotic events were reported, dose-dependent increases incoagulation markers F1+2, TAT, and D-dimer, and dose-dependent decreases in TFPI, afteradministration of andexanet alfa were observed. These markers were not measured in patients enrolledin studies 14-505 and 18-513, but thromboembolic events have been observed (see sections 4.8and 5.1). Monitoring for signs and symptoms of thrombosis is therefore strongly recommended andshould be started early after treatment.

Use of andexanet alfa in conjunction with other supportive measures

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

The safety of andexanet alfa has not been evaluated in patients who received prothrombin complexconcentrates, recombinant factor VIIa, or whole blood within seven days prior to the bleedingevent, as they were excluded from clinical studies. Pro-coagulant factor treatments (e.g. 3- or4-factor prothrombin complex concentrate (PCC)/activated PCC, recombinant factor VIIa, freshfrozen plasma) and whole blood should be avoided unless absolutely required, due to lack of data incombination with these treatments.

Interaction with heparin

Use of andexanet alfa prior to heparinisation e.g. during surgeries or procedures should be avoided asandexanet alfa causes unresponsiveness to heparin. Use of andexanet alfa as an antidote for heparin orlow-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 moderatesymptoms, consideration may be given to a brief interruption or slowing of the infusion withresumption 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 numberof the administered product should be clearly recorded.

Excipient with known effect

This medicinal product contains 2 mg of polysorbate 80 in each vial. Polysorbates may cause allergicreactions.

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) complexand 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 causeunresponsiveness to heparin (see section 4.4). Use of andexanet alfa as an antidote for heparin orlow-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 insufficientwith respect to reproductive toxicity (see section 5.3). Andexanet alfa is not recommended duringpregnancy 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 cannotbe 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 most frequently observed adverse reactions in healthy volunteers were mild or moderateinfusion-related reactions comprising symptoms such as flushing, feeling hot, cough, dysgeusia, anddyspnoea occurring within a few minutes to a few hours of the infusion. Among the healthy subjectsstudied, 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 werepyrexia (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 withandexanet alfa. The adverse reactions are classified by system organ class (SOC) and frequency, usingthe following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); or not known (cannot be estimatedfrom 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

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 embolismmediastinal disorders

General disorders and Pyrexiaadministrative site conditions

Injury, poisoning and procedural Infusion related reactionacomplicationsa Reported signs/symptoms (rigors, chills, hypertension, oxygen desaturation, agitation and confusion) were transient andmild to moderate in severity.b Ischaemic stroke 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

Arterial and venous thrombotic events including ischaemic stroke, myocardial infarction, pulmonaryembolism, deep vein thrombosis, arterial systemic embolism and transient ischaemic attack have beenobserved in clinical trials, with frequent reports of early manifestation (within 72 hours) followingtreatment with andexanet alfa (see section 4.4 and 5.1).

Reversing FXa inhibitor therapy exposes patients to the thrombotic risk of their underlying disease. Inaddition, anti-FXa-independent procoagulant effects of andexanet alfa may pose an additional risk ofdeveloping thrombosis after treatment.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

4.9 Overdose

There is no clinical experience with overdose of andexanet alfa. No dose-limiting toxicities have beenobserved during clinical studies.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: All other therapeutic products, antidotes. ATC code: V03AB38

Mechanism of action

Andexanet alfa is a recombinant form of human FXa protein that has been modified to lack FXaenzymatic activity. The active site serine was substituted with alanine, rendering the molecule unableto cleave and activate prothrombin, and the gamma-carboxyglutamic acid (Gla) domain was removedto eliminate the ability of the protein to assemble into the prothrombinase complex, thus removing anyanti-coagulant effects.

Andexanet alfa is a specific reversal agent for FXa inhibitors. The mechanism of action includes thebinding and sequestration of the FXa inhibitor. In addition, andexanet alfa has been observed to bindto, and inhibit tissue factor pathway inhibitor (TFPI). Inhibition of TFPI activity can increase tissuefactor-initiated thrombin generation inducing a pro-coagulant effect.

Pharmacodynamic effects

The effects of andexanet alfa can be measured through pharmacodynamic markers, including freefraction of available FXa inhibitor as well as through restoration of thrombin generation. In addition,andexanet alfa has been shown to inhibit TFPI-activity.

Commercial anti-FXa-activity assays are unsuitable for measuring anti-FXa activity followingadministration of andexanet alfa. Due to the reversible binding of andexanet alfa to the FXa inhibitor,the high sample dilution currently used in these assays leads to dissociation of the inhibitor fromandexanet alfa, resulting in detection of erroneously elevated anti-FXa activity levels, thereby causinga substantial underestimation of the reversal activity of andexanet alfa.

In prospective, randomised, placebo-controlled, dose-ranging studies in healthy subjects, the dose anddose regimen of andexanet alfa required to reverse anti-FXa activity and restore thrombin generationfor FXa inhibitors (apixaban or rivaroxaban) were determined with modified assays that are notcommercially available.

The maximal reversal of anti-FXa activity was achieved within two minutes of completing the bolusadministration. Administration of andexanet alfa as a bolus followed by continuous infusion resultedin a sustained decrease in anti-FXa activity. The anti-FXa activity returned to the placebo levels andabove approximately two hours after the end of a bolus or infusion dependent on dosage.

When andexanet alfa was administered as a bolus followed by a continuous infusion, the maximumdecrease in unbound FXa inhibitors was rapid (within two minutes of the end of the bolus) and wassustained over the course of the infusion then gradually increased over time, reaching a maximum atapproximately two hours following the end of infusion.

Restoration of thrombin generation following administration was dose- and dose-regimen-dependentand did not correlate with anti-FXa-activity beyond approximately four hours (see below, “restorationof thrombin generation”).

Plasma TFPI activity has been shown to be inhibited completely from 2 minutes to 14.5 hours afterandexanet alfa bolus-administration in healthy subjects, and returned to baseline within 3 days.

Tissue-factor (TF)-initiated thrombin generation immediately increased above the baseline (prior toanticoagulation) and remained elevated for > 20 hours in contrast to placebo. Plausibility of apro-coagulant effect of TFPI-inhibition is supported by consecutive and sustained slopes of D-Dimers,

TAT, and F1+2.

Immunogenicity

Anti-drug antibodies (ADA) were rarely detected. No evidence of ADA impact on pharmacokinetics,efficacy or safety was observed. However, data are still limited.

Population pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation

PK/PD modelling and simulations rely on the interplay between andexanet alfa and FXa inhibitor PKand on the relationships between biomarkers, here anti FXa-activity, TFPI-activity, and ETP. Thereremain uncertainties regarding the differing effect of the anticoagulant apixaban or rivaroxaban, theduration of the reversal effect dependent on the anti-TFPI-effect, and on the necessity of continuousinfusion. Precision of simulations in bleeding patients is less than that within healthy volunteers due tothe high inter-individual variability.

Clinical efficacy and safety

The efficacy and safety of andexanet alfa have been evaluated in the following: 1) randomised,placebo-controlled, Phase II dose-ranging studies with healthy volunteers administered FXa inhibitorsto establish doses required for reversal; 2) two Phase III studies, one with apixaban and the other withrivaroxaban, to confirm the efficacy of the high and low dose regimens; 3) a global, multicentre,prospectively defined, open-label Phase IIIb/IV study (ANNEXA-4) in patients with an acute majorbleeding episode requiring urgent reversal of FXa anticoagulation; and 4) a randomised, open-label,

Phase IV study (ANNEXA-I) in patients presenting with acute intracranial haemorrhage (ICrH).

Reversal of anticoagulation in healthy subjects aged 50-75 (Studies 14-503 and 14-504)

In a prospective, randomised, placebo-controlled study, healthy subjects with a median age of56.5 years on apixaban 5 mg twice daily received andexanet alfa (n=24) administered as a 400 mg IVbolus immediately followed by a 4 mg per minute IV infusion for 120 minutes (480 mg) or placebo(n=8).

In a similar study, subjects with a median age of 57 years on rivaroxaban 20 mg daily receivedandexanet alfa (n=26) administered as an 800 mg IV bolus immediately followed by an 8 mg perminute IV infusion for 120 minutes (960 mg) or placebo (n=13).

Reduction in anti-FXa activity

The primary endpoint for both Study 14-503 (apixaban) and Study 14-504 (rivaroxaban) was thepercent change in anti-FXa activity from baseline to post-infusion nadir.

Among the apixaban-treated subjects in Study 14-503, the percent change [± standard deviation (SD)]in anti-FXa activity was -92.34% (± 2.809%) for the andexanet alfa group and -32.70% (± 5.578%) forthe placebo group (p < 0.0001), the latter reflecting the intrinsic clearance of the anticoagulant.

Among the rivaroxaban-treated subjects in Study 14-504, the percent change (± SD) in anti-FXaactivity was -96.72% (± 1.838%) for the andexanet alfa group and -44.75% (± 11.749%) for theplacebo group (p < 0.0001), the latter reflecting the intrinsic clearance of the anticoagulant.

The time courses of anti-FXa activity before and after andexanet alfa administration are shown in

Figure 1. Reduction in anti-FXa activity correlates with restoration of thrombin generation. The anti-

FXa activity threshold for normalisation of thrombin generation (defined by mean ETP and standarddeviations) was estimated to be 44.2 ng/mL (within one standard deviation of normal ETP) based onpooled data from Studies 14-503 and 14-504.

Figure 1: Change in anti-FXa activity (ng/mL) in healthy subjects anticoagulated withapixaban (A) and rivaroxaban (B)(A)(B)

Restoration of thrombin generation

In both Study 14-503 and Study 14-504, treatment with andexanet alfa also resulted in a statisticallysignificant increase in thrombin generation in healthy subjects anticoagulated with apixaban orrivaroxaban versus placebo (p < 0.0001). Restoration of thrombin generation to within normal ranges(defined as one standard deviation from baseline levels) within two minutes and maintained for20 hours was achieved with bolus only and bolus plus infusion for low-dose andexanet alfa in subjectson apixaban. For subjects on rivaroxaban, high-dose andexanet alfa (bolus plus infusion) resulted inincreased thrombin generation above two standard deviations. No clinical evaluation for apixaban-treated subjects with high-dose andexanet alfa and no evaluation for rivaroxaban-treated subjects withlow-dose andexanet alfa was performed in these studies.

Change from baseline in free FXa inhibitor concentration at nadir

The mean unbound concentrations of apixaban and rivaroxaban were < 3.5 ng/mL and 4 ng/mL,respectively, after bolus andexanet alfa administration and were maintained throughout the continuousinfusion.

Reversal of FXa inhibitor anticoagulation in patients with acute major bleeding (study 14-505)

In Study 14-505 (ANNEXA-4), a Phase IIIb/IV multinational, prospective, single-arm, open-labelstudy, andexanet alfa was administered to 477 patients on FXa inhibitors, 419 of whom were onapixaban and rivaroxaban, who presented with acute major bleeding. The two co-primary endpointswere: a) percent change in anti-FXa activity from baseline to the nadir between five minutes after theend of the bolus up until the end of the infusion, and; b) rate of good or excellent (compared to poor ornone) haemostatic efficacy within 12 hours after infusion, as rated by an independent endpointadjudication committee.

Approximately half of the patients were male, and the mean age was 77.9 years. Most patients hadpreviously received either apixaban (245/477; 51.4%) or rivaroxaban (174/477; 36.5%), or edoxaban(36/477; 7.5%) or enoxaparin (22/477; 4.6%) and experienced either an intracranial haemorrhage(ICrH) (329/477; 69%) or a gastrointestinal (GI) bleed (109/477; 22.9 %). 381/477 (79.9%) receivedthe low-dose regimen of andexanet alfa, while 96/477 patients (20.1%) received the high-doseregimen, accordingly to section 4.2.

Anti-FXa change from baseline to nadir

Of the 477 enrolled patients, 347 (73%) were evaluable for efficacy as they were dosed with andexanetalfa for a confirmed major bleed and had a baseline anti-FXa activity above 75 ng/mL. For thesepatients, median anti-FXa activity at baseline was 147 ng/mL for patients taking apixaban, and214 ng/mL for patients taking rivaroxaban. For anti-FXa activity, the median (95% CI) decrease frombaseline to nadir in anti-FXa activity for apixaban was −93.3% (−94.2%, −92.5%) and rivaroxabanwas −94.1% (−95.1%; −93.0%).

Haemostatic efficacy

Haemostatic efficacy was rated as good or excellent in 79% of 169 patients taking apixaban and in80% of 127 patients taking rivaroxaban.

Analysis of study 14-505 demonstrated that the change in anti-FXa activity (surrogate) was notpredictive for achievement of haemostatic efficacy.

Anti-TFPI-effect

An immediate and sustained (for about 3 days post infusion) pro-coagulant anti-TFPI-effect wasdocumented in patients with major bleeding - consistent with respective results from studies in healthyvolunteers (14-503, 14-504, 16-508, 19-514).

Deaths

In the safety population (n=419), 75 patients (18%) died. The mortality rates were 19.0% (55/289) inpatients presenting with ICrH, 14.7% (14/95) with GI bleeding, and 17.1% (6/35) with other types ofbleeding. Cardiovascular causes of death (n=36) included: haemorrhagic stroke (n=6), ischaemicstroke (n=10), sudden cardiac death (including unwitnessed) (n=6), cardiomechanical/pump failure(n=4), myocardial infarction (n=2), bleeding other than haemorrhagic stroke (n=2), and othercardiovascular causes (n=6). Non-cardiovascular deaths (n=39) included: infection/sepsis (n=11),respiratory failure (n=6), accident/trauma (n=2), cancer (n=2), and other/non-vascular cause (n=18).

The average time to death was 15 days after treatment. All deaths occurred before Day 44.

Thromboembolic events

In study 14-505, 45/419 (11%) patients experienced one or more of the following thromboembolicevents: 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%). Themedian time to first thromboembolic event was 10 days. A total of 38% of patients withthromboembolic events (17/45) experienced the thromboembolic event during the first three days. Ofthe 419 subjects who received andexanet alfa, 266 received at least one anticoagulation dose within 30days after treatment as a prophylactic measure based on clinical judgment.

Haemostatic efficacy and reversal of FXa activity in patients with ICrH (study 18-513)

Study 18-513 (ANNEXA-I) was a randomised, open-label Phase IV study with blinded adjudicationon primary efficacy and safety endpoints, to determine the efficacy and safety of andexanet alfacompared to usual care in patients presenting with acute intracranial haemorrhage (ICrH) with ahaematoma volume of ≥ 0.5 to ≤ 60 mL, within 6 hours of symptom onset to baseline scan, and within15 hours of taking an oral FXa inhibitor.

The primary endpoint was to evaluate the effect of andexanet alfa versus usual care on the rate ofeffective haemostasis, which was assessed at 12 hours after randomisation and defined as a compositeof ≤ 35% increase in haematoma volume compared to baseline AND a less than 7-point change frombaseline NIHSS score points AND no receipt of rescue therapies within 3 to 12 hours afterrandomisation. The secondary endpoint was percent change from baseline to nadir in anti-FXa activityduring the first 2 hours post-randomisation.

In ANNEXA-I, eligible patients were randomised 1:1 to andexanet alfa or usual care. In total, 530patients were enrolled, of whom 320 (60.4%) had received apixaban and 154 (29.1%) had receivedrivaroxaban. These formed the extended population used for safety and sensitivity analyses. Efficacywas assessed in an interim analysis that included 452 patients (primary efficacy population), of whom275 (60.8%) had received apixaban and 129 (28.5%) had received rivaroxaban. In the extendedpopulation, the median age was 80 years, 52.3% were male, and 93.3% of the patients were white. Themost common indication for FXa inhibitors was atrial fibrillation (84.0%).

Overall, 76.8% and 21.2% of patients in the andexanet alfa group received the low and high doseregimen, respectively. In the usual care group, 87.6% of patients were treated with PCC, 10.3% ofpatients received no haemostatic treatment (platelets or packed red blood cells were allowed) and 0.9%of patients were treated with other therapy.

The most common bleeding location was intracerebral haemorrhage (91.7%), most bleeds werespontaneous (86.9%) and the median (IQR) haematoma volume at baseline was 9.9 (3.6, 24.5) mL.

The median time from symptom onset to treatment was 4.1 hours.

Haemostatic efficacy

In the primary efficacy population, andexanet alfa was statistically superior to usual care in achievingeffective haemostasis at 12 hours in acute ICrH in patients receiving a direct oral FXa inhibitor (67.0%versus 53.1%, difference 13.4% [95% CI 4.6%, 22.2%], p=0.0032).

Anti-FXa change from baseline to nadir

In the primary efficacy population, andexanet alfa was statistically superior to usual care in reducinganti-FXa activity from baseline to nadir during the first 2 hours post-randomisation in acute ICrH inpatients receiving a direct oral FXa inhibitor (−94.4% versus −27.5% median reduction, p < 0.0001).

The median on treatment nadir in anti-FXa activity was 5.1 ng/mL in the andexanet alfa group and80.9 ng/mL in the usual care group. The median (95% CI) reduction from baseline to nadir in anti-FXaactivity was −94.1% (-95.1%, -93.3%) versus −20.8% (-28.4%, -13.9%) for patients who hadpreviously taken apixaban and −96.4% (-97.3%, -94.9%) versus −46.8% (-60.6%, -35.5%) forrivaroxaban, in the andexanet alfa and usual care group, respectively.

Thrombotic events

In the ANNEXA-I study, adjudicated thrombotic events through 30 days post-randomisation werereported in 26 patients (10.9%) in the andexanet alfa group and 13 patients (5.6%) in the usual caregroup.

When considering underlying disease history, patients in the andexanet alfa group with a priorhistory of stroke or myocardial infarction, or history of heart failure, were found to have anumerically higher rate of thrombotic events, compared with patients without a history of theseunderlying diseases. Of the 73 patients who had a prior history of stroke or myocardial infarction,10 patients (13.7%) had a thrombotic event, compared with 16 of 166 patients (9.6%) without thismedical history. In the 40 patients who had a history of heart failure, 8 patients (20.0%) had athrombotic event, compared with 18 of 199 patients (9.0%) without this medical history (seesection 4.4). Such numerical increases were not observed in the corresponding sub-groups in theusual care treatment group.

Patients in the andexanet alfa group and usual care group experienced one or more of the followingadjudicated thrombotic events, respectively: ischaemic stroke (6.7% versus 1.3%), myocardialinfarction (4.6% versus 1.3%), pulmonary embolism (0.4% versus 2.6%), arterial systemic embolism(1.3% versus 0.4%) and deep vein thrombosis (0.4% versus 0.9%). The median time to thromboticevent was 3 and 14 days in the andexanet alfa and usual care group, respectively. In the andexanet alfagroup, 14 patients experienced a thrombotic event during the first 3 days, compared to 1 patient in theusual care group. All thrombotic events that occurred within the first 5 days after treatment werearterial events. None of the affected patients had received any dose of anticoagulant prior to thethrombotic event. Adjudicated thrombotic events leading to death were reported in 6 patients (2.5%) inthe andexanet alfa group and 2 patients (0.9%) in the usual care group.

Overall, 182 patients (76.2%) in the andexanet alfa group and 168 patients (72.4%) in the usual caregroup were restarted with any anticoagulant within 30 days post-randomisation based on clinicaljudgement.

Mortality

In total, 67 patients (28.0%) in the andexanet alfa group and 61 patients (26.3%) in the usual caregroup died before Day 30 post-randomisation. Overall, there were 54 patients (22.6%) in theandexanet alfa group and 51 patients (22.0%) in the usual care group with in-hospital death. Bleeding-related deaths within 72 hours post-randomisation were reported in 12 patients (5.0%) in the andexanetalfa group and 16 patients (6.9%) in the usual care group.

Functional outcomes

The change from baseline in NIHSS score up to 72 hours post-randomisation was numerically better inthe andexanet alfa group compared to the usual care group, with a difference of -1.2, 95%

CI (-2.3%, -0.2%) for the average over 72 hours. The effects on neurologic deterioration (NIHSSscore increase ≥4 or a GCS score decrease ≥2 at 24 hours post-randomisation), mRS score and GCSscores were similar between both treatment groups. The odds ratio for functional independence (mRS0-3) at 30 Day when comparing andexanet alfa to usual care was 1.23, 95% CI (0.78, 1.92), with a

GCS score difference of 0.1, 95% CI (-0.4, 0.6) for the average over 72 hours.

Pro-thrombotic laboratory markers

Dose-dependent increases in coagulation markers F1+2, TAT, and D-dimers after administration ofandexanet alfa were observed, in 223 healthy volunteers who received FXa inhibitors and were treatedwith andexanet alfa; no thromboembolic events occurred in these healthy volunteers. F1+2, TAT and

D-dimers were not measured in patients enrolled in study 14-505 and 18-513; their relevance inbleeding patients is not known.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies withandexanet alfa in one or more subsets of the paediatric population in treatment and prevention of FXainhibitor-associated haemorrhages (see section 4.2 for information on paediatric use).

Conditional approval

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited. The European Medicines Agencywill review new information on this medicinal product at least every year, and this SmPC will beupdated as necessary.

5.2 Pharmacokinetic properties

Studies of andexanet alfa in the presence of direct FXa inhibitors in healthy subjects demonstrateddose proportional pharmacokinetics over the intended therapeutic dose range evaluated for both Cmaxand area under the curve (AUC). The pharmacokinetics of andexanet alfa has not been studied inbleeding patients due to feasibility reasons.

Table 5: Pharmacokinetic parameters for andexanet alfa bolus-injection of 400 and 800 mg

PK Parameter 400 mg Bolus 800 mg Bolus61.3 127

AUC0-∞ (hr*µg/mL)[43.8, 94.9] [57.5, 209]61.0 118

Cmax (µg/mL)[40.3, 98.5] [50.2, 191]6.52 6.29

Clearance (L/hr)[4.21, 9.13] [3.83, 13.9]3.78 4.24

T1/2 (hr)[2.59, 6.39] [2.47, 6.52]9.47 8.94

Vss (L)[6.08, 15.3] [5.36, 23.1]

Source: Study 19-514

Data presented are geometric mean [min, max].

Pharmacokinetics in special populations
Elderly population

In a study comparing andexanet alfa pharmacokinetics in elderly (65-69 years) and younger(26-42 years) healthy subjects who had received apixaban, the pharmacokinetics of andexanet alfain the elderly subjects were not statistically different than those in the younger subjects.

Renal impairment

No studies have been conducted to investigate the pharmacokinetics of andexanet alfa inrenally impaired patients. Based on the available PK data, andexanet alfa has little to no renalclearance, and thus would not require dose adjustment for patients with renal impairment.

Hepatic impairment

No studies have been conducted to investigate the pharmacokinetics of andexanet alfa in patientswith hepatic impairment. Biliary and/or faeces elimination of protein therapeutics is not a knownroute of protein elimination. Therefore, dose adjustment is not considered needed for patients withhepatic impairment.

Gender

Based on population pharmacokinetics analysis, gender does not have a clinically meaningful effect onthe pharmacokinetics of andexanet alfa.

Paediatric population

The pharmacokinetics of andexanet alfa has not been studied in paediatric patients.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology and repeated dose toxicity studies up to two weeks in rats and monkeys.

Studies to evaluate the mutagenic and carcinogenic potential of andexanet alfa have not beenperformed. Based on its mechanism of action and on the characteristics of proteins, no carcinogenicor genotoxic effects are anticipated.

Animal reproductive and developmental studies have not been conducted with andexanet alfa.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tris base

Tris hydrochloride

L-arginine hydrochloride

Sucrose

Mannitol

Polysorbate 80

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

6.3 Shelf life

Vial (unopened)

Five years stored at 2°C to 8°C.

Reconstituted medicinal product

Chemical and physical in-use stability has been demonstrated for 16 hours at 2°C to 8°C in theprimary packaging vial. If needed, the reconstituted solution once transferred into the IV bag can bestored for an additional eight hours at room temperature. From a microbiological point of view, oncereconstituted, the product should be used immediately. If not used immediately, in-use storage timesand conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Store in a refrigerator (2°C to 8°C).

Do not freeze.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Powder in a 20 mL vial (Type I glass) with a stopper (butyl rubber).

Pack size of four or five vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Reconstitution

The following are needed before starting reconstitution:

* Calculated number of vials (see section 4.2).

* Same number of 20 mL (or larger) solvent syringes equipped with a 20 gauge (or smaller indiameter, e.g. 21 gauge) needle.

* Alcohol swabs.

* Large (50 mL or larger) sterile syringe. If a syringe pump is used for administration, multiplesyringes should be used to contain the final volume of reconstituted product.

* Intravenous bags of polyolefin (PO) or polyvinyl chloride (PVC) material (150 mL or larger) tocontain the final volume of reconstituted product (if administration is performed with IV bag).

* Water for injections.

* 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter.

Andexanet alfa does not need to be brought to room temperature before reconstitution oradministration to the patient. Aseptic technique during the reconstitution procedure should be used.

Each vial is reconstituted according to the following instructions:

1. Remove the flip-top from each vial.

2. Wipe the rubber stopper of each vial with an alcohol swab.

3. Using a 20 mL (or larger) syringe and a 20 gauge (or smaller in diameter, e.g. 21 gauge) needle,withdraw 20 mL of water for injections.

4. Insert the syringe needle through the centre of the rubber stopper.

5. Push the plunger down to slowly inject the 20 mL of water for injections into the vial, directingthe stream toward the inside wall of the vial to minimise foaming.

6. Gently swirl each vial, until all of the powder is completely dissolved. DO NOT SHAKE thevials, as this can lead to foaming. The dissolution time for each vial is approximately three tofive minutes.

7. The reconstituted solution should be inspected for particulate matter and/or discolouration priorto administration. Do not use if opaque particles or discolouration are present.

8. For the most efficient reconstitution of the needed dose, and to minimise errors, inject each vialneeded with 20 mL of water for injections before proceeding to the next step.

9. Use within eight hours after reconstitution when stored at room temperature.

Administration using a syringe pump1. Once all required vials are reconstituted, the reconstituted solution is withdrawn from each vial,using the large volume (50 mL or larger) syringe equipped with a 20 gauge (or smaller indiameter, e.g. 21 gauge) needle.

2. The bolus and infusion are prepared in separate large volume syringes.

3. Due to the additional volume, the high dose bolus and infusion have to be further separated intoadditional syringes (two syringes apiece for bolus and infusion).

4. To prevent the inadvertent transfer of air, be careful to hold the syringe needle up, and do not setthe syringe down between multiple withdrawals from vials.

5. Attach ancillary equipment (i.e. extension tubing, 0.2 or 0.22 micron in-line polyethersulfone(PES) or equivalent low protein-binding filter, syringe pump) in preparation for administration.

6. Administer the reconstituted solution at the appropriate rate.

7. Discard all used syringes, needles, and vials, including any unused portion of reconstitutedsolution.

Administration using intravenous bags1. Once all required vials are reconstituted, withdraw the reconstituted solution from each vial,using the large volume (50 mL or larger) syringe equipped with a 20 gauge (or smaller indiameter, e.g. 21 gauge) needle.

2. Transfer the reconstituted solution from the syringe into an appropriate IV bag.

3. Repeat steps 1 and 2 as necessary to transfer the complete volume of the bolus and the infusioninto a PO or PVC IV bags.

4. It is recommended that the bolus and infusion be split into two separate bags to ensure thecorrect administration rate. Although it is also permissible to use one PO or PVC IV bag for thebolus and infusion, the correct infusion rate must be ensured when switching from the bolus tothe infusion.

5. Attach ancillary equipment (i.e. extension tubing, 0.2 or 0.22 micron in-line polyethersulfone(PES) or equivalent low protein-binding filter, IV pump) in preparation for administration.

6. Administer the reconstituted solution at the appropriate rate.

Disposal

All used syringes, needles, and vials, including any unused portion of reconstituted solution, should bedisposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB

SE-151 85 Södertälje

Sweden

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/18/1345/001 4 vials

EU/1/18/1345/002 5 vials

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 26 April 2019

Date of latest renewal: 04 April 2025

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.

Leaflet ONDEXXYA 200mg powder for solution for infusion

General data about ONDEXXYA 200mg

Marketing authorisation