ONDEXXYA 200mg powder infusion solution medication leaflet

Ondexxya 200 mg powder for solution for infusion

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.

For the full list of excipients, see section 6.1.

Powder for solution for infusion

White to off-white lyophilized powder

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.

Restricted to hospital use only.

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

Initial Continuous Total numberintravenous intravenous of 200 mgbolus infusion vials needed

Low dose 400 mg at a target rate of 4 mg/min for 120 minutes 530 mg/min (480 mg)

High dose 800 mg at a target rate of 8 mg/min for 120 minutes 930 mg/min (960 mg)

The recommended dose regimen of Ondexxya is based on the dose of apixaban the patient is takingat the time of anticoagulation reversal, as well as on the time since the patient’s last dose ofapixaban (see table 2). If the strength of the last dose of anticoagulant or the interval between thelast 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

Timing of last dose before

Ondexxya initiation

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

Apixaban > 5 mg High dose Low dose

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 > 10 mg High dose Low dose

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 ifthe patient is clinically stable and adequate haemostasis has been achieved. Medical judgementshould balance the benefits of anticoagulation with the risks of re-bleeding (see section 4.4).

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.

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)or polyvinyl chloride (PVC) material (see section 6.6). Prior to administration by IV infusion a 0.2or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein-binding filter should beused.

Ondexxya is administered as an IV bolus at a target rate of approximately 30 mg/min over 15minutes (low dose) or 30 minutes (high dose), followed by administration of a continuousinfusion 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.

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

Known allergic reaction to hamster proteins.

Clinical efficacy is based upon reversal of anti-FXa-activity in healthy volunteers and bleedingpatients dosed with apixaban or rivaroxaban. Andexanet alfa is not suitable for pre-treatment ofurgent 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 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 on anti-

FXa-activity. Commercial anti-FXa-activity assays are unsuitable for measuring anti-FXa activityfollowing administration of andexanet alfa as these assays result in erroneously elevated anti-FXaactivity levels, thereby causing a substantial underestimation of the reversal activity of andexanetalfa.

Dosage recommendation is based upon data-modelling in healthy volunteers. Validation has not beensuccessful, yet. Data from bleeding patients are limited. Data suggest higher risk of thrombosis forpatients receiving the higher dose of andexanet, previous lower dose of the anti-FXa inhibitor, andpatients on rivaroxaban.

In study 14-505, intracranial haemorrhage (ICH) patients (GCS > 7 and haematoma volume <60 mL) have been included. Treatment of patients with more severe ICH with andexanet alfa hasnot been studied.

Thrombotic events have been reported following treatment with andexanet alfa (see sections 4.8 and5.1). Patients being treated with FXa inhibitor therapy have underlying disease states that predisposethem to thrombotic events. Reversing FXa inhibitor therapy exposes patients to the thrombotic riskof 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 maypose a risk of developing thrombosis. Duration of this effect in bleeding patients is not known.

Laboratory parameters as anti- FXa activity, endogenous thrombotic potential (ETP), or markers ofthrombosis might not be reliable for guidance. To reduce this risk, resumption of anticoagulanttherapy should be considered as soon as medically appropriate after completion of treatment.

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 nothromboembolic events were reported. These markers were not measured in patients enrolled instudy 14-505, but thromboembolic events have been observed (see section 4.8 and 5.1). Monitoringfor signs and symptoms of thrombosis is, therefore, strongly recommended.

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 bleeding event,as they were excluded from clinical trials. Pro-coagulant factor treatments (e.g., 3- or 4-factorprothrombin complex concentrate (PCC)/activated PCC, recombinant factor VIIa, fresh frozenplasma) and whole blood should be avoided unless absolutely required, due to lack of data incombination with these treatments.

Use of andexanet prior to heparinization e.g. during surgery should be avoided as andexanet causesunresponsiveness to heparin. Use of andexanet as an antidote for heparin or low-molecular weightheparin has not been evaluated and is not recommended (refer to section 4.5.).

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.

In order to improve the traceability of biological medicinal products, the name and the batchnumber of the administered product should be clearly recorded.

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 neutralization of the anticoagulant effect of heparin. Off-label use of andexanet alfa pre-surgerywith intended heparin-anticoagulation has been reported to cause unresponsiveness to heparin (refer tosection 4.4). Use of andexanet as an antidote for heparin or low-molecular weight heparin has not beenevaluated and is not recommended.

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.

It is unknown whether andexanet alfa is excreted in human milk. A risk to newborns/infants cannot beexcluded. Breast-feeding should be discontinued during treatment with andexanet alfa.

There are no data on the effects of andexanet alfa on human fertility.

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

The safety of andexanet alfa has been evaluated in clinical trials including 417 healthy subjectsadministered an FXa inhibitor, as well as in 419 patients in a Phase IIIb/IV trial (study 14-505), whohad acute major bleeding and were under treatment with an FXa inhibitor (apixaban andrivaroxaban).

In clinical studies in healthy subjects who were administered a FXa inhibitor and then receivedandexanet 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 reactionswere 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 the healthy subject trials, elevations > 2 x ULN in D-dimer and prothrombin fragments F1+2 werefrequently observed. These elevations were maintained between several hours to a few daysfollowing administration, but no thrombotic events were reported.

In patients with major bleedings thrombosis-markers have not been investigated since bleeding caninterfere with the thrombosis marker results. Thromboses and thromboembolic events havecommonly been documented.

Table 4 provides the list of adverse reactions in patients with major bleeds from study 14-505including 419 patients on apixaban and rivaroxaban with acute major bleeding treated withandexanet 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 (cannotbe estimated from available data).

Table 4: List of adverse reactions in patients with major bleeds

System Organ Class Very common Common Uncommon≥ 1/10 ≥ 1/100 to < 1/10 ≥ 1/1,000 to < 1/100

Nervous system disorders Cerebrovascular Cerebral infarctionaccident

Transient ischaemic attack

Ischaemic stroke

Cardiac disorders Acute myocardial Cardiac arrestinfarction

Myocardialinfarction

Vascular disorders Deep vein Iliac artery occlusionthrombosis

Respiratory, thoracic and Pulmonarymediastinal disorders embolism

General disorders and Pyrexiaadministrative siteconditions

Injury, poisoning and Infusion related reactionaprocedural complicationsareported signs/symptoms (rigors, chills, hypertension, oxygen desaturation, agitation and confusion) were transient and mildto moderate in severity.

Based on data from 419 patients from the Phase IIIb/IV study 14-505 treated with apixaban andrivaroxaban and experiencing an acute major bleeding episode, two patients (0.5%) experienced aninfusion-related reaction, neither of which was assessed as severe (1 moderate; 1 mild).

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.

There is no clinical experience with overdose of andexanet alfa. No dose-limiting toxicities havebeen observed during clinical trials.

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

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 predominant mechanism of actionis the binding and sequestration of the FXa inhibitor. In addition, andexanet alfa has been observedto bind to, and inhibit tissue factor pathway inhibitor (TFPI). Inhibition of TFPI activity can increasetissue factor-initiated thrombin generation inducing a pro-coagulant effect.

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 infusionresulted in a sustained decrease in anti-FXa activity. The anti-FXa activity returned to the placebolevels and above 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,“restoration of 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 a pro-coagulant effect of TFPI-inhibition is supported by consecutive and sustained slopes of D-Dimers,

TAT, and F1+2.

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,duration 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 dueto the high inter-individual variability.

The efficacy and safety of andexanet alfa have been evaluated in the following: 1) randomised,placebo-controlled, Phase II dose-ranging trials with healthy volunteers administered FXa inhibitors toestablish 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; and 3) a global, multicentre,prospectively defined, open-label Phase IIIb/IV study 14-505 in patients with an acute major bleedingepisode requiring urgent reversal of FXa anticoagulation.

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).

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 thresholds for normalization of thrombin generation (defined by mean ETP and standarddeviations) were estimated to be 44.2 ng/mL (within one standard deviation of normal ETP) based onpooled data from Studies 14-503 and 14-504, as indicated in the figure.

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

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 for 20hours 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.

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 thecontinuous infusion. These levels of unbound FXa inhibitor provide little or no anticoagulant effect.

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, Ondexxya 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 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 ICH (329/477; 69%) or agastrointestinal (GI) bleed (109/477; 22.9 %).

381/477 (79.9%) received the low-dose regimen of andexanet, while 96/477 patients (20.1%) receivedthe high-dose regimen, accordingly to section 4.2.

Of 477 enrolled patients, 347 (73%) were evaluable for efficacy as they were dosed with andexanetfor 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, and 214ng/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 was good or excellent in 79% of 169 patients taking apixaban and in 80% of127 patients taking rivaroxaban.

Anti-TFPI-effect

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).

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

In the safety population (n=419), 75 patients (18%) died. Of the 75 subjects who died, the bleedingtype was intracranial bleeding in 55 (73%), gastrointestinal bleeding in 14 (19%), and other bleedingtypes in 6 (8%) subjects. The mortality rates were 19.0% (55/289) in patients presenting with ICH,14.7% (14/95) with GI bleeding, and 17.1% (6/35) with other types of bleeding. The mortality rateswere 23.0% (64/278) in patients aged > 75 years old and 7.8% (11/141) in patients aged ≤ 75 years.

According to region, death rates were 24.9% (53/213) in patients recruited in the European Unionand 11.3% (22/194) in patients recruited in North America. The higher mortality rate in Europe isonly present in older patients or patients with heart failure. Compared with patients recruited in

North America, EU patients were significantly older (81.0 years vs. 79.0 years), more frequently had

ICH as index event (75.1% vs. 60.3%) and more ICHs were intraparenchymal (69.3% vs. 42.7%).

Cardiovascular causes of death (n=36) included: haemorrhagic stroke (n=6), ischaemic stroke(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.

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. Of these 266, 14 subjects (5%) had a thrombotic eventafter resumption of anticoagulation; while of the 153 subjects who did not receive anticoagulation as aprophylactic, 31 (20.3%) had a thrombotic event (see section 4.4).

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 weretreated with andexanet alfa; no thromboembolic events occurred in these healthy volunteers. F1+2,

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

Immunogenicity345 andexanet alfa-treated healthy subjects were tested for antibodies cross reacting with andexanetalfa and antibodies to factor X and FXa. Treatment-emergent, non-neutralizing antibodies toandexanet alfa were detected in approximately 10% (35/345). These antibodies were generally lowtitre, and no clinical consequences were observed. No neutralising antibodies or antibodies to factor

X or FXa were detected. The occurrence of positive, non-neutralizing antibodies to andexanet alfafollowing treatment in patients in the study 14-505 (8% or 22/276 patients) has been similar to thatobserved in healthy subjects.

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

FXa inhibitor-associated haemorrhages (see section 4.2 for information on paediatric use).

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.

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 bolus-injection of 400 and 800mg

PK Parameter 400 mg Bolus 800 mg Bolus61.3 127

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

Cmax (g/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]

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 alfa inthe elderly subjects were not statistically different than those in the younger subjects.

No trials have been conducted to investigate the pharmacokinetics of andexanet alfa in renallyimpaired patients. Based on the available PK data, andexanet alfa has little to no renal clearance, andthus would not require dose adjustment for patients with renal impairment.

No trials have been conducted to investigate the pharmacokinetics of andexanet alfa in patients withhepatic impairment. Biliary and/or faeces elimination of protein therapeutics is not a known route ofprotein elimination. Therefore, dose adjustment is not considered needed for patients with hepaticimpairment.

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

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

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.

Tris base

Tris hydrochloride

L-arginine hydrochloride

Sucrose

Mannitol

Polysorbate 80

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

Four years stored at 2°C to 8°C.

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.

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.

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.

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 larger)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 orlarger) to contain the final volume of reconstituted product (if administration is performedwith 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 larger) needle, withdraw 20 mL ofwater 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 thevial, directing the 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/ordiscolouration prior to administration. Do not use if opaque particles or discolourationare present.

8. For the most efficient reconstitution of the needed dose, and to minimise errors, injecteach vial needed 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 eachvial, using the large volume (50 mL or larger) syringe equipped with a 20 gauge (or larger)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 furtherseparated into additional 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 donot set the syringe down between multiple withdrawals from vials.5. Attach ancillary equipment (i.e., extension tubing, 0.2 or 0.22 micron in-linepolyethersulfone (PES) or equivalent low protein-binding filter, syringe pump) inpreparation for administration.

6. Administer the reconstituted solution at the appropriate rate.7. Discard all used syringes, needles, and vials, including any unused portion ofreconstituted solution.

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 larger)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 andthe infusion into 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 bagfor the bolus and infusion, the correct infusion rate must be ensured when switching fromthe bolus to the infusion.

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

6. Administer the reconstituted solution at the appropriate rate.

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

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/18/1345/001 4 vials

EU/1/18/1345/002 5 vials

Date of first authorisation: 26 April 2019

Date of latest renewal: 24 April 2023

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

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