Ondexxya 200 mg powder for solution for infusion

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.

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). Posology of andexanet alfa is based upon PK/PD-modelling and simulation exercises (see sections 5.1 and 5.2).

Table 1: Dosing regimens

Reversal of apixaban

The recommended dose regimen of Ondexxya is based on the dose of apixaban the patient is taking at the time of anticoagulation reversal, as well as on the time since the patient's last dose of apixaban (see table 2). If the strength of the last dose of anticoagulant or the interval between the last dosage and the bleeding episode are unknown, no dose recommendation is available. Measurement of baseline anti-FXa-level should support the clinical decision of starting treatment (if level is available in an acceptable time frame).

Table 2: Summary of dosing for reversal of apixaban

Reversal of rivaroxaban

The recommended dose regimen of Ondexxya is based on the dose of rivaroxaban the patient is taking at the time of anticoagulation reversal, as well as on the time since the patient's last dose of rivaroxaban (see table 3). If the strength of the last dose of anticoagulant or the interval between the last dosage and the bleeding episode are unknown, no dose recommendation is available. Measurement of baseline anti-FXa-level should support the clinical decision of starting treatment (if level is available in an acceptable time frame).

Table 3: Summary of dosing for reversal of rivaroxaban

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. 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 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.

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

Known allergic reaction to hamster proteins.

Limitations of use

Clinical efficacy is based upon reversal of anti-FXa-activity in healthy volunteers and bleeding patients dosed with apixaban or rivaroxaban. Andexanet alfa is not suitable for pre-treatment of urgent surgery. Use for edoxaban or enoxaparin-reversal is not recommended due to lack of data. Andexanet alfa will not reverse the effects of non-FXa inhibitors (see section 5.1).

Treatment monitoring should be based mainly on clinical parameters indicative of appropriate response (i.e., achievement of haemostasis), lack of efficacy (i.e., re-bleeding), and adverse events (i.e., thromboembolic events). Treatment monitoring of andexanet alfa should not be based on anti-FXa-activity. Commercial anti-FXa-activity assays are unsuitable for measuring anti-FXa activity following administration of andexanet alfa as these assays result in erroneously elevated anti-FXa activity levels, thereby causing a substantial underestimation of the reversal activity of andexanet alfa.

Dosage recommendation is based upon data-modelling in healthy volunteers. Validation has not been successful, yet. Data from bleeding patients are limited. Data suggest higher risk of thrombosis for patients receiving the higher dose of andexanet, previous lower dose of the anti-FXa inhibitor, and patients 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 has not been studied.

Thrombotic events

Thrombotic events have been reported following treatment with andexanet alfa (see sections 4.8 and 5.1). Patients being treated with FXa inhibitor therapy have underlying disease states that predispose them to thrombotic events. Reversing FXa inhibitor therapy exposes patients to the thrombotic risk of their underlying disease. In addition, independent pro-coagulant effect of andexanet alfa, mediated by inhibition of tissue factor pathway inhibitor (TFPI), has been demonstrated, which may pose 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 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.

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, 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 trials. 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 prior to heparinization e.g. during surgery should be avoided as andexanet causes unresponsiveness to heparin. Use of andexanet as an antidote for heparin or low-molecular weight heparin has not been evaluated and is not recommended (refer to 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.

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

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.

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

Summary of the safety profile

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

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 the healthy subject trials, 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 in patients with major bleeds from study 14-505 including 419 patients on apixaban and rivaroxaban with acute major bleeding 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 in patients with major bleeds

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

Description of selected adverse reactions

Based on data from 419 patients from the Phase IIIb/IV study 14-505 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).

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.

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

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 FXa enzymatic activity. The active site serine was substituted with alanine, rendering the molecule unable to cleave and activate prothrombin, and the gamma-carboxyglutamic acid (Gla) domain was removed to eliminate the ability of the protein to assemble into the prothrombinase complex, thus removing any anti-coagulant effects.

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

Pharmacodynamic effects

The effects of andexanet alfa can be measured through pharmacodynamic markers, including free fraction 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 following administration 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 from andexanet alfa, resulting in detection of erroneously elevated anti-FXa activity levels, thereby causing a substantial underestimation of the reversal activity of andexanet alfa.

In prospective, randomised, placebo-controlled, dose-ranging studies in healthy subjects, the dose and dose regimen of andexanet alfa required to reverse anti-FXa activity and restore thrombin generation for FXa inhibitors (apixaban or rivaroxaban) were determined with modified assays that are not commercially available.

The maximal reversal of anti-FXa activity was achieved within two minutes of completing the bolus administration. Administration of andexanet alfa as a bolus followed by continuous infusion resulted in a sustained decrease in anti-FXa activity. The anti-FXa activity returned to the placebo levels 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 maximum decrease in unbound FXa inhibitors was rapid (within two minutes of the end of the bolus) and was sustained over the course of the infusion then gradually increased over time, reaching a maximum at approximately two hours following the end of infusion.

Restoration of thrombin generation following administration was dose- and dose-regimen-dependent and 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 after andexanet 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 to anticoagulation) 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 PK and on the relationships between biomarkers, here anti FXa-activity, TFPI-activity, and ETP. There remain 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 continuous infusion. Precision of simulations in bleeding patients is less than that within healthy volunteers due to the 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 trials with healthy volunteers administered FXa inhibitors to establish doses required for reversal; 2) two Phase III studies, one with apixaban and the other with rivaroxaban, 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 bleeding episode requiring urgent reversal of FXa anticoagulation.

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 of 56.5 years on apixaban 5 mg twice daily received andexanet alfa (n=24) administered as a 400 mg IV bolus 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 received andexanet alfa (n=26) administered as an 800 mg IV bolus immediately followed by an 8 mg per minute 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 the percent 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%) for the 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-FXa activity was ‑96.72% (± 1.838%) for the andexanet alfa group and -44.75% (± 11.749%) for the placebo 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 standard deviations) were estimated to be 44.2 ng/mL (within one standard deviation of normal ETP) based on pooled 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 with apixaban (A) and rivaroxaban (B)

Restoration of thrombin generation

In both, Study 14-503 and Study 14-504, treatment with andexanet alfa also resulted in a statistically significant increase in thrombin generation in healthy subjects anticoagulated with apixaban or rivaroxaban 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 20 hours was achieved with bolus only and bolus plus infusion for low-dose andexanet alfa in subjects on apixaban. For subjects on rivaroxaban, high-dose andexanet alfa (bolus plus infusion) resulted in increased 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 with low-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 continuous 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-label study, Ondexxya was administered to 477 patients on FXa inhibitors, 419 of whom were on apixaban and rivaroxaban, who presented with acute major bleeding. The two co-primary endpoints were: a) percent change in anti-FXa activity from baseline to the nadir between five minutes after the end of the bolus until the end of the infusion, and; b) rate of good or excellent (compared to poor or none) haemostatic efficacy within 12 hours after infusion, as rated by an independent endpoint adjudication committee.

Approximately half of the patients were male, and the mean age was 77.9 years. Most patients had previously 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 a gastrointestinal (GI) bleed (109/477; 22.9%).

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

Of 477 enrolled patients, 347 (73%) were evaluable for efficacy as they were dosed with andexanet for a confirmed major bleed and had a baseline anti-FXa activity above 75 ng/mL. For these patients, median anti-FXa activity at baseline was 147 ng/mL for patients taking apixaban, and 214 ng/mL for patients taking rivaroxaban. For anti-FXa activity, the median (95% CI) decrease from baseline to nadir in anti-FXa activity for apixaban was -93.3% (-94.2%, -92.5%); and rivaroxaban was -94.1% (-95.1%; -93.0%).

Haemostatic efficacy was good or excellent in 79% of 169 patients taking apixaban and in 80% of 127 patients taking rivaroxaban.

Anti-TFPI-effect

Immediate and sustained (for about 3 days post infusion) pro-coagulant anti-TFPI-effect was documented in patients with major bleeding – consistent with respective results from studies in healthy volunteers (14-503, 14-504, 16-508, 19-514).

Analysis of study 14-505 demonstrated that the change in anti-FXa activity (surrogate) was not predictive for achievement of haemostatic efficacy.

Deaths

In the safety population (n=419), 75 patients (18%) died. Of the 75 subjects who died, the bleeding type was intracranial bleeding in 55 (73%), gastrointestinal bleeding in 14 (19%), and other bleeding types 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 rates were 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 Union and 11.3% (22/194) in patients recruited in North America. The higher mortality rate in Europe is only 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 other cardiovascular 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 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, 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).

Pro- thrombotic laboratory markers

Dose-dependent increases in coagulation markers F1+2, TAT, and D-dimers after administration of andexanet alfa were observed, in 223 healthy volunteers who received FXa inhibitors and were treated 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 in bleeding patients is not known.

Immunogenicity

345 andexanet alfa-treated healthy subjects were tested for antibodies cross reacting with andexanet alfa and antibodies to factor X and FXa. Treatment-emergent, non-neutralizing antibodies to andexanet alfa were detected in approximately 10% (35/345). These antibodies were generally low titre, 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 alfa following treatment in patients in the study 14-505 (8% or 22/276 patients) has been similar to that observed in healthy subjects.

Paediatric population

The licensing authority has deferred the obligation to submit the results of studies with andexanet 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).

Conditional approval

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The licensing authority will review new information on this medicinal product at least every year, and this SmPC will be updated as necessary.

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

Table 5. Pharmacokinetic parameters for Andexanet bolus-injection of 400 and 800mg

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

Renal impairment

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

Hepatic impairment

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

Gender

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

Paediatric population

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 safety pharmacology 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 been performed. Based on its mechanism of action and on the characteristics of proteins, no carcinogenic or 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 medicinal products.

Vial (unopened)

Four 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 the primary packaging vial. If needed, the reconstituted solution once transferred into the IV bag can be stored for an additional eight hours at room temperature. From a microbiological point of view, once reconstituted, the product should be used immediately. If not used immediately, in-use storage times and 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.

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 larger) needle.

• Alcohol swabs.

• Large (50 mL or larger) sterile syringe. If a syringe pump is used for administration, multiple syringes 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) to contain 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 or administration 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 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, 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 the vials, as this can lead to foaming. The dissolution time for each vial is approximately three to five minutes.

7. The reconstituted solution should be inspected for particulate matter and/or discolouration prior to 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 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 pump

1. 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 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 further separated 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 do not set the 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 reconstituted solution.

Administration using intravenous bags

1. 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 and the 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 the correct administration rate. Although it is also permissible to use one PO or PVC IV bag for the bolus and infusion, the correct infusion rate must be ensured when switching from the bolus to the 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 be disposed of in accordance with local requirements.