ONDEXXYA 200 MG POWDER FOR SOLUTION FOR INFUSION - summary of medicine characteristics

Y This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

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.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Powder for solution for infusion

White to off-white lyophilized powder

4 CLINICAL PARTICULARS

4.1

For adult patients treated with a direct factor Xa (FXa) inhibitor (apixaban or rivaroxaban) when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

4.2 Posology and method of administration

Restricted to hospital use only.

Posology

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

Table 1: Dosing regimens

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).

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).

Table 3: Summary of dosing for reversal of rivaroxaban

Restarting antithrombotic therapy

Following administration of Ondexxya and cessation of a major bleed, reanticoagulation 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 to 30 minutes, 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 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., rebleeding), 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. Preliminary 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 ANNEXA-4, 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 the ANNEXA-4 study, but thromboembolic events have been observed (see section 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.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies with andexanet alfa have been performed.

In vitro data suggest interaction of andexanet alfa with the heparin- anti-thrombin III (ATIII) complex and 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no data from the use of andexanet alfa in pregnant women. Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Andexanet alfa is not recommended during pregnancy or in women of childbearing potential not using contraception.

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The safety has been evaluated in clinical trials including 247 healthy subjects administered an FXa inhibitor, as well as in 352 patients in a Phase IIIb/IV trial (ANNEXA-4), who had acute major bleeding and were under treatment with an FXa inhibitor (mostly apixaban and rivaroxaban).

In the clinical trials in healthy subjects administered an FXa inhibitor and then receiving andexanet alfa, no serious or severe adverse reactions were reported. The most frequently observed adverse reactions were mild or moderate infusion-related reactions (see table 4) 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. Clinical relevance in the target population (patients with uncontrolled or life-threatening bleeding who are anticoagulated due to high to very high risk of thrombosis) is unknown.

Tabulated list of adverse reactions

Table 4 provides the list of adverse reactions from clinical studies of healthy subjects treated with andexanet alfa. The second column provides the list of adverse reactions from the interim results of the Phase IIIb/IV ANNEXA-4 study, including 352 patients 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 healthy subjects and bleeding patients

General disorders and administrative site conditions

Description of selected adverse reactions

Based on data from 352 patients from the Phase IIIb/IV ANNEXA-4 study treated with an FXa inhibitor and experiencing an acute major bleeding episode, one patient experienced a serious or severe infusion-related reaction. Thirty-six of 352 patients with complete 30-day safety follow up (10.3%) had thrombotic events, including venous thromboembolism (VTE), myocardial infarction (MI), and stroke. Ten of 36 (27.8%) patients had restarted antithrombotic therapy at the time of the event, and all 36 patients had been anticoagulated for a prior history of VTE and/or atrial fibrillation at the time of receiving andexanet alfa (see sections 4.4 and 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important, as it allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system detailed below:

Yellow Card Scheme

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

4.9 Overdose

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

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 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, randomized, 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, 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.

PK/PD modelling

Bolus strengths of andexanet alfa being necessary to achieve mean unbound apixaban (400 mg bolus) and unbound rivaroxaban concentrations (800 mg bolus) below the anticipated respective threshold for no anticoagulant effect were twice as high for rivaroxaban (20 mg QD) compared to apixaban (5 mg BID), due to the differential PK characteristics and dose levels of respective FXa inhibitor.

Clinical efficacy and safety

The efficacy and safety of andexanet alfa have been evaluated in the following: 1) randomized, 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 (ANNEXA-4) 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 14504)

In a prospective, randomized, 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 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 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)

(A)

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 In Study 14–505 (ANNEXA-4), a Phase IIIb/IV multinational, prospective, single-arm, openlabel study, Ondexxya was administered to 352 patients on FXa inhibitors who presented with acute major bleeding. The two co-primary endpoints are: 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.

In an updated interim analysis, data of 352 patients were evaluated.

Approximately half of the patients were male, and the mean age was 77.4 years. Most patients had previously received either apixaban (194/352; 55.1%) or rivaroxaban (128/352; 36.4%), and experienced either an ICH (230/352; 65.3%) or a gastrointestinal (GI) bleed (94/352; 26.7%).

297/352 Patients (84.4%) received the low-dose regimen of andexanet, while 55 patients (15.6%) received the high-dose regimen.

Of 352 enrolled patients, 249 (70.7%) were included in the efficacy-analysis. For these patients, median anti-FXa activity at baseline was 149.7 ng/mL for patients taking apixaban, and 211.8 ng/mL for patients taking rivaroxaban. Median change from baseline to nadir in anti-FXa activity was –93.4% (95% CI –94.3%, –92.4%) for apixaban, and –92.5% (95% CI –94.2%, –90.3%) for rivaroxaban.

Haemostatic efficacy was good or excellent in 81.9% of 249 patients.

The updated interim analysis demonstrated that the change in anti-FXa activity (surrogate) was not predictive for achievement of hemostatic efficacy in the overall patient population.

Deaths

In the ANNEXA-4 study, of the patients in the safety population completing 30-day follow up (N=351), 54 patients (15.4%) died. The 30-day mortality rates were 16.2% (37/229) in patients presenting with ICH, 12.8% (12/94) with GI bleeding, and 17.9% (5/28) with other types of bleeding. The 30-day mortality rates were 20.1% (44/219) in patients aged > 75 years old and 7.6% (10/132) in patients aged < 75 years. According to region, death rates were 22.1% (31/140) in patients recruited in the European Union and 10.9% (23/211) in patients recruited in North America. Compared with patients recruited in North America, EU patients were significantly older (79.0 years vs. 76.3 years), more frequently had ICH as index event (72.9% vs. 59.0%) and more ICHs were intraparenchymal (54.9% vs. 34.4%).

Cardiovascular causes of death (n=27) included: haemorrhagic stroke (n=6), ischaemic stroke (n=5), sudden cardiac death (including unwitnessed) (n=5), cardiomechani­cal/pump failure (n=4), myocardial infarction (n=2), bleeding other than haemorrhagic stroke (n=1), and other cardiovascular causes (n=4). Non-cardiovascular deaths (n=27) included: respiratory failure (n=5), infection/sepsis (n=5), accident/trauma (n=2), cancer (n=1), and other/non-vascular cause (n=14).

Thromboembolic events

In the ANNEXA-4 study, 36 (10.3%) patients experienced a total of 42 thromboembolic events: cerebrovascular accident (CVA) (15/42; 35.7%), deep venous thrombosis (13/42; 33.1%), acute myocardial infarction (8/42; 19.0%), pulmonary embolism (5/42; 11.9%), and transient ischaemic attack (1/42; 2.4%). The median time to event was nine days. A total of 33.3% of patients with thromboembolic events (12/36) experienced the thromboembolic event during the first three days. Of the 209 patients who were re-anticoagulated prior to a thrombotic event, 10 (4.8%) patients experienced a thromboembolic event. At the time of the event 10/36 (27.8%) patients were on antithrombotic therapy. The occurrence of thromboembolic events was generally comparable between patients > 75 years (11.0%; 24/219) and those < 75 years of age (9.1%; 12/132).

No thromboembolic events were observed in 223 healthy volunteers who received FXa inhibitors and were treated with andexanet alfa. Dose-dependent increases in coagulation markers F1+2, TAT, and D-dimers after administration of andexanet alfa were observed, but these markers were not measured in patients enrolled in the ANNEXA-4 study, and 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. To date, the occurrence of positive, non-neutralizing antibodies to andexanet alfa following treatment in patients in the ANNEXA-4 study (8.5% or 20/236 patients) has been similar to that observed in healthy subjects.

Paediatric population

The European Medicines Agency 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 European Medicines Agency will review new information on this medicinal product at least every year, and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

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 Cmax and area under the curve (AUC). FXa inhibitors did not affect andexanet alfa pharmacokinetics at therapeutic levels.

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.

5.3 Preclinical safety data

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.

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 medicinal products.

6.3 Shelf life

Vial (unopened)

Three 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.

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 vials.

6.6 Special precautions for disposal

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 bags).

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.

7 MARKETING AUTHORISATION HOLDER

Alexion Europe SAS

103–105 rue Anatole France

92300 Levallois-Perret

France

8 MARKETING AUTHORISATION NUMBER(S)

PLGB 31187/0021

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

01/01/2021