Ondexxya

1 

ANNEX I 

SUMMARY OF PRODUCT CHARACTERISTICS 



2  

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 Therapeutic indications 

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

 
4.2 Posology and method of administration 

Restricted to hospital use only. 

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

 
Table 1:  Dosing regimens 

 
 Initial 

intravenous 
bolus 

Continuous 
intravenous 

infusion 

Total number 
of 200 mg 

vials needed 

Low dose 400 mg at a target rate of 
30 mg/min 

4 mg/min for 120 minutes 
(480 mg) 5 

High dose 800 mg at a target rate of 
30 mg/min 

8 mg/min for 120 minutes 
(960 mg) 9 



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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 

 
 
 
 

FXa inhibitor 

 
 
 

Last dose 

Timing of last dose before 
Ondexxya initiation 

< 8 hours or unknown ≥ 8 hours 

 
 

Apixaban 

≤ 5 mg Low dose  
 

Low dose > 5 mg/ 
Unknown 

 
High dose 

 

Reversal of rivaroxaban 
The recommended dose regimen of Ondexxya is based on the dose of rivaroxaban the patient is taking 
at the time of anticoagulation reversal, as well as on the time since the patient’s last dose of 
rivaroxaban (see table 3). 

 
Table 3:  Summary of dosing for reversal of rivaroxaban 

 
 
 
 

FXa inhibitor 

 
 
 

Last dose 

Timing of last dose before 
Ondexxya initiation 

< 8 hours or unknown ≥ 8 hours 

 
 

Rivaroxaban 

≤ 10 mg Low dose  
 

Low dose > 10 mg/ 
Unknown 

 
High dose 

 

Restarting antithrombotic therapy 
Following administration of Ondexxya and cessation of a major bleed, re-anticoagulation should be 
considered to prevent thrombotic events due to the patient’s underlying medical condition. 
Antithrombotic therapy can be re-initiated as soon as medically indicated following treatment if the 
patient is clinically stable and adequate haemostasis has been achieved. 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). 



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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) is transferred to a suitable empty intravenous bag comprised of polyolefin (PO) or 
polyvinyl chloride (PVC) material without further dilution (see section 6.6) prior to administration by 
IV infusion using a 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent low protein- 
binding filter. 

 
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., 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. 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-thrombotic effect of andexanet alfa cannot be 
ruled out.  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. 



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In healthy volunteers, dose-dependent increases in coagulation markers F1+2, TAT, and D-dimer 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. 

 
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. 

 
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 



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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 

 

System organ class/ 
Preferred term 

Frequency in 
healthy 

volunteers 

Frequency in 
bleeding 
patients 

Immune system disorders 

Urticaria common  

Nervous system disorders 

Cerebral infarction  uncommon 

Cerebrovascular accident  uncommon 

Dizziness postural common  

Headache common  

Ischaemic stroke  common 

Transient ischaemic attack  uncommon 

Cardiac disorders 

Acute myocardial infarction  uncommon 

Cardiac arrest  uncommon 

Myocardial infarction  uncommon 

Palpitations common  

Vascular disorders 

Deep vein thrombosis  uncommon 

Iliac artery occlusion  uncommon 

Respiratory, thoracic and mediastinal disorders 

Cough common  

Dyspnoea common  

Pulmonary embolism  uncommon 



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System organ class/ 
Preferred term 

Frequency in 
healthy 

volunteers 

Frequency in 
bleeding 
patients 

Gastrointestinal disorders 

Abdominal discomfort common  

Abdominal pain common  

Dry mouth common  

Dysgeusia common  

Nausea common  

Skin and subcutaneous tissue disorders 

Pruritus common  

Pruritus generalised common  

Musculoskeletal and connective tissue disorders 

Back pain common  

Muscle spasms common  

General disorders and administrative site conditions 

Flushing very common  

Feeling hot very common  

Chest discomfort common  

Hyperhidrosis common  

Peripheral coldness common  

Pyrexia  common 

Investigations 
Transient elevations of D-dimer and F1+2 fragments very common  

 
 
 

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 
listed in Appendix V. 

 
4.9 Overdose 

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



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5. PHARMACOLOGICAL PROPERTIES 
 

5.1 Pharmacodynamic properties 
 

Pharmacotherapeutic group:  All other therapeutic products, antidotes.  ATC code: V03AB38 
Mechanism of action 
Andexanet alfa is a recombinant form of human FXa protein that has been modified to lack 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, although there may be a minor contribution from 
the inhibition of tissue factor pathway inhibitor (TFPI) activity through binding to TFPI.  The 
interaction between andexanet alfa and TFPI has not been fully characterized.  Andexanet alfa binds 
direct FXa inhibitors with high affinity, making them unavailable to exert their anticoagulant effects. 

 
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. 

 
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 for 10 to 20 hours following andexanet alfa 
administration. The clinical relevance of this interaction in terms of maintenance of thrombin 
generation and the potential for a prothrombotic effect has not been fully elucidated. 

 
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. 
 



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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 14-504) 
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) 



10 
 

 

 
 

(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 
In Study 14-505 (ANNEXA-4), a Phase IIIb/IV multinational, prospective, single-arm, open-label 
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. 



11 
 

 
 
 
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 



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

 
5.2 Pharmacokinetic properties 

 
Phase II studies of andexanet alfa in the presence of direct FXa inhibitors demonstrated the same dose 
proportional pharmacokinetics over the intended therapeutic dose range evaluated for both Cmax and 
area under the curve (AUC) with an effective half-life of approximately one hour. The volume of 
distribution at steady state (Vdss) and volume of distribution (Vd) at sub-therapeutic levels decreased 
with dose, consistent with the saturation of a high-affinity compartment, likely to reflect binding to 
endothelial cell bound TFPI, the only endogenous molecule known to bind andexanet alfa. FXa 
inhibitors did not affect andexanet alfa pharmacokinetics at therapeutic levels. 

 
All PK studies were conducted using a former drug substance generation. PK comparability with 
andexanet alfa in Ondexxya (Generation 2) has not yet been proven. 

 
 

Distribution 
The Vd for andexanet alfa is 5.3 ± 2.6 L, approximately equivalent to the blood volume. 

 
Elimination 
Clearance (L/hr) for andexanet alfa is 4.4 ± 1.2 L/hr with low renal elimination. The elimination half- 
life ranges from four to seven hours.  Based on what is known about the disposition kinetics of native 
FXa, andexanet alfa is likely rapidly broken down in plasma by endogenous proteases, consistent with 
its relatively short effective half-life (one hour). 

 
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. 



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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 and other handling 
 

Reconstitution 
 

The following are needed before starting reconstitution: 
• Calculated number of vials (see section 4.2). 



14  

• Same number of 20 mL (or larger) solvent syringes equipped with a 20 gauge (or larger) 
needle. 

• Alcohol swabs. 
• Large (60 mL or larger) sterile syringe. If a syringe driver is used for administration, multiple 

syringes should be used to contain the final volume of reconstituted product. 
• Intravenous PO or PVC bag (150 mL or larger) to contain the final volume of reconstituted 

product (if administration is performed with an IV bag). 
• Water for injections 

 
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 (60 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, air filters, syringe driver) 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 an intravenous bag 
 

1. Once all required vials are reconstituted, withdraw the reconstituted solution from each vial, 
using the large volume (60 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 an IV bag. 
4. While it is permissible to combine the bolus and infusion into a single IV bag, it is 

recommended that the bolus and infusion be split into two separate bags to ensure the correct 
administration rate. 



15  

5. Attach ancillary equipment (i.e., extension tubing, air filters, 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) 
 

EU/1/18/1345/001 
 
 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 26 April 2019 
Date of latest renewal: 01 April 2020 

 
 

10. DATE OF REVISION OF THE TEXT 
 

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



16  

 
ANNEX II 

 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 
FOR THE CONDITIONAL MARKETING AUTHORISATION 



17  

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

Name and address of the manufacturer of the biological active substance 

Lonza Biologics Porrino, S.L. 
C/ La Relba s/n 
Porrino 
Pontevedra 36410 
Spain 

Name and address of the manufacturer responsible for batch release  
 
Portola Netherlands B.V. 
Prins Bernhardplein 200 
1097 JB 
Amsterdam 
Netherlands 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

• Periodic safety update reports 

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 

The marketing authorisation holder shall submit the first periodic safety update report for this 
product within 6 months following authorisation. 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

• Risk Management Plan (RMP) 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 



18  

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 
FOR THE CONDITIONAL MARKETING AUTHORISATION 

This being a conditional marketing authorisation and pursuant to Article 14(7) of Regulation (EC) 
No 726/2004, the MAH shall complete, within the stated timeframe, the following measures: 

 

Description Due date 
In order to further substantiate correlation of the biomarker (antiFXa-activity) with 
haemostatic efficacy and clarify the risk of thromboses and thromboembolic events, the 
MAH should submit the results of ANNEXA-4, an interventional non-randomized, 
multicentre, prospective, open-label, single-group study in patients with acute major 
bleeding. 

Submission of 
the final CSR 
by 30 June 
2021 

In order to further confirm the posology of Ondexxya, the MAH should submit the 
results of a comparative PK study with Generation 1, process 3, and Generation 2 
material (study 19-514). The study should be based on an agreed protocol. 

Submission 
of the final 
CSR by 
31 January 
2020 
 
Immunogen-
icity report 
by 
28 February 
2020  

In order to substantiate correlation of the biomarker (antiFXa-activity) with haemostatic 
efficacy and clarify the risk of thromboses and thromboembolic events, the MAH 
should submit the results of a global randomised controlled clinical trial to investigate 
the use of andexanet versus standard of care treatment in patients with intracranial 
haemorrhage (ICH) taking apixaban, rivaroxaban, or edoxaban (study 18-513). 

Submission of 
the final CSR 
by 30 June 
2023 

In order to further confirm the efficacy and safety, the MAH should submit an updated 
PK/PD model using all previously incorporated data (from studies 11-501, 12-502, 14- 
503, 14-504, and 14-506) as well as newly incorporated data from study 16-512 (PK- 
PD study of Generation 2 andexanet versus Generation 1), study 16-508 (PK-PD study 
of andexanet in individuals of Japanese ethnicity), and study 14-505 (ANNEXA-4). 

Submission by 
30 September 
2019 



19  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



20  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



21  

 

 
 
 

 
 

Ondexxya 200 mg powder for solution for infusion 
andexanet alfa 

 
 

 
 

Each vial contains 200 mg of andexanet alfa. 
 
 

 
 

Excipients: Tris base, Tris hydrochloride, L-arginine hydrochloride, sucrose, mannitol, polysorbate 80 
 
 

 
 

Powder for solution for infusion 
4 x 1 vial of 200 mg 

 
 

 
 

For single use only. 
Read the package leaflet before use. 
Intravenous use. 

 
 

 
 

Keep out of the sight and reach of children. 
 
 

 
 
 

 
 

EXP 
 
 

 
 

Store in a refrigerator. Do not freeze. 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 

1. NAME OF THE MEDICINAL PRODUCT 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

3. LIST OF EXCIPIENTS 

4. PHARMACEUTICAL FORM AND CONTENTS 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

8. EXPIRY DATE 

9. SPECIAL STORAGE CONDITIONS 



22  

 

 
 
 

 
 
Alexion Europe SAS 
103-105 rue Anatole France 
92300 Levallois-Perret 
France 
 

 
 

EU/1/18/1345/001 
 

 
 

Lot 
 
 

 
 
 

 
 
 

 
 

Justification for not including Braille accepted. 
 
 

 
 

2D barcode carrying the unique identifier included. 
 
 

 
 

PC: 
SN: 
NN: 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

12. MARKETING AUTHORISATION NUMBER(S) 

13. BATCH NUMBER 

14. GENERAL CLASSIFICATION FOR SUPPLY 

15. INSTRUCTIONS ON USE 

16. INFORMATION IN BRAILLE 

17. UNIQUE IDENTIFIER – 2D BARCODE 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 



23  

 

 
 
 

 
 

Ondexxya 200 mg powder for solution for infusion 
andexanet alfa 
Intravenous use 

 
 

 
 
 

 
 

EXP 
 
 

 
 

Lot 
 
 

 
 

200 mg 
 
 

 
 

Store in a refrigerator. 
Do not freeze. 
For single use only. 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

2. METHOD OF ADMINISTRATION 

3. EXPIRY DATE 

4. BATCH NUMBER 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

6. OTHER 



24  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



25  

Package Leaflet:  Information for the patient and user 
 

Ondexxya 200 mg powder for solution for infusion 
andexanet alfa 

 
 

This medicine is subject to additional monitoring.  This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 

 
Read all of this leaflet carefully, because it contains important information for you. Please note 
this medicine is mainly used in emergency situations, and the doctor will have decided that you 
needed it. 

• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or nurse. 
• If you get any side effects, talk to your doctor or nurse. This includes any possible side effects 

not listed in this leaflet.  See section 4. 
 

What is in this leaflet 
1. What Ondexxya is and what it is used for 
2. What you need to know before you receive Ondexxya 
3. How Ondexxya is used 
4. Possible side effects 
5. How Ondexxya is stored 
6. Contents of the pack and other information 

 
 

1. What Ondexxya is and what it is used for 
 

Ondexxya contains the active ingredient andexanet alfa.  It reverses the effects of certain 
anticoagulants called factor Xa inhibitors (apixaban or rivaroxaban).  Factor Xa inhibitors are given to 
prevent clots in your blood vessels. Your doctor may decide to give you Ondexxya to rapidly reverse 
the effects of the anticoagulant in case of a life-threatening or uncontrolled bleeding situation. 

 

2. What you need to know before you receive Ondexxya 

Do not use Ondexxya: 
• if you are allergic to andexanet alfa or any of the other ingredients of this medicine (listed in 

section 6). 
• if you are allergic to hamster proteins 

 
Warnings and precautions 

 
Reversing the effect of a factor Xa inhibitor with Ondexxya may increase the risk of blood clots. 
After treatment with Ondexxya, your doctor will decide when to restart anticoagulant therapy. 

 
If you suffer side effects when you are being given Ondexxya by infusion (drip), your doctor may 
decide to slow down or pause your treatment.  Your doctor may give you an antihistamine medicine to 
help with any side effects (see section 4). 

 
Children and adolescents 

 
There is no information on the use of Ondexxya in children and adolescents. 



26  

Other medicines and Ondexxya 
 

Tell your doctor if you are taking, have recently taken, or might take, any other medicines. 
 

This medicine has been designed to reverse the effects of factor Xa inhibitor medicines only.  It is 
unlikely that Ondexxya will influence the effect of other medicines or that other medicines will 
influence Ondexxya. 

 
Pregnancy and breast-feeding 

 
Tell your doctor if you are pregnant or breast-feeding, think you may be pregnant, or are planning to 
have a baby. 

 
Ondexxya is not recommended during pregnancy or if you have the potential to become pregnant and 
are not using birth control. 

 
Do not breast-feed your child while you are taking this medicine. It is unknown if andexanet alfa is 
excreted in human milk. 

 
Driving and using machines 

 
This medicine is unlikely to affect your ability to drive and use machines. 

 
 

3. How Ondexxya is used 
 

This medicine is for hospital use only. 
 

Your doctor or nurse will give you this medicine by injection or infusion into a vein. 
 

Your doctor or nurse will work out the dose of this medicine that you need. This is based on the 
specific anticoagulant medicine you take as well as on the dose and the time since your last dose of 
anticoagulant medicine. 

 
After you have received Ondexxya, your doctor will decide when to restart your anticoagulant 
treatment. 

 
Detailed instructions for your doctor or nurse on how to give Ondexxya are given at the end of this 
package leaflet (see ‘Handling instructions’). 

 
If you have any further questions on the use of this medicine, ask your doctor. 

 
 

4. Possible side effects 
 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 

The most common side effects associated with Ondexxya in clinical trials of healthy people were 
infusion–related reactions with usually mild symptoms such as flushing or feeling hot (very common 
side effects which may affect more than 1 in 10 people). Headache, cough, or shortness of breath 
(common side effects which may affect up to 1 in 10 people) happened within a few minutes to a few 
hours of the infusion. In clinical trials of patients with life-threatening bleeding, fever and stroke may 
affect up to 1 in 10 people; transient ischaemic attack (TIA), heart attack, and blood clots in the legs or 
lungs may affect up to 1 in 100 people (uncommon side effects). 



27  

List of possible side effects 
 

Very common (may affect more than 1 in 10 people) 
• flushing or feeling hot 
• effects on blood clotting markers: some markers which affect blood clotting were increased for 

a little while and then returned to normal. There were no blood clots in these healthy people. 
 

Common (may affect up to 1 in 10 people) 
• hives 
• dizziness 
• rapid or irregular heartbeat 
• stomach pain or discomfort 
• dry mouth 
• disturbance of taste 
• nausea (feeling sick) 
• chest discomfort 
• feeling cold 
• excessive sweating 
• itching 
• back pain 
• muscle spasms 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not 
listed in this leaflet.  You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects, you can help provide more information on the safety of this 
medicine. 

 
 

5. How Ondexxya is stored 
 

This medicine will be stored in the hospital, and these instructions are intended for hospital staff only. 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the vial and the carton after EXP. 
The expiry date refers to the last day of that month. 

 
Store in a refrigerator (2°C to 8°C). 

Do not freeze. 

Once reconstituted, Ondexxya is for immediate use. 
 

6. Contents of the pack and other information 

What Ondexxya contains 
• The active substance is andexanet alfa. 
• The other ingredients are Tris base, Tris hydrochloride, L-arginine hydrochloride, sucrose, 

mannitol, and polysorbate 80. 
 

What Ondexxya looks like and contents of the pack 
Ondexxya is supplied in glass vials as a white to off-white powder for solution for infusion, which is 
reconstituted (dissolved) before use. The reconstituted solution is a clear, colourless, or slightly 
yellow solution. 



28  

Each pack contains four vials. 
 

Marketing Authorisation Holder 
 

Alexion Europe SAS 
103-105 rue Anatole France 
92300 Levallois-Perret 

   France 
 

Manufacturer 
 

Portola Netherlands B.V. 
Prins Bernhardplein 200 
1097 JB Amsterdam 
Netherlands 
 

 
 

This leaflet was last revised in Month YYYY. 
 

This medicine has been given ‘conditional approval’. This means that there is more evidence to come 
about this medicine. 
The European Medicines Agency will review new information on this medicine at least every year and 
this leaflet will be updated as necessary. 

 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 

 
------------------------------------------------------------------------------------------------------------------------ 

 
The following information is intended for healthcare professionals only. 

 

Andexanet alfa reverses the anticoagulant effect of direct factor Xa (FXa) inhibitor products (apixaban, 
rivaroxaban) only.  Reversal of the effects of other FXa inhibitors (e.g., fondaparinux, unfractionated 
heparin) with andexanet alfa has not been studied in humans.  It will not reverse the effects of non-FXa 
inhibitors. 

 
Dosage and administration 

 
Andexanet alfa is administered as an intravenous (IV) bolus at a target rate of approximately 
30 mg/min over 15 (low dose) or 30 minutes (high dose), immediately 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). 

 
Table 1:  Dosing regimens 

 
 Initial 

intravenous 
bolus 

Continuous 
intravenous 

infusion 

Total number 
of 200 mg 

vials needed 

Low dose 400 mg at a target rate of 
30 mg/min 

4 mg/min for 120 minutes 
(480 mg) 5 

High dose 800 mg at a target rate of 
30 mg/min 

8 mg/min for 120 minutes 
(960 mg) 9 



29  

Dosage recommendations have been defined from the effects of andexanet alfa in healthy volunteers 
administered a direct FXa inhibitor and from the ability to reverse the levels of anti-FXa activity. The 
posology was confirmed in a study in patients with acute major bleeding. 

 
Reversal of apixaban 
The recommended dose regimen of andexanet alfa 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 

 
 

FXa 
inhibitor 

 
FXa inhibitor 

last dose 

Timing of FXa inhibitor last dose before 
andexanet alfa initiation 

< 8 hours or unknown ≥ 8 hours 

 
 

Apixaban 

≤ 5 mg Low dose  
 

Low dose > 5 mg/ 
Unknown 

 
High dose 

 

Reversal of rivaroxaban 
The recommended dose regimen of andexanet alfa 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 

 
 

FXa 
inhibitor 

 
FXa inhibitor 

last dose 

Timing of FXa inhibitor last dose before 
andexanet alfa initiation 

< 8 hours or unknown ≥ 8 hours 

 
 

Rivaroxaban 

≤ 10 mg Low dose  
 

Low dose > 10 mg/ 
Unknown 

 
High dose 

 

Patients being treated with FXa inhibitor therapy have underlying disease states that predispose them 
to thromboembolic events. Reversing FXa inhibitor therapy exposes patients to the thrombotic risk of 
their underlying disease. To reduce this risk, resumption of anticoagulant therapy should be 
considered as soon as medically appropriate. 

 
Handling instructions 
Andexanet alfa is to be reconstituted and the 10 mg/mL solution then transferred to a suitable IV bag 
comprised of polyolefin (PO) or polyvinyl chloride (PVC) material without further dilution prior to 
administration by IV infusion using a 0.2 or 0.22 micron in-line polyethersulfone (PES) or equivalent 
low protein-binding filter. 

 
For reconstituted solutions, chemical and physical in-use stability have been demonstrated for at least 
eight hours at 25°C. From a microbiological point of view, once opened, 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. 



30  

Reconstitution 
 

Before starting reconstitution, you will need the following: 
• Calculated number of vials as given in table 1. 
• Same number of 20 mL (or larger) solvent syringes equipped with a 20 gauge (or larger) 

needle. 
• Alcohol swabs. 
• Large (60 mL or larger) sterile syringe.  If administration is done with a syringe driver, 

multiple syringes should be used to contain the final volume of reconstituted product. 
• IV PO or PVC bag (150 mL or larger) to contain the final volume of reconstituted product (if 

administration is done with an IV bag). 
• Water for injection 

 
Andexanet alfa does not need to be brought to room temperature before reconstitution or 
administration to the patient.  Use aseptic technique during the reconstitution procedure. 

 
Reconstitute each vial 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 injection. 
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 andexanet alfa within eight hours after reconstitution when stored at room temperature. 
 

Administration using a syringe pump 
1. Once all required vials are reconstituted, withdraw the reconstituted solution from each vial, 

using the large volume (60 mL or larger) syringe equipped with a 20 gauge (or larger) needle. 
2. Prepare the bolus and infusion in separate large volume syringes. 
3. Due to the additional volume, the high dose bolus and infusion will need 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, air filters, syringe driver) 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 an intravenous bag 
1. Once all required vials are reconstituted, withdraw the reconstituted solution from each vial, 

using the large volume (60 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 an IV bag. 
4. While it is permissible to combine the bolus and infusion into a single IV bag, to ensure the 

correct administration rate, it is recommended that the bolus and infusion are split into two 
separate bags. 



31  

5. Attach ancillary equipment (i.e., extension tubing, air filters, 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. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	1. NAME OF THE MEDICINAL PRODUCT
	2. QUALITATIVE AND QUANTITATIVE COMPOSITION
	3. PHARMACEUTICAL FORM
	4. CLINICAL PARTICULARS
	4.1 Therapeutic indications
	4.2 Posology and method of administration
	Table 1: Dosing regimens
	Table 2: Summary of dosing for reversal of apixaban
	Table 3: Summary of dosing for reversal of rivaroxaban

	4.3 Contraindications
	4.4 Special warnings and precautions for use
	4.5 Interaction with other medicinal products and other forms of interaction
	4.6 Fertility, pregnancy and lactation
	4.7 Effects on ability to drive and use machines
	4.8 Undesirable effects
	Table 4: List of adverse reactions in healthy subjects and bleeding patients

	4.9 Overdose

	5. PHARMACOLOGICAL PROPERTIES
	5.1 Pharmacodynamic properties
	Figure 1: Change in anti-FXa activity (ng/mL) in healthy subjects anticoagulated with apixaban (A) and rivaroxaban (B)

	5.2 Pharmacokinetic properties
	5.3 Preclinical safety data

	6. PHARMACEUTICAL PARTICULARS
	6.1 List of excipients
	6.2 Incompatibilities
	6.3 Shelf life
	6.4 Special precautions for storage
	6.5 Nature and contents of container
	6.6 Special precautions for disposal and other handling

	7. MARKETING AUTHORISATION HOLDER
	8. MARKETING AUTHORISATION NUMBER(S)
	9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
	10. DATE OF REVISION OF THE TEXT
	ANNEX II
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE CONDITIONAL MARKETING AUTHORISATION

	ANNEX III
	A. LABELLING
	B. PACKAGE LEAFLET