Andexxa Formulary Kit

Formulary Kit
IMPORTANT SAFETY INFORMATION FOR ANDEXXA®

(coagulation factor Xa [recombinant], inactivated-zhzo)
WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, AND SUDDEN DEATHS
Treatment with ANDEXXA has been associated with serious and life-threatening adverse events, including:
• Arterial and venous thromboembolic events
• Ischemic events, including myocardial infarction and ischemic stroke
• Cardiac arrest
• Sudden deaths
Monitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for
symptoms and signs that precede cardiac arrest and provide treatment as needed.
INDICATION
ANDEXXA® (coagulation factor Xa [recombinant], inactivated-zhzo) is a recombinant modified human factor Xa
(FXa) protein indicated for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation is
needed due to life-threatening or uncontrolled bleeding.
This indication is approved under accelerated approval based on the change from baseline in anti-FXa
activity in healthy volunteers. An improvement in hemostasis has not been established. Continued approval
for this indication may be contingent upon the results of studies that demonstrate an improvement in
hemostasis in patients.
Limitations of Use
ANDEXXA has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to
any FXa inhibitors other than apixaban or rivaroxaban.
Please see Important Safety Information throughout, and read US full

1 Prescribing Information including Boxed WARNING.
Table of Contents
Part 1: Disease Description....................................................................................... 3
Direct FXa Inhibitors and the Coagulation Cascade..................................... 3
Clinical burden and unmet need..................................................................... 3
Part 2: Product Information...................................................................................... 4
Indication and mechanism of action............................................................... 4
Part 3: Supporting Evidence.................................................................................... 5
Clinical Development Program......................................................................... 5
ANNEXA-A and ANNEXA-R........................................................................... 6
ANNEXA-4....................................................................................................... 9
Multicenter retrospective safety analysis (Coleman et al).................... 14
Indirect retrospective analysis (Cohen et al)........................................... 16
Conclusions.................................................................................................. 19
Pending confirmatory clinical trial.................................................................. 20
Anticoagulant reversal guidelines and recommendations......................... 21
Part 4: Additional Resources.................................................................................. 23
Clinical protocol example............................................................................... 23

Dosing information............................................................................................ 24
Reconstitution and preparation guide .......................................................... 25

Pricing and ordering......................................................................................... 27
Additional resources and support................................................................... 28
Part 5: References................................................................................................... 30
Please see Important Safety Information throughout, and read US full

2 Prescribing Information including Boxed WARNING.
PART 1: Disease Description
Direct FXa Inhibitors and the Coagulation Cascade

Apixaban and rivaroxaban are direct oral anticoagulants (DOACs) that selectively inhibit factor Xa (FXa),
thus reducing thrombin formation and preventing the formation of fibrin clots.1,2 FXa plays a central role in the
cascade of blood coagulation (Figure 1).3
Figure 1. Coagulation cascade3,4
Intrinsic pathway
XII XI Extrinsic pathway

IX
VIII VII
X Xa
Common pathway
Prothrombin (II) Thrombin (IIa)
Fibrinogen (I) Fibrin (Ia)
Clinical Burden and Unmet Need

Treatment with FXa inhibitors has potential for major bleeding events associated with a substantial burden,
including high morbidity and mortality.5 In 2 large, randomized, controlled studies of patients with nonvalvular
atrial fibrillation (NVAF) taking apixaban or rivaroxaban, 4% and 6% of patients experienced a major bleed,
respectively.6,7 ARISTOTLE was a double-blind, double-dummy, randomized clinical trial comparing apixaban
with warfarin in patients with atrial fibrillation (N=18,201).6 Major bleeding events reported were 12% ICH, 24%
GI-related, and 64% at other sites.6 ROCKET-AF was a multinational, randomized, double-blind, double-dummy
clinical trial comparing rivaroxaban with warfarin in patients with atrial fibrillation (N=14,264).7 Major bleeding
events reported were 14% ICH, 57% GI-related, and 29% at other sites.7 A high mortality risk is associated with
FXa inhibitor–related ICH, with a 30-day mortality rate observed in 45% of patients in the ARISTOTLE trial and an
all-cause mortality rate observed in 48% of patients in the ROCKET-AF trial.8,9
The number of FXa inhibitor–related bleeds continues to increase as FXa inhibitor use grows, resulting in
approximately 190,000 hospitalizations in apixaban- and rivaroxaban-treated patients from October 1, 2018, to
September 30, 2019.10
The use of FXa inhibitors is expected to continue to increase as the US population ages.11,12 As such, there is a
growing unmet need for the availability of agents used to rapidly reverse anticoagulant activity.11,12
3
PART 2: Product Information
Indication and Mechanism of Action

Indication and usage13
ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo) is a recombinant modified human
FXa protein indicated for patients treated with apixaban or rivaroxaban, when reversal of anticoagulation
is needed due to life-threatening or uncontrolled bleeding.
This indication is approved under accelerated approval based on the change from baseline in anti-FXa
activity in healthy volunteers. An improvement in hemostasis has not been established.
Continued approval for this indication may be contingent upon the results of studies to demonstrate an
improvement in hemostasis in patients.
Limitations of use13
ANDEXXA has not been shown to be effective for, and is not indicated for, the treatment of bleeding related
to any FXa inhibitors other than apixaban and rivaroxaban.
Mechanism of action13
ANDEXXA exerts its procoagulant effect by binding and sequestering the FXa inhibitors apixaban and
rivaroxaban. Another observed procoagulant effect of the ANDEXXA protein is its ability to bind to and inhibit
the activity of tissue factor pathway inhibitor (TFPI). Inhibition of TFPI activity can increase tissue factor–initiated
thrombin generation.
Figure 2. Mechanism of action of ANDEXXA for direct FXa inhibitors13,14
Native FXa ANDEXXA decoy molecule
Active site
Cannot form a Binds to and sequesters

prothrombinase complex the FXa inhibitors rivaroxaban
and apixaban
ANDEXXA is the only antidote for the reversal of apixaban or rivaroxaban activity in patients with major
bleeding.
IMPORTANT SAFETY INFORMATION (CONTINUED)

WARNINGS AND PRECAUTIONS
• Arterial and venous thromboembolic events, ischemic events, and cardiac events, including sudden death,
have occurred during treatment with ANDEXXA. To reduce thromboembolic risk, resume anticoagulant
therapy as soon as medically appropriate following treatment with ANDEXXA. The safety of ANDEXXA has
not been evaluated in subjects who experienced thromboembolic events or disseminated intravascular
coagulation within two weeks prior to the life-threatening bleeding event requiring treatment with ANDEXXA.
Safety of ANDEXXA also has not been evaluated in subjects who received prothrombin complex concentrates,
recombinant factor VIIa, or whole blood products within seven days prior to the bleeding event.
Please see Important Safety Information throughout, and read US full Prescribing Information
4 including Boxed WARNING.
PART 3: Supporting Evidence
Clinical Development Program

The efficacy and safety of ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo) has been
evaluated in preclinical animal models; Phase 1, 2, and 3 studies in healthy subjects; and a Phase 3b/4 study
in patients with major bleeding.14-18
In addition, several real-world evidence studies have been published.5,19 Findings from these studies
lend further support to the totality of evidence supporting the use of ANDEXXA for patients treated with
apixaban or rivaroxaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled
bleeding.5,19
Table 1. Phase 2, 3, and 4 studies in the ANDEXXA clinical development program in patients taking
apixaban and/or rivaroxaban5,14-16,18
Study Study design N Primary endpoint(s)
Phase 2: • Percent change in

54 healthy subjects anti-FXa activity
apixaban15
• Restoration of thrombin
Phase 2, randomized, generation
double-blind, • Prothrombin time
Phase 2: placebo-controlled (PT), activated partial
48 healthy subjects thromboplastin time
rivaroxaban16
(aPTT), and activated
clotting time (ACT)
ANNEXA-A:
Phase 3, randomized, 65 older healthy subjects
apixaban14
double-blind, • Percent change in
placebo-controlled anti-FXa activity
ANNEXA-R:
80 older healthy subjects
rivaroxaban14
• Percent change in
anti-FXa activity
Phase 3b/4, prospective, 352 patients with acute
ANNEXA-418 • Proportion of patients
single-arm, open-label major bleeding
with good or excellent
hemostatic efficacy
• Proportion of patients
Ongoing study: Phase 4, prospective, Estimated 1200 patients
with good or excellent
ANNEXA-I20 randomized, open-label with acute ICH
hemostatic efficacy

WARNINGS AND PRECAUTIONS (CONTINUED)
• Re-elevation or incomplete reversal of anticoagulant activity can occur.
• ANDEXXA may interfere with the anticoagulant effect of heparin. If anticoagulation is needed, use an
alternative anticoagulant to heparin.
ANNEXA-A and ANNEXA-R: Reversal of FXa Inhibitor

Activity in Healthy Subjects
Objective14
The primary objective was to evaluate the efficacy and safety of ANDEXXA® (coagulation factor Xa
(recombinant), inactivated-zhzo) for the reversal of FXa inhibitor anticoagulation with apixaban (ANNEXA-A)
or rivaroxaban (ANNEXA-R) in healthy subjects aged 50-75 years.
Study design14
ANNEXA-A and ANNEXA-R were two Phase 3, randomized, double-blind, placebo-controlled studies
designed to establish the efficacy and safety of ANDEXXA for the reversal of anticoagulation with apixaban
or rivaroxaban in older, healthy subjects. In ANNEXA-A (apixaban reversal), 23/31 subjects received ANDEXXA.
Healthy subjects received apixaban 5 mg twice daily for 3.5 days. At 3 hours after the last dose, ANDEXXA or
placebo was administered as a 400-mg IV bolus followed by a 4 mg/minute continuous infusion for 2 hours. In
ANNEXA-R (rivaroxaban reversal), 26/39 subjects received ANDEXXA. Healthy subjects received rivaroxaban
20 mg once daily for 4 days. At 4 hours after the last dose, ANDEXXA or placebo was administered as an 800-
mg IV bolus followed by an 8 mg/minute continuous infusion for 2 hours.
Inclusion/exclusion criteria21
Key inclusion criteria included healthy subjects (aged 50-75 years) with normal laboratory reference ranges
for PT, aPTT, and ACT; serum creatinine <1.5 mg/dL; and a body mass index (BMI) of 19 to 32 kg/m2 with a
weight of at least 60 kg. Exclusion criteria included subjects with history of abnormal bleeding or risk factors
for bleeding, past or current medical history of thrombosis, and an absolute or relative contraindication
to anticoagulation.
Study endpoints14
The primary efficacy outcome was mean percent change in anti-FXa activity from baseline to nadir for the
low-dose and high-dose regimens of bolus followed by continuous infusion. Nadir is defined as the smallest
value measured within 5 minutes after the end of the continuous infusion. Key secondary endpoints included
the proportion of participants with ≥80% reduction in anti-FXa activity from baseline to nadir after ANDEXXA
administration or placebo; the occurrence of an endogenous thrombin potential above the lower limit of the
baseline-derived range at its peak after ANDEXXA administration or placebo; and the change in unbound
inhibitor plasma concentration from baseline to nadir after ANDEXXA administration or placebo.
Safety endpoints included the incidence of adverse events, thromboembolic events, and antibodies to factor
X (FX), FXa, and ANDEXXA.

ADVERSE REACTIONS
The most common adverse reactions (≥ 5%) in bleeding subjects receiving ANDEXXA were urinary tract
infections and pneumonia. The most common adverse reactions (≥ 3%) in healthy volunteers treated with
ANDEXXA were infusion-related reactions.
ANNEXA-A and ANNEXA-R: Study Results

Primary efficacy endpoint14
Anti-FXa activity was rapidly reduced in 2 minutes after a bolus dose of ANDEXXA® (coagulation factor Xa
(recombinant), inactivated-zhzo), and reversal was sustained for 2 hours. When ANDEXXA was administered
as a bolus plus a 2-hour infusion, it also reduced anti-FXa activity to a greater extent than did placebo, both
in the apixaban study (92% vs 33%, p<0.001) and in the rivaroxaban study (97% vs 45%, p<0.001).
Figure 3. Anti-FXa activity in apixaban- and rivaroxaban-treated healthy subjects14
ANNEXA-A (apixaban-treated patients) ANNEXA-R (rivaroxaban-treated patients)
End of bolus End of 2-hour infusion End of bolus End of 2-hour infusion
250 400
Anti-FXa activity (ng/mL)

200
300
150
200
100
100
50
0 0
0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10 11 12 0 0.2 0.4 0.6 1 2 3 4 5 6 7 8 9 10 11 12
Time after bolus (hours) Time after bolus (hours)
ANDEXXA 400-mg bolus Placebo bolus + 2-hour infusion (n=8) ANDEXXA 800-mg bolus Placebo bolus + 2-hour infusion (n=13)
+ 480 mg x 2-hour infusion (n=23) + 960 mg x 2-hour infusion (n=26)
The points on the graph represent the mean anti-FXa activity level. There was a significant difference (p<0.05) in the percent change in anti-FXa
activity (relative to the prebolus activity level) between ANDEXXA and placebo until 2 hours after administration of the bolus or infusion.14
Secondary efficacy endpoint14

The mean concentration of unbound (pharmacologically active) apixaban and rivaroxaban in plasma
was reduced by a significantly greater amount after administration of a bolus of ANDEXXA than after
administration of placebo (apixaban reduction, 9.3 ng/mL vs 1.9 ng/mL; rivaroxaban reduction, 23.4 ng/mL
vs 4.2 ng/mL; p<0.001 for both). After administration of bolus plus an infusion of ANDEXXA, the mean plasma
concentrations of unbound apixaban and rivaroxaban were reduced by a significantly greater amount with
ANDEXXA than with placebo (apixaban reduction, 6.5 ng/mL vs 3.0 ng/mL; rivaroxaban reduction, 30.3 ng/mL
vs 12.1 ng/mL; p<0.001 for both). This reversal was sustained with a bolus plus an infusion of ANDEXXA.
IMPORTANT SAFETY INFORMATION

• Cardiac arrest
• Sudden deaths
ANNEXA-A and ANNEXA-R: Study Results (Continued)

Secondary efficacy endpoint (continued)14
After administration of bolus plus 2-hour infusion of ANDEXXA, the mean change in thrombin generation
was significantly greater among participants who received ANDEXXA compared to those who received
placebo in both studies (p<0.001 for both). Thrombin generation was restored to above the lower limit of the
normal range in all participants who received ANDEXXA in both studies compared to 25% of participants who
received placebo in the apixaban study and 0 participants2500
ANNEXA-A who received
End of bolus placebo in the
End of 2-hour rivaroxaban study
infusion
(apixaban-
(p<0.001 vs placebo for each comparison). Thrombin
treated patients)generation
2000
was restored within 2 to 5 minutes following
ETP (nM/min)
the bolus dose of ANDEXXA and was sustained through infusion 1500
for at least 22 hours.
Pre-anticoagulant
mean ± SD
1000
500 ANDEXXA 40-mg bolus + 480 mg x 2-hour infusion (n=23)

Figure 4. Thrombin generation in apixaban- and rivaroxaban-treated
0
healthyPlacebo
subjects 14
bolus + 2-hour infusion (n=8)
e .0 8 10 12 14 16 18 20 22
se
lin 0 0.2 0.4 0.6 2 4 6
Ba
ANNEXA-A (apixaban-treated patients) ANNEXA-R (rivaroxaban-treated
Time after bolus (hours) patients)
End of bolus End of 2-hour infusion End of bolus End of 2-hour infusion
2500 ANNEXA-R 2500
(rivaroxaban-
tients) 2000
treated patients)
2000
ETP (nM/min)
ETP (nM/min)
1500 1500 Pre-anticoagulant

Pre-anticoagulant
mean ± SD mean ± SD
1000 1000
500 ANDEXXA 40-mg bolus + 480 mg x 2-hour infusion (n=23) 500 ANDEXXA 800-mg bolus + 960 mg x 2-hour infusion (n=26)
Placebo bolus + 2-hour infusion (n=8) Placebo bolus + 2-hour infusion (n=13)
0 0
e .0 e 8 10 12 14 16 18 20 22
lin 0 0.2 0.4 0.6 2 4 6 8 10 12 14 16 18 20 22 lin 0.0 0.2 0.4 0.6 2 4 6
se se
Ba Ba
Time after bolus (hours) Time after bolus (hours)
The points on the

End graph represent
of bolus End of the mean
2-hour endogenous thrombin potential (ETP), and I bars indicate the standard error. There was a significant
infusion
2500
difference (p<0.001) between ANDEXXA and placebo for at least 12 hours after administration of the bolus alone or bolus + infusion.14
an-
2000
tients)
ETP (nM/min)
ANNEXA-A and ANNEXA-R: Safety in Healthy

1500 Pre-anticoagulant
mean ± SD
1000
Volunteers 500
0
e
ANDEXXA 800-mg bolus + 960 mg x 2-hour infusion (n=26)
Placebo bolus + 2-hour infusion (n=13)
In the pooled
0.2 0safety
.4
analysis,
2 4 6 8 10 there
lin 0.0
0.6
se
12 14 16 were
18 20 22 no serious or severe adverse events, and no thromboembolic
Ba
Time after bolus (hours)
events were reported. 13,14
Frequency of adverse reactions was similar between the ANDEXXA-treated and
the placebo-treated groups. Infusion-related AEs occurred in 18% (39/233) of the ANDEXXA-treated group,
and these AEs occurred more frequently than in the placebo-treated.13 ANDEXXA infusion was discontinued
in 1 subject due to mild hives.13 Antibodies to FX or FXa did not develop in any participants.14 Neutralizing
antibodies against ANDEXXA were not detected.14 Low titers of anti-ANDEXXA antibodies were observed in
26/145 healthy subjects (17%); 6% (9/145) were first observed at day 30, with 20 subjects (14%) still having titers
at the last time point (days 44-48).13

ANNEXA-4: Acute Major Bleeding Associated With

Factor Xa Inhibitors
Objective18
The primary objective was to evaluate the efficacy and safety of ANDEXXA® (coagulation factor Xa
(recombinant), inactivated-zhzo) in patients with acute major bleeding and administration of an FXa
inhibitor within 18 hours.
Study design
ANNEXA-4 was a Phase 3b/4 multicenter, prospective, single-arm, open-label study that evaluated the use
of ANDEXXA in patients with acute major bleeding administered an FXa inhibitor within 18 hours (N=352).18 All
patients in the ANNEXA-4 trial received an ANDEXXA bolus dose (over a period of 15-30 minutes) followed
by a 2-hour continuous infusion.18 A low-dose or high-dose regimen of ANDEXXA was used, depending on
the specific FXa inhibitor, dose of FXa inhibitor, and time since the patient’s last dose of FXa inhibitor prior
to enrollment. The low-dose regimen consisted of a bolus dose of 400 mg at a target rate of 30 mg/minute,
and an infusion dose of 480 mg at 4 mg/minute for 2 hours. The high-dose regimen consisted of a bolus
dose of 800 mg at a target rate of 30 mg/minute, and an infusion dose of 960 mg at 8 mg/minute for 2
hours.22 The independent adjudication committee reviewed each case to determine hemostatic efficacy
based on predetermined criteria to provide a rating of excellent/good (effective hemostasis) or poor/none
(noneffective hemostasis).18,22 For patients with intracranial hemorrhage, CT or MRI of the head was performed
within 2 hours before ANDEXXA and at 1 and 12 hours after continuous infusion.22
Inclusion/exclusion criteria18
Key inclusion criteria included patients ≥18 years of age with acute major bleeding and had received apixaban
or rivaroxaban within 18 hours. Key exclusion criteria included surgery scheduled within 12 hours after ANDEXXA
administration (with the exception of minimally invasive operations or procedures); Glasgow Coma Scale (GCS)
score of <7 or an intracerebral hematoma volume >60 cc; expected survival of <1 month; the occurrence of
a thrombotic event within 2 weeks of enrollment; and use of vitamin K antagonists, dabigatran, prothrombin
complex concentrates (PCCs), recombinant factor VII, whole blood, or plasma within the preceding 7 days.
Study endpoints
The coprimary endpoints were: (a) percent change in anti-FXa activity from baseline to the nadir between
5 minutes after the end of the bolus up until the end of the infusion, and (b) rate of effective hemostasis within
12 hours after infusion as rated by an independent endpoint adjudication committee.18
Safety outcomes included thrombotic events, antibodies to FX and FXa or ANDEXXA, and mortality at
30 days.18

ANNEXA-4: Patient Demographics and Baseline

Characteristics
Patients enrolled in ANNEXA-4 represented a high-risk population for thrombotic events.18 All patients received
a bolus and subsequent ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo) infusion and
were followed for 30 days or until death.18
Table 2. Characteristics of patients at baseline18a

Safety Population (N=352) Efficacy Population (n=254)
Age, years, mean (SD) 77.4 (10.8) 77.1 (11.1)
Male, n (%) 187 (53) 129 (51)
White race, n (%)b 307 (87) 222 (87)
BMI (kg/m2), mean (SD) 27.0 (5.9) 27.0 (6.2)
Medical history, n (%)
Myocardial infarction 48 (14) 36 (14)
Stroke 69 (20) 57 (22)
Deep vein thrombosis 67 (19) 53 (21)
Pulmonary embolism 41 (12) 28 (11)
Atrial fibrillation 286 (81) 204 (80)
Heart failure 71 (20) 56 (22)
Diabetes mellitus 107 (30) 80 (31)
FXa inhibitors, n (%)
Apixabanc 194 (55) 134 (53)
Rivaroxaban 128 (36) 100 (39)
Site of bleeding, n (%)
Intracranial 227 (64) 171 (67)
GI 90 (26) 62 (24)
Other 35 (10) 21 (8)
SD=standard deviation.
a
Percentages may not total 100 because of rounding.18
b
Race was reported by the investigators.18
c
In 1 patient who reported receiving apixaban, analysis of plasma indicated a high concentration of rivaroxaban.18

ADVERSE REACTIONS
ANNEXA-4: Anti-FXa Efficacy Results

The efficacy-evaluable population included 234 patients with baseline anti-FXa activity of ≥75 ng/mL for
apixaban or rivaroxaban who had confirmed major bleeding at presentation.18 The total efficacy analysis set
included 254 patients, of which 53% of patients were on apixaban and 39% of patients were on rivaroxaban.18
The median decrease from baseline to nadir in anti-FXa activity for apixaban was –93% (95% CI, –94% to –92%)
and for rivaroxaban was –93% (95% CI, –94% to –90%). The change from baseline to end of bolus can be seen
in Figure 5.13
Figure 5. Anti-FXa activity in apixaban- and rivaroxaban-treated patients in ANNEXA-418
ANNEXA-4 (apixaban) ANNEXA-4 (rivaroxaban)

Anti-FXa activity Anti-FXa activity
–92 (95% CI, 88 to 94)

250
211.8
–92 (95% CI, 91 to 93)
200
149.7
150
121.7
104.6 101.4
100 97.2 91.2
85.5
50
11.1 11.5 14.2 16.5

0
Baseline End of End of 4 hr 8 hr 12 hr Baseline End of End of 4 hr 8 hr 12 hr
bolus infusion bolus infusion

• Cardiac arrest
• Sudden deaths
ANNEXA-4: Hemostatic Efficacy Results

Of the 254 patients in the efficacy analysis, 249 could be evaluated for hemostatic efficacy.18 For intracerebral
hemorrhage, an increase in hematoma volume of ≤20% at both 1 hour and 12 hours compared to baseline
constituted an excellent rate, while an increase of >20% but ≤35% at 12 hours constituted a good rate.22 For GI,
urinary, or other nonvisible bleeding, a decrease in both hemoglobin and hematocrit of ≤10% compared to
baseline constituted an excellent rate, while a decrease of >10% but ≤20% constituted a good rate.22 Clinical
hemostasis was adjudicated as excellent or good in 82% of patients (204/249) 12 hours after ANDEXXA®
(coagulation factor Xa (recombinant), inactivated-zhzo) infusion.18 Please note that additional studies are
needed to establish an improvement in hemostasis in patients managed with ANDEXXA. Continued approval
for this indication may be contingent upon these results.13
Table 3. Clinical hemostatic efficacy 12 hours after ANDEXXA infusion in ANNEXA-418
No. of patients/
Group Percent with excellent or good hemostasis (95% CI)
total no.
Overall 204/249 82 (77-87)
Drug
Apixaban 109/131 83 (77-90)
Rivaroxaban 79/99 80 (72-88)
Sex
Male 101/127 80 (73-87)
Female 103/122 84 (78-91)
Site of bleeding
Gastrointestinal 51/60 85 (76-94)
Intracranial 135/168 80 (74-86)
Other 18/21 86 (71-100)
Age
<65 years 23/28 82 (68-96)
65-75 years 57/66 86 (78-95)
>75 years 124/155 80 (74-86)
ANDEXXA dose
Low 172/208 83 (78-88)
High 32/41 78 (65-91)
0 25 50 75 100

ANNEXA-4: Safety Results

The safety analysis population included all 352 patients who received ANDEXXA® (coagulation factor
Xa (recombinant), inactivated-zhzo).18 There were 54 deaths (15%) prior to the 30-day visit; with 42
cardiovascular deaths, including 3 with unknown causes and 2 that were unadjudicated; and 12
non-cardiovascular deaths.13 Of the 236 subjects with available samples, 6.8% (16/236) had antibodies
against ANDEXXA. None of these anti-ANDEXXA antibodies were neutralizing. No neutralizing antibodies
cross-reacting with FX or FXa have been detected in healthy subjects (0/145) or in bleeding subjects
(0/209) to date.13
There were 18% (63/352) of subjects who experienced 1 or more of the following overall thromboembolic
events: cerebrovascular accident (CVA) (16/63; 25%), deep vein thrombosis (DVT) (16/63; 25%), acute
myocardial infarction (10/63; 16%), pulmonary embolism (5/63; 8%), and transient ischemic attack (TIA)
(1/63; 2%).13 Of the 352 subjects who received ANDEXXA, 223 received at least 1 dose of parenteral or
oral anticoagulant therapy within 30 days after treatment.13 Restart of any anticoagulation includes
the use of any form of heparin or low–molecular-weight heparin, fondaparinux, or argatroban, or any
oral anticoagulant, including vitamin K antagonists and non–vitamin K antagonists (at any dose and for
any duration).18 Of these 223, 18 subjects (8%) experienced a thromboembolic event and/or ischemic
event after restarting anticoagulation.13 No thromboembolic events were reported in these patients after
restarting oral anticoagulation.18

ADVERSE REACTIONS
Multicenter Retrospective Safety Analysis

(Coleman et al)
Objective19
The aim of this study was to describe patient demographics, utilization of reversal or replacement agents,
including ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo) and 4-factor prothrombin
complex concentrate (4F-PCC), and outcomes associated with management of FXa inhibitor–associated
major bleeds in US hospitals.19
Study design19
This was a multicenter, retrospective, electronic medical record survey of adult patients hospitalized with
FXa inhibitor–related bleeding.19 The aim was to describe the real-world utilization and outcomes associated
with management of these bleeds.
Limitations19
Data from this study were retrospective and observational in nature, were not based on controlled clinical
studies, and did not support any conclusions on the comparative safety or efficacy of reversal agents
described herein.19 The study results should not be interpreted as providing evidence of either superiority or
noninferiority of ANDEXXA or supportive care therapies. Further study is warranted to confirm clinically and
statistically relevant differences in in-hospital mortality rates. Results from these analyses were not adjusted
for confounding factors and may differ from results seen in the clinical practice of a particular provider.
Other than ANDEXXA, agents in this analysis are not approved for the management of FXa inhibitor–related
bleeding. ANDEXXA is the only antidote indicated to reverse apixaban- or rivaroxaban-related severe
bleeding.

• Cardiac arrest
• Sudden deaths

Multicenter Retrospective Safety Analysis: Results

Real-world evidence has started to emerge since the availability of ANDEXXA® (coagulation factor Xa
(recombinant), inactivated-zhzo).19 In a chart review of 3030 FXa inhibitor–related hospitalizations for major
bleeds from 45 hospitals across the US, 342 bleeds were managed with ANDEXXA. Forty-five percent of FXa
inhibitor–related bleeds were associated with apixaban and 49% were associated with rivaroxaban.
Observed inpatient mortality was 4% for patients managed with ANDEXXA (n=342) and 8% to 11% for patients
managed with other supportive care options (n=2688). Other supportive care options were defined as
4F-PCC, fresh frozen plasma (FFP), 3-factor prothrombin complex concentrate (3F-PCC), recombinant factor
VIIa, activated 4F-PCC, tranexamic acid, vitamin K, or no reversal/replacement administered. Other than
ANDEXXA, agents in this analysis are not approved for the management of apixaban- or rivaroxaban-related
bleeding.19
Figure 6. Inpatient mortality by bleed type: all FXa inhibitor–related bleeds (safety analysis)19
ANDEXXA
30%
4F-PCC
27%
25% FFP
25%
23% 23% ALL OTHER
21% NO REVERSAL OR REPLACEMENT

Inpatient mortality
20%
16%
15% 14%
11% 11%
10% 10% 10%
10% 9%
8% 8%
7% 7%
5%
5% 4% 4% 4% 4% 4% 4% 4% 4% 4%
1% 0%
0%
0%
All bleeds Intracranial hemorrhage Trauma GI bleeds Critical compartment Other bleeds
(N=3030) (ICH)
The study was not designed to provide comparative safety data and should not be interpreted as providing evidence of either superiority or
noninferiority of ANDEXXA or supportive care therapies. Further study is warranted to confirm clinically and statistically relevant differences in
in-hospital mortality. Due to the descriptive nature of this study, no inferential comparisons should be made across subgroups.

ADVERSE REACTIONS
Indirect Retrospective Analysis (Cohen et al)

Objective5
The goal of this analysis was to evaluate 30-day mortality outcomes associated with the management of FXa
inhibitor–related major bleeds by comparing data from patients treated with ANDEXXA® (coagulation factor
Xa (recombinant), inactivated-zhzo) or prothrombin complex concentrates (PCCs).
Study design5
This indirect, retrospective analysis of results from the ANNEXA-4 and ORANGE studies used propensity score
matching (PSM) to compare all-cause 30-day mortality in the whole cohort and by type of bleed: ICH,
GI bleed, and other major bleeds. ANNEXA-4 and ORANGE were 2 prospective studies that enrolled patients
with FXa inhibitor–related bleeding:
• ORANGE was an observational, prospective registry study that collected information from 32 UK hospitals on
the presentation and clinical outcomes of patients who were admitted for a major bleeding episode while
on oral anticoagulant therapy from 2013 to 2016 (N=2192)
– Refinement of the ORANGE patient population for this analysis: Of the total safety population, patients
were excluded if they were receiving anticoagulants other than apixaban or rivaroxaban, did not have
observed mortality data, did not have observed age data, or did not have observations for all relevant
covariates (n=145)
• Refinement of the ANNEXA-4 patient population for this analysis: Of the total safety population, patients
were excluded if they were receiving anticoagulants other than apixaban or rivaroxaban, did not have
observed mortality data, or did not have observations for all relevant covariates (n=322)
• Using PSM, all 322 patients included in this analysis from the ANNEXA-4 study were matched with 88 of the
145 patients included from the ORANGE study. Patients who were included in this analysis from the ORANGE
study could be matched with multiple patients from the ANNEXA-4 study if they were the best match (a total
of 53 patients from the ORANGE study were matched multiple times)
• Since this was a real-world analysis derived from 2 datasets, a power analysis was not calculated and all
patients who met inclusion/exclusion criteria were included

• Cardiac arrest
• Sudden deaths
Indirect Retrospective Analysis (Cohen et al)

Limitations5
The main limitation of indirect retrospective analyses is the potential for bias due to baseline differences in the
patient populations. While PSM reduced the risk of bias, differences across the 2 studies in eligibility criteria,
variables reported, and how variables were measured remained. The degree of bias associated with each of
these sources is inherently immeasurable in PSM. This analysis was limited by different inclusion/exclusion criteria
across the 2 studies, with the ANNEXA-4 trial excluding patients with a GCS <7, ICH with hematoma
>60 cc, and expected survival less than 1 month. A GCS threshold was used as an exclusion criterion for ICH
in ANNEXA-4 but not in ORANGE. Baseline size or volume of bleeds, blood pressure, ventricular involvement
for ICH, and time from ICH symptoms to computed tomography could not be included in the propensity
score regression model because these were not measured in the ORANGE study. Similarly, location of GI
bleed (known to influence severity) could not be used in the propensity score model due to a large number
of unknown sites of GI bleeding in ANNEXA-4. Additionally, histories of myocardial infarction and ischemic
heart disease were excluded because each study defined these differently. Lastly, even after matching, there
were still some significant differences between the 2 treatment groups regarding a previous medical history
of TIA, stroke, and hypertension. Lack of matching for potential confounding and highly predictive variables
may have biased the outcomes. Due to the indirect nature of this analysis, further research is warranted to
evaluate differences between these agents for DOAC-related bleeding. ANDEXXA® (coagulation factor Xa
(recombinant), inactivated-zhzo) is the only antidote indicated to reverse apixaban- or rivaroxaban-related
severe bleeding.

ADVERSE REACTIONS
Indirect Retrospective Analysis (Cohen et al): Results

All-cause 30-day mortality was reduced by 57% in patients receiving ANDEXXA® (coagulation factor
Xa (recombinant), inactivated-zhzo).5 The PSM-adjusted all-cause 30-day mortality rate for the whole cohort
was 14.6% in ANDEXXA-treated patients compared with 34.1% in PCC-treated patients (RR, 0.43; 95% CI, 0.29-0.63).
ICH subgroup adjusted all-cause 30-day mortality was 15.3% in patients treated with ANDEXXA compared
to 48.9% in patients treated with PCC (RR, 0.31; 95% CI, 0.20-0.48).
Figure 7. Adjusted (after matching) all-cause 30-day mortality rates for ANDEXXA and PCC5a
60%
–69%
ANDEXXA
50% –57%
49% PCC
40% (34%-64%) –51%
Relative percent
30% 34% 29% change PCC to
(24%-44%) ANDEXXA (95% CI)
20% 25%
(8%-42%)
10% 15% 15% 16%
(11%-19%) (10%-20%) 12% (2%-30%) 13%
(5%-19%) (–17% to 42%)
0%
n=322 n=88 n=209 n=47 n=82 n=28 n=31 n=8
Whole cohort ICH subgroup GI subgroup Other major bleeds subgroup
Due to the indirect nature of this analysis, further research is warranted to confirm the mortality differences between agents for
DOAC-related bleeding.
a
PCC is not indicated to treat patients taking FXa inhibitors with life-threatening bleeding.

• Cardiac arrest
• Sudden deaths

Supporting Evidence: Conclusions

Unmet need and value of ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo)
In clinical studies, major bleeding occurred in up to 6% of patients with NVAF taking DOACs.6,7 In the ARISTOTLE
trial, 12% were ICH, 24% GI-related, and 64% occurring at other sites.6 In the ROCKET-AF trial, major bleeds
reported were 14% ICH, 57% GI-related, and 29% at other sites.7 A high mortality risk is associated with FXa
inhibitor–related ICH, with a 30-day mortality rate observed in 45% of patients in the ARISTOTLE trial and an
all-cause mortality rate observed in 48% of patients in the ROCKET-AF trial.8,9 FXa inhibitor use continues to rise,
resulting in approximately 190,000 hospitalizations in apixaban- and rivaroxaban-treated patients in 2019.10
Prior to FDA approval of ANDEXXA, there was a need to address the reversal of oral FXa inhibitors in response
to a major bleeding episode. ANDEXXA is a specific, rapid reversal agent for FXa inhibitors apixaban or
rivaroxaban in patients with acute major bleeding.13,14 ANDEXXA is a recombinant modified human FXa
protein that is catalytically inactive but rapidly binds and sequesters FXa inhibitors with high affinity to reduce
the concentration of the unbound (pharmacologically active) inhibitors.14 This allows for the restoration of
thrombin generation via endogenous native FXa.14
Efficacy characteristics
Specific reversal agent: ANDEXXA is the only FDA-approved treatment designed to specifically target FXa
inhibition and reverse anticoagulation effects in patients treated with apixaban or rivaroxaban when reversal
of anticoagulation is needed due to life-threatening or uncontrolled bleeding.13
Rapid reversal of apixaban or rivaroxaban anticoagulation: ANDEXXA showed a rapid and significant
reduction in anti-FXa activity (>90%) and unbound apixaban or rivaroxaban concentration within 2 minutes
after administration of a bolus of ANDEXXA in older healthy subjects, and the effects were sustained
throughout a 2-hour infusion.13,14 ANDEXXA (bolus plus infusion) restored thrombin generation to above the
lower limit of the normal range in all apixaban- and rivaroxaban-treated subjects.14
Efficacy in FXa inhibitor–related acute major bleeding: ANDEXXA reduced anti-FXa activity in patients with
acute major bleeding by 93% for both apixaban and rivaroxaban.13 Hemostatic efficacy was also evaluated
and was adjudicated as excellent or good in 82% (95% CI, 77-87) of patients 12 hours after ANDEXXA infusion.
The rates of excellent or good hemostatic efficacy were 85% (95% CI, 76-94) for GI bleeding and 80% (95% CI,
74-86) for ICH.18 Additional studies are needed to establish an improvement in hemostasis
in patients managed with ANDEXXA. Continued approval for this indication may be contingent upon
these results.

ADVERSE REACTIONS
Supporting Evidence: Conclusions (Continued)

Safety and tolerability
In pooled safety data from Phase 3 ANNEXA-A and ANNEXA-R studies in healthy subjects, there were no
reported thromboembolic events, and no serious or severe adverse events.14 Infusion-related reactions (eg,
flushing, feeling hot, dysgeusia, and dyspnea) which were classified as mild to moderate in severity occurred
in 18% of subjects.13
Furthermore, in the safety analysis of the ANNEXA-4 trial in patients with acute major bleeding, there were
54 deaths (15%) overall, with 42 cardiovascular deaths, including 3 with unknown causes and 2 that were
unadjudicated, and 12 non-cardiovascular deaths.13 At day 30, thromboembolic events were reported in
18% of patients, with 8% being reported after restarting any anticoagulation.13 No thromboembolic events
occurred after restarting oral anticoagulation.18
Real-world evidence and outcomes

A multicenter, retrospective electronic medical record (EMR) analysis from 45 US hospitals was conducted
to evaluate real-world utilization and outcomes associated with reversal or replacement agents for the
management of oral FXa inhibitor–related major bleeds.19 Of the 3030 FXa inhibitor–related hospitalizations for
major bleeds, 342 bleeds were managed with ANDEXXA® (coagulation factor Xa (recombinant), inactivated-
zhzo). Observed inpatient mortality for patients managed with ANDEXXA (n=342) was 4%, and 8% to 11% was
observed for patients managed with other supportive care options (n=2688).19
In an indirect, retrospective PSM analysis, 2 single-arm patient-level datasets (ANNEXA-4 and ORANGE) compared
the 30-day mortality of ANDEXXA vs PCC following life-threatening apixaban- and rivaroxaban-related major
bleeding.5 A 57% relative reduction in adjusted (after matching) all-cause 30-day mortality was seen for the
entire cohort of patients treated with ANDEXXA, and a 69% relative reduction was seen for patients treated with
ANDEXXA in the ICH subgroup.5
Pending Confirmatory Clinical Trial

ANNEXA-I is an ongoing, randomized, open-label, two-arm, Phase 4 study.20 The primary objective of the
study is to evaluate the efficacy and safety of ANDEXXA vs usual care in patients with ICH anticoagulated
with a FXa inhibitor. Usual care consists of any treatment(s) (including no treatment) other than ANDEXXA that
the investigator considers to be appropriate. The primary outcome measure is the proportion of patients with
good or excellent hemostatic efficacy, and the secondary outcome measure is percent change in anti-FXa
activity from baseline to nadir. The trial assessments will also include evaluation of occurrence of the safety
outcomes, including death and thrombotic events.

• Cardiac arrest
• Sudden deaths
Anticoagulant Reversal Guidelines and

Recommendations
For patients with FXa inhibitor–related life-threatening or uncontrolled bleeding, expert guidance supports
the use of a specific reversal agent
Table 4. Anticoagulant reversal guidelines
AMERICAN HEART ASSOCIATION/ Class 2a (MODERATE)a recommendation:
AMERICAN STROKE ASSOCIATION ANDEXXA® (coagulation factor Xa (recombinant),
AHA/ 2022 Guideline for the Management of inactivated-zhzo) is reasonable to reverse the
ASA23 Patients With Spontaneous Intracerebral anticoagulant effect of FXa inhibitors in patients
Hemorrhage with direct FXa inhibitor–associated spontaneous
intracerebral hemorrhage
NATIONAL COMPREHENSIVE For patients with cancer currently receiving

CANCER NETWORK® (NCCN ®) apixaban or rivaroxaban who develop
Clinical Practice Guidelines in Oncology ICH requiring reversal of anticoagulation,
NCCN24
consider coagulation factor Xa (recombinant),
inactivated–zhzo (ANDEXXA)
AMERICAN COLLEGE ANDEXXA is listed as a tier 1b recommendation for

OF EMERGENCY PHYSICIANS anticoagulation reversal in patients taking apixaban
ACEP25 Anticoagulant Reversal Strategies in or rivaroxaban experiencing life-threatening bleeds
the Emergency Department (ED) Setting
AMERICAN COLLEGE OF CARDIOLOGY Administer ANDEXXA first line for the reversal of
2020 ACC Expert Consensus Decision anticoagulation in patients taking apixaban or
ACC26 Pathway on Management of Bleeding in rivaroxaban with life-threatening or uncontrolled
Patients on Oral Anticoagulants bleeds, when available
ANTICOAGULATION FORUM In patients with apixaban-associated or

AC Guidance from the rivaroxaban-associated major bleeding in whom a
Anticoagulation Forum reversal agent is warranted, we suggest treatment
FORUM27 with ANDEXXA dosed according to the US Food and
Drug Administration label
a
Class 2a (MODERATE): Is reasonable or can be useful/effective/beneficial.23
b
Tier 1 recommendations are most aligned with FDA-approved indications and have the highest quality of evidence to support their use.25
Limitations of Use13
ANDEXXA has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any FXa
inhibitors other than apixaban or rivaroxaban.

Anticoagulant Reversal Guidelines and

Recommendations (Continued)
AMERICAN HEART ASSOCIATION/ ANDEXXA® (coagulation factor Xa (recombinant),
AMERICAN COLLEGE OF inactivated-zhzo) can be useful for the reversal
AHA/ CARDIOLOGY/ of apixaban and rivaroxaban in the event of life-
ACC/ HEART RHYTHM SOCIETY threatening or uncontrolled bleeding
HRS28 Focused Update of the 2014
Guideline for the Management of
Patients With Atrial Fibrillation
AMERICAN SOCIETY OF HEMATOLOGY For patients with life-threatening bleeding during oral
2018 Guidelines for Management of direct Xa inhibitor treatment of VTE, the ASH guideline
ASH29 Venous Thromboembolism: Optimal panel suggests using ANDEXXA in addition to cessation
Management of Anticoagulation of oral direct Xa inhibitor rather than no ANDEXXA
Therapy
AMERICAN COLLEGE OF CHEST In patients with severe or life-threatening bleeding

PHYSICIANS treated with non-vitamin K antagonist oral
CHEST30 Antithrombotic Therapy for Atrial anticoagulants (NOACs) a specific reversal agent
Fibrillation (where available) should be used
Joint Commission31
SENTINEL EVENT ALERT #61

DOACs present different risks than heparin and warfarin and have different reversal mechanisms
For each type of anticoagulant medication, use evidence-based protocols and practice guidelines for
drug initiation and maintenance, reversal of anticoagulation and management of bleeding events, and
perioperative management. Use pharmacy staff as a resource for questions about DOACs
A reversal mechanism that works for one DOAC may not work for another
Hospitals and critical access hospitals should stock blood products and any antidotes appropriate for use
with each type of anticoagulant
Limitations of Use13
ANDEXXA has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any FXa
inhibitors other than apixaban or rivaroxaban.

PART 4: Additional Resources
Clinical Protocol Example

To optimize patient care and ensure timely treatment, health systems may develop their own protocols
reflecting evidence-based practice guidelines and the individual needs of their institutions.31,32
• This protocol applies to multiple facilities within an integrated delivery network that could potentially treat
patients requiring anticoagulant reversal33
• ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo) is listed as the first-line reversal agent for
patients on apixaban or rivaroxaban who are experiencing life-threatening or critical-site bleeding when
standard measures to manage bleeding are insufficient33
Figure 8. Clinical protocol example33
Life-threatening bleeding or critical-site bleeding NO Exclude
YES
Does the patient meet ALL following criteria?

• Patient medical history includes apixaban or rivaroxaban
• Provider is reasonably certain that therapeutic levels of
apixaban and rivaroxaban are present
• Standard measures for bleeding management are NO Exclude
insufficient
• Continuous bleeding puts patient at higher risk than potential
thrombotic event
YES
Administer ANDEXXA
Does the patient have any of the following? Dosing and administration
• Last dose of apixaban or rivaroxaban was >18 hours are on label (see ANDEXXA
NO
• Recent thromboembolic event within the past 2 weeks Dosage and Administration,
Section 2 in the ANDEXXA
YES Prescribing Information)
Exclude

ADVERSE REACTIONS
Dosing Information
The recommended dose is based on the type of FXa inhibitor, the last dose of FXa inhibitor, and
the time of last dose13
Table 5. ANDEXXA dose based on apixaban or rivaroxaban dose13
Dose Time
Drug Strength Since last dose taken
FXa inhibitor
of last dose <8 hours or unknown ≥8 hours
≤5 mg Low dose
Apixaban
>5 mg or unknown High dose
Low dose
≤10 mg Low dose
Rivaroxaban
>10 mg or unknown High dose
ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo)

has 2 dosing regimens13
Administration includes an initial bolus followed by an infusion
Approximately 83% of patients with acute major bleeding who received ANDEXXA in ANNEXA-4 were given
the low dose.
Table 6. ANDEXXA dosing regimens

Initial IV bolus Continuous IV infusion Vial total (200-mg vial)
400 mg 4 mg/min 5 vials

Low dose at a target rate for up to 120 minutes (2 vials bolus +
of 30 mg/minute (480 mg) 3 vials infusion)
800 mg 8 mg/min 9 vials

High dose at a target rate for up to 120 minutes (4 vials bolus +
of 30 mg/minute (960 mg) 5 vials infusion)
The safety and effectiveness of more than one dose of ANDEXXA have not been evaluated.

• Cardiac arrest
• Sudden deaths
Monitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for symptoms
and signs that precede cardiac arrest and provide treatment as needed.
Reconstitution and Preparation Guide13

NOTE: For dosing, choose either the low dose or high dose based on the specific FXa inhibitor, dose of FXa inhibitor,
and time since the patient’s last dose per the table on the previous page. ANDEXXA® (coagulation factor Xa
(recombinant), inactivated-zhzo) is administered using an initial IV bolus followed by a continuous IV infusion.
Reconstitution
• Reconstituted ANDEXXA in vials is stable at room temperature for up to 8 hours
• Reconstituted vials may be stored for up to 24 hours at 2 °C to 8 °C (36 °F to 46 °F)
• Reconstituted ANDEXXA in IV bags is stable at room temperature for up to 8 hours
IV bolus preparation
• Determine total number of vials required (see “ANDEXXA has 2 dosing regimens” table on
the previous page)
• Reconstitute the 200-mg vial of ANDEXXA with 20 mL of Sterile Water for Injection (SWFI)
• Using a 20-mL (or larger) syringe and 20-gauge (or higher) needle, slowly inject the SWFI,
directing the solution onto the inside wall of the vial to minimize foaming
• To reduce the total reconstitution time needed during preparation, reconstitute all required
vials in succession
• To ensure dissolution of the cake or powder, gently swirl each vial until complete dissolution
of powder occurs
DO NOT SHAKE the vials as it can lead to foaming.

• Dissolution time for each vial is approximately 3 to 5 minutes
• If dissolution is incomplete, discard the vial, and do not use the product
• Inspect reconstituted vials for particulate matter and discoloration prior to administration:
– Solution should be clear, colorless to light yellow
• Use 60-mL (or larger) syringe with a 20-gauge (or higher) needle to withdraw the
reconstituted ANDEXXA solution from each of the vials until the required dosing volume is
achieved. Note the total volume withdrawn into the syringe
• Transfer the ANDEXXA solution from the syringe into an empty polyolefin or polyvinyl
chloride IV bag with a volume of 250 mL or less
• Finally, discard all used syringes, needles, and vials, including any unused portion of
reconstituted solution

Reconstitution and Preparation Guide (Continued)13

Continuous IV infusion preparation
• Follow the same procedure outlined for IV bolus preparation. Reconstitute the total number of vials needed
based on the dose requirements. More than one 40- to 60-mL syringe, or an equivalent 100-mL syringe, may
be used for transfer of reconstituted solution to the IV bag
• Infusion will require a 0.2 or 0.22 micron in-line polyethersulfone or equivalent low protein-binding filter
Administration
• Upon reconstitution, the parenteral drug product should be inspected visually for particulate matter
and discoloration prior to administration
• Administer ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo) intravenously, using a 0.2 or
0.22 micron in-line polyethersulfone or equivalent low protein-binding filter
• Start the bolus at a target rate of approximately 30 mg/minute
• Within 2 minutes following the bolus dose, administer the continuous IV infusion for up to 120 minutes
Restarting anticoagulant therapy

Patients 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 the risk of thrombosis, resume anticoagulant therapy as soon as medically
appropriate following treatment with ANDEXXA.

ADVERSE REACTIONS
Pricing and Ordering

55% reduction in wholesale acquisition cost (WAC) as of April 1, 202234
Table 7. How supplied
ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo) is a sterile,

white to off-white lyophilized powder available in single-use vials.
Description13 Each 200-mg vial delivers 200 mg of coagulation FXa formulated with the inactive
ingredients tromethamine (Tris base), Tris hydrochloride, L-arginine hydrochloride,
sucrose (1% w/v), mannitol (2.5% w/v), and polysorbate 80 (0.01% w/v) at pH 7.
4-vial box NDC: 0310-3200-04

• 4 single-use vials per box, each containing 200 mg of ANDEXXA
NDC numbers13
5-vial box NDC: 0310-3200-05
• 5 single-use vials per box, each containing 200 mg of ANDEXXA
• 4-vial box: $10,000 per box (4 single-use vials each containing 200 mg of ANDEXXA)
Wholesale acquisition cost34
• 5-vial box: $12,500 per box (5 single-use vials each containing 200 mg of ANDEXXA)
• Low dose (5 vials): $12,50013,34

• High dose (9 vials): $22,50013,34
Price per dose
pproximately 83% of patients with acute major bleeding who received ANDEXXA
A
in ANNEXA-4 were given the low dose.18
Table 8. Storage and handling13
Unopened vials should be stored refrigerated at 2 °C to 8 °C (36 °F-46 °F).

Unopened vials
DO NOT FREEZE.
• Reconstituted ANDEXXA in vials is stable at room temperature for up

to 8 hours, or may be stored for up to 24 hours at 2 °C to 8 °C
Reconstituted solutions
• Reconstituted ANDEXXA in IV bags is stable at room temperature for up
to 8 hours

• Cardiac arrest
• Sudden deaths
Additional Resources and Support

Support When You Need It
866-ANDEXXA (866-263-3992)
Call for more information regarding:

• Product information • Reimbursement support
• Medical inquiries and adverse • Insurance questions
event reporting
Access and Reimbursement

The AstraZeneca Access 360™ program provides personal support to help streamline access and
reimbursement for select AstraZeneca medicines.
My Access 360™
Visit for more information regarding:

• Reimbursement • Specialty distributers
• Coding and billing • Sample letter of appeal

Additional Resources and Support (Continued)
Contact order fulfillment at Returns Policy

Returns or Orderfulfillment.wilmington@
Spoilage astrazeneca.com
ANDEXXA Website Explore our Medical Resources
Additional
Clinical Mechanism of Action Video Dosing and Reconstitution Video
Information
24/7
Reconstitution 866-ANDEXXA (866-263-3992)
Dosing and Reconstitution
Support
Demonstrator
For Formulary Decision-Makers Only:

Additional information, including the cost-effectiveness model,
can be found on FormularyDecisions.a
a
Users will need to be credentialed to access materials on FormularyDecisions.

ADVERSE REACTIONS
PART 5: References
References
1. Eliquis. Prescribing information. Bristol-Myers Squibb Company; April 2021.
2. Xarelto. Prescribing information. Janssen Pharmaceuticals Inc; February 2023.
3. Lassen MR, Laux V. Emergence of new oral antithrombotics: a critical appraisal of their clinical potential. Vasc
Health Risk Manag. 2008;4(6):1373-1386.
4. Morales-Vidal S, Schneck MJ, Flaster M, et al. Direct thrombin inhibitors and factor Xa inhibitors in patients with
cerebrovascular disease. Expert Rev Neurother. 2012;12(2):179-189.
5. Cohen AT, Lewis M, Connor A, et al. Thirty day mortality with andexanet alfa compared with prothrombin
complex concentrate therapy for life-threatening direct oral anticoagulant-related bleeding. J Am Coll Emerg
Physicians Open. 2022;3(2):e12655.
6. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation.
N Engl J Med. 2011;365(11):981-992.
7. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med.
2011;365(10):883-891.
8. Held C, Hylek EM, Alexander JH, et al. Clinical outcomes and management associated with major bleeding
in patients with atrial fibrillation treated with apixaban or warfarin: insights from the ARISTOTLE trial. Eur Heart J.
2015;36(20):1264-1272.
9. Hankey GJ, Stevens SR, Piccini JP, et al. Intracranial hemorrhage among patients with atrial fibrillation
anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor Xa inhibition compared
with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke. 2014;45(5):1304-1312.
10. Merative Healthcare Solutions. Alexion Bleed Report. Data month ending September 2019.
11. Nutescu EA, Dager WE, Kalus JS, Lewin JJ III, Cipolle MD. Management of bleeding and reversal strategies for
oral anticoagulants: clinical practice considerations. Am J Health Syst Pharm. 2013;70(21):1914-1929.
12. Summers RL, Sterling SA. Emergent bleeding in patients receiving direct oral anticoagulants. Air Med J.
2016;35(3):148-155.
13. ANDEXXA. Prescribing information. AstraZeneca Pharmaceuticals LP; July 2023.
14. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity.
N Engl J Med. 2015;373(25):2413-2424.
15. Siegal DM, Lu G, Leeds J, et al. Safety, pharmacokinetics, and reversal of apixaban anticoagulation with
andexanet alfa. Blood Adv. 2017;1(21):1827-1838.
16. Lu G, Conley PB, Leeds JM, et al. A Phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and
edoxaban anticoagulation in healthy volunteers. Blood Adv. 2020;4(4):728-739.
17. Lu G, Hollenbach SJ, Baker DC, et al. Preclinical safety and efficacy of andexanet alfa in animal models.
J Thromb Haemost. 2017;15(9):1747-1756.
18. Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with
Factor Xa inhibitors. N Engl J Med. 2019;380(14):1326-1335.
19. Coleman CI, Dobesh PP, Danese S, et al. Real-world management of oral factor Xa inhibitor-related bleeds with
reversal or replacement agents including andexanet alfa and four-factor prothrombin complex concentrate: a
multicenter study. Future Cardiol. 2021;17(1):127-135.
20. AstraZeneca. Trial of andexanet in ICH patients receiving an oral FXa inhibitor. ClinicalTrials.gov identifier:
NCT03261528. Updated September 6, 2022. Accessed September 27, 2022. https://www.clinicaltrials.gov/ct2/show/
NCT03661528
PART 5: References
References (Continued)
21. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity.
Protocol. N Engl J Med. 2015;373(25):2413-2424. https://www.nejm.org/doi/suppl/10.1056/NEJMoa1510991/suppl_file/
nejmoa1510991_protocol.pdf
22. Connolly SJ, Crowther M, Eikelboom JW, et al. Full study report of andexanet alfa for bleeding associated with
Factor Xa inhibitors. Supplementary Appendix. N Engl J Med. 2019;380(14):1326-1335. https://www.nejm.org/doi/
suppl/10.1056/NEJMoa1510991/suppl_file/nejmoa1510991_appendix.pdf
23. Greenberg SM, Ziai WC, Cordonnier C, et al. 2022 Guideline for the Management of Patients With Spontaneous
Intracerebral Hemorrhage: a guideline from the American Heart Association/American Stroke Association. Stroke.
2022;53(7):e282-e361.
24. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ®) for
Cancer-Associated Venous Thromboembolic Disease V1.2022. © National Comprehensive Cancer Network, Inc.
2022. All rights reserved. Accessed March 11, 2022. To view the most recent and complete version of the guideline, go
online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application
and disclaims any responsibility for their application or use in any way.
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recommendations of a multidisciplinary expert panel. Ann Emerg Med. 2020;76(4):470-485.
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bleeding in patients on oral anticoagulants: a report of the American College of Cardiology Solution Set Oversight
Committee. J Am Coll Cardiol. 2020;76(5):594-622.
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Forum. Am J Hematol. 2019;94(6):697-709.
28. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS Guideline
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Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm.
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Venous Thromboembolism: optimal management of anticoagulation therapy. Blood Adv. 2018;2(22):3257-3291.
30. Lip GYH, Banerjee A, Boriani G, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert
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Reference. 2018;19:1-4.
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Use. Published August 2019. Accessed May 4, 2022. https://www.pbm.va.gov/apps/VANationalFormulary
34. Data on file. REF-144709. AstraZeneca Pharmaceuticals LP.
You may report side effects related to AstraZeneca products .
Please see Important Safety Information throughout, and read US full Prescribing Information, including Boxed
WARNING.
ANDEXXA is a registered trademark of the AstraZeneca group of companies.

Other brands noted herein are the property of their respective owners.
32 ©2023 AstraZeneca. All rights reserved. US-76645 Last Updated 6/23

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IMPORTANT SAFETY INFORMATION FOR ANDEXXA®

Please see Important Safety Information throughout, and read US full

ANNEXA-A and ANNEXA-R........................................................................... 6

Multicenter retrospective safety analysis (Coleman et al).................... 14

Indirect retrospective analysis (Cohen et al)........................................... 16

Pending confirmatory clinical trial.................................................................. 20

Anticoagulant reversal guidelines and recommendations......................... 21

Part 4: Additional Resources.................................................................................. 23

Clinical protocol example............................................................................... 23

Reconstitution and preparation guide .......................................................... 25

Please see Important Safety Information throughout, and read US full

Direct FXa Inhibitors and the Coagulation Cascade

Figure 1. Coagulation cascade3,4

XII XI Extrinsic pathway

Prothrombin (II) Thrombin (IIa)

Fibrinogen (I) Fibrin (Ia)

Clinical Burden and Unmet Need

Indication and Mechanism of Action

Figure 2. Mechanism of action of ANDEXXA for direct FXa inhibitors13,14

Native FXa ANDEXXA decoy molecule

Cannot form a Binds to and sequesters

IMPORTANT SAFETY INFORMATION (CONTINUED)

Clinical Development Program

Study Study design N Primary endpoint(s)

Phase 2: • Percent change in

IMPORTANT SAFETY INFORMATION (CONTINUED)

ANNEXA-A and ANNEXA-R: Reversal of FXa Inhibitor

IMPORTANT SAFETY INFORMATION (CONTINUED)

ANNEXA-A and ANNEXA-R: Study Results

Figure 3. Anti-FXa activity in apixaban- and rivaroxaban-treated healthy subjects14

ANNEXA-A (apixaban-treated patients) ANNEXA-R (rivaroxaban-treated patients)

Anti-FXa activity (ng/mL)

Secondary efficacy endpoint14

IMPORTANT SAFETY INFORMATION

ANNEXA-A and ANNEXA-R: Study Results (Continued)

500 ANDEXXA 40-mg bolus + 480 mg x 2-hour infusion (n=23)

1500 1500 Pre-anticoagulant

The points on the

ANNEXA-A and ANNEXA-R: Safety in Healthy

IMPORTANT SAFETY INFORMATION (CONTINUED)

ANNEXA-4: Acute Major Bleeding Associated With

IMPORTANT SAFETY INFORMATION (CONTINUED)

ANNEXA-4: Patient Demographics and Baseline

Table 2. Characteristics of patients at baseline18a

IMPORTANT SAFETY INFORMATION (CONTINUED)

ANNEXA-4: Anti-FXa Efficacy Results

Figure 5. Anti-FXa activity in apixaban- and rivaroxaban-treated patients in ANNEXA-418

ANNEXA-4 (apixaban) ANNEXA-4 (rivaroxaban)

–92 (95% CI, 88 to 94)

11.1 11.5 14.2 16.5

IMPORTANT SAFETY INFORMATION

ANNEXA-4: Hemostatic Efficacy Results

IMPORTANT SAFETY INFORMATION (CONTINUED)

ANNEXA-4: Safety Results

IMPORTANT SAFETY INFORMATION (CONTINUED)

Multicenter Retrospective Safety Analysis

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Multicenter Retrospective Safety Analysis: Results

21% NO REVERSAL OR REPLACEMENT

IMPORTANT SAFETY INFORMATION (CONTINUED)

Indirect Retrospective Analysis (Cohen et al)