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Andexxa: First Reversal Agent for Anti-Factor Xa Inhibitors

Thursday, October 18, 2018  
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Xinwei Li, PharmD Candidate 2019

Philadelphia College of Pharmacy, University of the Sciences in Philadelphia


Oludamilola Olugbile PharmD

Clinical Pharmacist

Magee Rehabilitation Hospital


Prior to the introduction of direct oral anticoagulants (DOACs), vitamin K antagonists were the agents of choice for treating and preventing thromboembolic disease. However, treatment with warfarin is accompanied by frequent blood tests and monitoring for therapeutic anticoagulant effects. DOACs (direct-acting anticoagulants) were introduced as alternative oral anticoagulants to warfarin. Between 2010 and 2018, five DOACs were approved for the treatment and prevention of venous thromboembolism, of which four are also indicated for reducing risk of stroke.1,2 DOACs exert different mechanisms of action by targeting specific coagulation factors: dabigatran is a direct thrombin inhibitor that competitively inhibits thrombin, while anti-factor Xa inhibitors (apixaban, rivaroxaban, edoxaban, and betrixaban) inhibit factor Xa in the coagulation cascade.3

DOACs have several advantages over vitamin K antagonists as they do not require frequent monitoring, have fewer drug interactions, and have wider therapeutic windows.4 Anti-factor Xa agents such as rivaroxaban and apixaban exert their anticoagulation effect by inhibiting coagulation factor Xa. The ROCKET-AF and ARISTOTLE trials showed that rivaroxaban was non-inferior to warfarin and apixaban was superior to warfarin in preventing stroke of systemic embolism in patients with atrial fibrillation.5,6 Since their introduction to the US market, DOACs have become increasingly prescribed for prevention of thromboembolic diseases. A cross-sectional analysis of medical and pharmacy claims for commercial and Medicare Advantage enrollees in a large, private, US health plan in the first quarter of 2017 showed that 78.9% of patients with nonvalvular atrial fibrillation started DOACs, while 21.1% started warfarin.7 Of those patients who started DOACs, 25% used rivaroxaban and 50.1% used apixaban, showing a trend of increasing DOAC use for atrial fibrillation.7 However, DOACs have similar bleeding risks as warfarin and are associated with risks of bleeding in the intracranial space, retroperitoneal space, and the gastrointestinal (GI) tract. Therefore, the lack of reversal agents for factor Xa inhibitors remained to be a concern while initiating these therapies. While idarucizumab (Praxbind(c)) can be used to reverse anticoagulation from dabigatran, previously, there were no FDA approved reversal agent available for factor Xa inhibitors. Options for anti-factor Xa inhibitor reversal were limited to administering activated charcoal if the anticoagulants were ingested within 2 hours, as well as clotting factor concentrates such as 4F-PCC (Kcentra(c)) and anti-inhibitor factor complex (factor VIII inhibitor bypassing activity, or FEIBA).8

On May 3, 2018, Andexxa(c) (andexanet alfa) was approved by the FDA under an accelerated approval pathway as the first anti-factor Xa inhibitor reversal agent. Andexxa(c) is indicated for patients who are treated with rivaroxaban or apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.9 AndexxaÒ is a recombinant protein of coagulation factor Xa, inactivated-zhzo that exerts its effect by binding to and sequestering factor Xa inhibitors, reversing their anticoagulant effect.9 Andexxa’s(c) accelerated approval was granted based on results from two phase III, randomized, double-blind, placebo-controlled trials on healthy older participants; Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXA Inhibitors, ANNEXA-A (apixaban) and ANNEXA-R (rivaroxaban).9

The objective of both ANNEXA studies was to establish the efficacy and safety of Andexxa(c) in reversing anticoagulation in older healthy volunteers (50-75 years of age) receiving apixaban or rivaroxaban. Efficacy was determined by evaluating the percent change in anti-factor Xa inhibitor activity.10

In the ANNEXA-A study, 32 healthy subjects were randomized in a 1:3 ratio into the placebo or andexanet alfa group. All subjects received apixaban 5 mg twice daily for 3.5 days to achieve steady state. On day four, participants were administered either placebo or andexanet alfa 400 mg IV bolus, followed by a continuous infusion of 4 mg/min for two hours.10

In the ANNEXA-R study, 39 healthy subjects were randomized in a 1:2 ratio into the placebo or andexanet alfa group. Participants were anticoagulated with rivaroxaban 20 mg once daily for four days and were administered andexanet alfa 800 mg IV bolus, followed by a continuous infusion of 8 mg/min for two hours.10

Results from both studies showed that andexanet alfa achieved greater reduction in anti-factor Xa inhibitor activity than placebo. The reversal effect was noted to be within 2 to 5 minutes. In ANNEXA-A, andexanet alfa reduced anti-factor Xa inhibitor activity of apixaban by 94%, as compared to 21% in placebo. Similar results were seen in ANNEXA-R, as anti-factor Xa inhibitor effect in rivaroxaban was decreased by 92% in andexanet alfa IV bolus as compared to 18% in placebo. As compared with placebo, continuous infusion of andexanet alfa achieved a greater change from baseline of anti-Xa activity in apixaban (92% vs. 33%) and in rivaroxaban (97% vs. 45%).10

The ANNEXA-4 trial is an ongoing phase 3B/4, single-arm, open-label study that aimed to confirm the efficacy and safety of andexanet alfa in patients with acute major bleeding. An interim study published in 2016 reported results in 67 patients who had acute major bleeding events (intracranial bleeding, GI bleeding, bleeding in other sites such as genital or urinary, pericardial, pleural, or retroperitoneal spaces) while treated with rivaroxaban, apixaban, edoxaban, or enoxaparin within 18 hours. Patients eligible for treatment of andexanet alfa must present with life threatening acute overt bleeding with hemodynamic compromise, hemoglobin decrease of 2 g/dL or more, or acute symptomatic bleeding in a critical area or organ. Patients were excluded if they had a recent thrombotic event, GCS < 7 or ICH volume > 60 cc, recent blood product use, expected mortality of less than 1 month, and if they had planned surgery.11

Safety of andexanet alfa is evaluated in all the patients who received treatment, and efficacy was determined in patients with baseline anti–factor Xa activity 75 ng/milliliter. The result of the interim study showed that treatment with andexanet alfa IV bolus followed by a 2-hour continuous infusion decreases anti-factor Xa inhibitor activity significantly; as median decrease of anticoagulation activity from baseline was 89% for rivaroxaban and 93 percent for apixaban.11  In March 2018, ANNEXA-4 researchers presented interim safety results for 227 patients and efficacy results for 132 patients.10 Andexxa(c) reduced anti-factor Xa inhibitor activity by 88%, and 83% patients achieved clinical homeostatsis.12 From a safety perspective, 24 patients (11%) experienced thrombotic events and 27 patients (12%) died within 30 days after administration of andexanet alfa.13

The post marketing study is required by FDA as part of Andexxa’s review and continuing approval. Safety events including stroke, TIA, acute MI, PE, DVT, and sudden death events suspicious for thrombosis, embolism, and ischemia will be evaluated. The trial is expected to be completed in October, 2022 and final study report is expected to be submitted in April 2023.

The most common adverse reactions related to Andexxa(c) were urinary tract infection, pneumonia, and infusion-related reactions. Andexxa(c) has a black box warning for increased risks for thromboembolic events, ischemia, cardiac arrest, and sudden deaths; it is recommended that close monitoring for these events and providing treatment as needed.9

Prior to administration, Andexxa(c) should be reconstituted prior to administration. It is administered as an intravenous bolus, with a target rate of 30 mg/min, followed by continuous infusion for up to 120 minutes. There are two dosing regimens: low dose regimen starts with initial IV bolus of 400 mg at a target rate of 30 mg/min for up to 120 minutes, followed by a continuous infusion of 4 mg/min for up to 120 minutes. The High Dose regimen starts with initial IV bolus of 800 mg at a target rate of 30 mg/min followed by continuous IV infusion of 8 mg/min for up to 120 minutes. The decision between high or low dose regimen depends on the specific factor Xa inhibitor, the dose, and time since last dose of the factor Xa inhibitor. If a patient ingested rivaroxaban ≤ 10 mg or apixaban ≤ 5 mg within 8 hours, low dose Andexxa(c) is indicated. For rivaroxaban >10 mg, apixaban > 5 mg, or unknown doses within 8 hours, high dose is indicated. If the time since last dose of factor Xa inhibitor is greater than 8 hours, the package insert recommends low dose Andexxa(c).9

Table 1. Dosing regimen of Andexxa(c)9


Initial IV Bolus

Follow-On IV Infusion

Low Dose

400 mg at a target rate of 30mg/min

4 mg/min for up to 120 minutes

High Dose

800 mg at a target rate of 30 mg/min

8 mg/min for up to 120 minutes


Table 2. Andexxa(c) dose based on rivaroxaban or apixaban dose (timing of factor Xa inhibitor last dose before Andexxa(c) initiation)9

Factor Xa Inhibitor

Last dose

< 8 Hour or Unknown

8 Hours


≤ 10 mg

Low dose

Low dose


>10 mg / Unknown

High dose


≤ 5 mg

Low dose


>5 mg / Unknown

High dose


Andexxa(c) is supplied through Portola Pharmaceuticals Inc. as a lyophilized powder in single-use vials containing 100 mg coagulation factor Xa recombinant, inactivated zhzo. The average wholesale price (AWP) for a package containing 4 vials is $13,200.14 For low dose treatment (400 mg IV bolus plus 480 mg for 120-minute continuous infusion), the cost would be approximately $29,700 (total of 9 vials). The cost doubles with high dose treatment (800 mg IV bolus plus 960 mg over 120-minute continuous infusion), with a total of $59,400.

 Andexxa(c) needs to be reconstituted prior to use; the manufacturer recommends slowly injecting 10 mL of water into the vial containing the powder and allowing 3-5 minutes for the powder to dissolve. The powder should be completely dissolved, swirling can ensure dissolution of the powder, but shaking should be avoided to prevent foaming. Once dissolution is completed, the solution should be drawn out of the vial and transferred to an empty polyolefin or polyvinyl chloride IV bag with a volume of 250 mL or less. Once reconstituted, AndexxaÒ is stable in IV bags for up to 8 hours in room temperature, or up to 16 hours at 2 °C to 8 °C.15

Currently, Andexxa(c) is indicated for the reversal of rivaroxaban and apixaban only. Edoxaban and betrixaban are also anti-factor Xa inhibitors that have similar mechanism of action as rivaroxaban and apixaban, therefore, Andexxa(c) may be useful in reversing these agents. However, currently there is no clinical evidence on Andexxa’sÒ efficacy in reversing these agents. With the current clinical data, Andexxa(c) has shown rapid onset of action and efficacy of decreasing rivaroxaban and apixaban levels (>90% reduction of anti-factor Xa inhibitor activity)10. Upon the completion of the ANNEXA-4 study, Andexxa(c) may become important in acute settings where reversal of anticoagulation from anti-factor Xa inhibitors is needed.



1.     Steuber T. The role of direct oral anticoagulants in the management of venous thromboembolism. Am J Manag Care. 2017 Dec;23(20 Suppl):S383-S390.

2.     López-López JA1, Sterne JAC2,3, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. 2017 Nov 28;359:j5058.

3.     schwarb Heike, Tsakiris DA. New Direct Oral Anticoagulants (DOAC) and Their Use Today. Dent J (Basel). 2016 Mar; 4(1):5.

4.     Patel P, Pandya J, Goldberg M. NOACs vs. Warfarin for Stroke Prevention in Nonvalvular Atrial Fibrillation. Cureus. 2017 Jun 26;9(6):e1395.

5.     Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011; 365:883-891.

6.     Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92.

7.     Zhu J1, Alexander GC, Nazarian S, Segal JB, Wu AW. Trends and Variation in Oral Anticoagulant Choice in Patients with Atrial Fibrillation, 2010-2017. Pharmacotherapy. 2018 Jun 19.

8.     American Society of Health-System Pharmacists. Managing and reversing direct oral anticoagulants: a discussion guide [Internet]. Available from

9.     Product Information: ANDEXXA(R) lyophilized powder for intravenous injection, coagulation factor Xa recombinant, inactivated-zhzo lyophilized powder for intravenous injection. Portola Pharmaceuticals, Inc (per manufacturer), South San Francisco, CA, 2018.

10.  Siegal DM, Curnutte JT, Connolly SJ, Lu G, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med. 2015 Dec 17;373(25):2413-24.

11.  Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet Alfa for Acute Major Bleeding Associated with Factor Xa Inhibitors. N Engl J Med. 2016 Sep 22;375(12):1131-41.

12.  American College of Cardiology. ANNEXA-4 Suggests Experimental Drug Controls Bleeding in Patients Taking Factor Xa Inhibitors [Internet]. 2018. Available from

13.  Portola Pharmaceuticals, Inc. FDA Approves Portola Pharmaceuticals’ Andexxa®, First and Only Antidote for the Reversal of Factor Xa Inhibitors [Internet]. 2018. Available from

14.  Active Ingredient: Andexxa. RED BOOK Online. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Truven Health Analytics; 2015. Accessed August 24, 2018.

15.  Portola Pharmaceuticals, Inc. Reconstitution Guide [Internet]. 2018. Available from

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