ANDEXXA® (coagulation factor Xa [recombinant], inactivated-zhzo) is a recombinant modified human factor Xa (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 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.
Boxed WARNING: 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.
Please see additional Important Safety Information below.
More than eight million people in the United States take a direct oral anticoagulant medication.1 While blood thinners can save lives, helping to prevent and treat dangerous blood clots, they can also cause serious side effects, including an increased risk of bleeding.2
Factor Xa (FXa) inhibitors, such as apixaban or rivaroxaban, are a specific type of blood thinner used to help reduce the risk of stroke and systemic embolism in conditions such as non-valvular atrial fibrillation (NVAF).3,4 Uncontrolled bleeding is one of the risks associated with FXa inhibitor use, and major bleeding occurred in approximately 4 to 6 percent of patients treated with these medicines in 2 large randomized controlled studies of patients with NVAF.5-6 Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) was a multinational double-blind, double-dummy, randomized clinical trial comparing apixaban with warfarin in patients with atrial fibrillation (N=18,201).6 Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) was a multinational, randomized, double-blind, double-dummy, clinical trial comparing rivaroxaban with warfarin in patients with atrial fibrillation (N=14,264).5
Bleeding admissions for patients taking the FXa inhibitors apixaban or rivaroxaban continue to rise as the use of these agents grows.1, 7-9 In 2019, there were approximately 190,000 hospital admissions related to these FXa inhibitor bleeds compared to approximately 90,000 in 2015—an increase of around 110 percent.1, 7-9 If untreated, these bleeds can lead to severe health consequences, including death, as noted in the ARISTOTLE study, which showed a 30-day mortality rate of more than 40 percent in patients with an intracranial hemorrhage (ICH).10
The Only Antidote for FXa Inhibitor Bleeds
ANDEXXA® (coagulation factor Xa [recombinant], inactivated-zhzo) is the only FDA-approved FXa inhibitor antidote for apixaban and rivaroxaban.
ANDEXXA 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.11 In ANNEXA-A (N=31) and ANNEXA-R (n=39), randomized, double-blind, placebo-controlled studies conducted in healthy volunteers, ANDEXXA provided a rapid, specific reversal of FXa activity within two minutes, following an initial IV bolus and was sustained throughout a two-hour, continuous IV infusion. There was a 92 percent decrease in anti-FXa activity in apixaban-treated subjects and a 97 percent decrease in anti-FXa activity in rivaroxaban-treated subjects.11
Additionally, ANDEXXA rapidly restored thrombin generation in healthy volunteers and thus, provides the rationale to help patients prescribed apixaban and rivaroxaban who are experiencing an acute major bleed.12
The benefits of ANDEXXA in meeting an area of high unmet medical need have been recognized with accelerated and conditional approvals in the United States and Europe in 2018 and 2019, respectively.13,14 More recently, the medicine was approved in Japan in March 2022.15
There are a number of guidelines that recommend the use of ANDEXXA when reversal of anticoagulation is needed due to acute major bleeding in patients on FXa-inhibitors. A multidisciplinary expert panel convened by the American College of Emergency Physicians (ACEP) in 2020 recommended ANDEXXA for patients experiencing anticoagulant-associated life-threatening or critical-site bleeding.16 In addition, the 2022 American Heart Association (AHA) and the American Stroke Association (ASA) Guideline for the Management of Patients with Spontaneous Intracerebral Hemorrhage recommends that ANDEXXA is reasonable to reverse the anticoagulant effect of FXa inhibitors in patients with direct FXa inhibitor-associated spontaneous intracerebral hemorrhage (2a recommendation).17 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.
The Urgent Need for ANDEXXA in the Emergency Department
As an emergency medicine physician at Tampa General Hospital, I use ANDEXXA for the management of apixaban and rivaroxaban-associated, life-threatening bleeds because it’s the only product approved to reverse anticoagulant activity in these patients—it’s as simple as that.
While I have treated many patients with ANDEXXA for ICH bleeds, some of my most impactful experiences with the medication have been other site bleeds, some of which resulted from blunt trauma.
One such case involved a patient taking rivaroxaban who was in a car accident and suffered a life-threatening intraabdominal bleed. This individual came to the emergency department with abdominal pain—a likely liver laceration. ANDEXXA was ordered to help manage the patient’s critical organ site bleed. As an emergency room physician, I was very thankful that ANDEXXA was on formulary at my institution.
As a physician in a large, academic institution, I see patients with apixaban or rivaroxaban-associated bleeds who are transferred to Tampa General from smaller hospitals. These community hospitals often have fewer resources and many of the patients transferred have received either no reversal agent or a non-FDA-approved reversal agent for their bleeds. These patients often lose valuable time in the minutes that matter most for reversing the effects of FXa inhibitors and can negatively impact health outcomes. Where a patient lives should not dictate whether they live when experiencing a life-threatening bleed. This treatment disparity underscores the urgent need for ANDEXXA to be included on more hospital formularies, especially in the community setting.
The Importance of Physician Advocates
Physicians and other health care providers have a responsibility to provide the best possible care to their patients, making informed treatment decisions based on clinical trial data and guideline recommendations.
With ANDEXXA being the only FDA-approved FXa inhibitor antidote for severe and uncontrolled bleeding in patients taking rivaroxaban and apixaban, there is a clear need for access to this medication at all hospitals across the United States, regardless of size or location.
I urge you to join me in advocating to your hospital leadership and P&T committees, on behalf of patients for whom access to ANDEXXA is critical. In citing the available data, which supports the approval of ANDEXXA, the clinical need for this treatment becomes evident and may help to improve the availability of the medicine within hospital formularies.
Since ANDEXXA was acquired by AstraZeneca in 2021, the company has made significant efforts to address barriers hospitals had previously experienced in accessing the drug. On April 1, 2022, AstraZeneca reduced the Wholesale Acquisition Cost (WAC) price of ANDEXXA by 55 percent.18 This price reduction would make the medicine more affordable for hospitals, and in turn, accessible to more patients. The reduced WAC for ANDEXXA takes into consideration several factors, including the clinical value for patients taking rivaroxaban or apixaban who experience a life-threatening bleed, ANDEXXA’s placement as the preferred agent in industry guidelines, feedback from stakeholders and the financial realities of hospitals in the United States.
Once ANDEXXA is included within your hospital formulary, I recommend implementing an institutional protocol to ensure best practices across health care providers, including:
- The creation of a multidisciplinary team to guide the implementation of an institutional protocol
- Required ANDEXXA education for prescribers
- The addition of ANDEXXA to electronic ordering systems including on-label dosing and administration instructions
- Implementation of a monitoring process to periodically review the utilization of ANDEXXA to inform routine use guidelines for all life-threatening bleeds in patients taking rivaroxaban or apixaban
With increased awareness of the urgent need for ANDEXXA and additional education on its clinical benefits, we, as physicians, can do our part to help save the lives of more people treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeds.
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.
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.
• 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.
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.
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Please see full Prescribing Information, including Boxed WARNING.
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.
References
1. IBM Watson Health. Alexion Bleed Report. Data month ending September 2019.
2. The National Blood Clot Alliance. Accessed June 15, 2020. November 18, 2022. https://www.stoptheclot.org/living-your-best-life-while-taking-blood-thinners/
3. Eliquis® (apixaban) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2021. Accessed January 17, 2023. Available from: https://packageinserts.bms.com/pi/pi_eliquis.pdf
4. Xarelto® (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceutical Companies; 2021. Accessed January 17, 2023. Available from: https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/XARELTO-pi.pdf
5. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. doi:10.1056/NEJMoa1009638
6. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. doi:10.1056/NEJMoa1107039
7. Bleed Events Report. Truven Health Analytics. 2016. REF-138702. AstraZeneca LP.
8. DOAC Market Data Report. Portola Pharmaceuticals. 2018. REF-138706. AstraZeneca LP.
9. DOAC Market Data Report. Portola Pharmaceuticals. 2019. REF-138707. AstraZeneca LP.
10. Held, Claes, 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, European Heart Journal, Volume 36, Issue 20, 21 May 2015, Pages 1264–1272, https://doi.org/10.1093/eurheartj/ehu463
11. ANDEXXA® (coagulation factor Xa [recombinant], inactivated-zhzo) [prescribing information]. Boston, MA: Alexion Pharmaceuticals, Inc.; 2021. Accessed November 18, 2022. Available from: https://www.andexxaplan.com/content/dam/open-digital/andexxa-patient/en/pdf/andexxa-pi.pdf
12. 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.
13. May 3, 2018 – Approval Letter- ANDEXXA. U.S. Food & Drug Administration; 2018. Accessed January 17, 2023. Available from: https://www.fda.gov/media/113285/download
14. Ondexxya. European Medicines Agency; 2019. Accessed January 17, 2023. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ondexxya
15. Ondexxya approved in Japan for reversal of acute major bleeds in patients on Factor Xa inhibitors. AstraZeneca Media Centre; 2022. Accessed January 17, 2023. Available from: https://www.astrazeneca.com/media-centre/press-releases/2022/ondexxya-approved-in-japan-for-fxai-reversal.html
16. Baugh CW, et al. Anticoagulant Reversal Strategies in the Emergency Department Setting: Recommendations of a Multidisciplinary Expert Panel. Ann Emerg Med. 2020 Oct;76(4):470-485. doi: 10.1016/j.annemergmed.2019.09.001. Epub 2019 Nov 13. PMID: 31732375; PMCID: PMC7393606.
17. Greenberg, SM, et al. (2022). 2022 guideline for the management of patients with spontaneous intracerebral hemorrhage: A guideline from the American Heart Association/American Stroke Association. Stroke, 53(7). https://doi.org/10.1161/str.0000000000000407
18. AstraZeneca Pharmaceuticals LP. ANDEXXA website. Accessed January 17, 2023. https://www.andexxa.com/