Andexanet Alfa

Mechanism of Action

Andexanet alfa acts as a decoy, sequestering rivaroxaban or apixaban and preventing them from binding to natural factor Xa. The increase in available factor Xa reduces anticoagulant action, which can be measured by anti-factor Xa activity, thrombin generation, or unbound factor Xa inhibitor plasma concentration from baseline.

In clinical trials, median anti-factor Xa activity declined by 88% or more for apixaban and rivaroxaban. Andexanet alfa’s binding to factor Xa inhibitors is dose-dependent. There is a rapid decrease in anti-factor Xa activity after bolus administration. This decrease in anti-factor Xa activity is maintained throughout the infusion. At the initiation of the infusion, anti-factor Xa activity increases and reaches its peak 4 hours later. After peaking, anti-factor Xa activity declines at a rate similar to factor Xa inhibitor clearance.

In ANNEXA-A, andexanet alfa restored thrombin generation in 100% of healthy volunteers receiving apixaban. In ANNEXA-R, thrombin generation returned in 96% of healthy volunteers on rivaroxaban who received andexanet alfa.[13][3] In cases of intracranial hemorrhage associated with apixaban or rivaroxaban, andexanet alfa reduces anti–factor Xa activity and increases endogenous thrombin potential within 1 hour. Greater anti–factor Xa reduction correlates with smaller hematoma expansion, whereas increased thrombin potential is associated with both reduced hematoma growth and higher thromboembolic risk.[14]

Pharmacokinetics

Absorption: Andexanet alfa is administered intravenously. Its effects can be assessed using assays for anti–factor Xa activity, free fraction of factor Xa inhibitors, and thrombin generation. When given as a bolus followed by a 2-hour continuous infusion, dosing results in a rapid decrease in anti–factor Xa activity within 2 minutes of bolus completion, with this reduction maintained throughout the infusion.

Distribution: Andexanet alfa sequesters factor Xa inhibitors such as rivaroxaban and apixaban, and also inhibits the activity of tissue factor pathway inhibitor. The volume of distribution at steady state (Vss) is approximately 4.4 L for the low dose and 3.0 L for the high dose.

Metabolism: Andexanet alfa is degraded by proteolytic pathways into small peptides and amino acids.

Excretion: Clearance occurs through normal protein catabolic pathways, averaging 4.4 L/h for the low dose and 3.1 L/h for the high dose. The terminal half-life (t½) is approximately 3.3 hours at the low dose and 2.7 hours at the high dose. The anti–factor Xa activity returns to placebo levels approximately 2 hours after completing the infusion, whereas tissue factor pathway inhibitor activity returns to pretreatment levels approximately 96 hours after administering andexanet alfa.[15]

Administration

Available Dosage Forms and Strengths

Andexanet alfa is available as a lyophilized powder in preservative-free, 100 mg single-use vials. These vials should be stored at a temperature of 2 to 8°C. Reconstitute each 100 mg vial with 10 mL of sterile water for injection to achieve a concentration of 10 mg/mL. Dissolution typically occurs within 3 to 5 minutes. The reconstituted solution is stable for up to 8 hours at room temperature or 24 hours at 2 to 8 °C when stored in the original vial. This solution may also be transferred to polyolefin or polyvinyl chloride intravenous bags, where it remains stable for 8 hours at room temperature or 16 hours at 2 to 8 °C.

Adult Dosage

Two dosing regimens—low and high—depend on the specific factor Xa inhibitor requiring reversal, the time elapsed since the patient’s last dose, and the dose size.

• The low-dose protocol consists of a 400 mg bolus administered at a rate of 30 mg/min, followed by an infusion of 4 mg/min for up to 2 hours.
• The high-dose protocol involves an 800 mg bolus administered at a rate of 30 mg/min, followed by an infusion of 8 mg/min lasting up to 2 hours.
• If the last rivaroxaban dose was 10 mg or less and was taken less than 8 hours ago, or the time is unknown, administer the low dose.
• If the last dose of rivaroxaban was more than 10 mg or the amount is unknown, and the time since the previous administration is less than 8 hours or unknown, administer the high dose.
• If the last dose of apixaban was 5 mg or less and drug administration was less than 8 hours ago or unknown, give the low dose.
• If the last dose of apixaban was more than 5 mg or unknown, and the drug administration occurred less than 8 hours ago or is unknown, give the high dose.
• If the last dose of either drug was taken 8 hours or more ago, administer the low dose.[3]

Andexanet alfa should be administered intravenously using a 0.2- or 0.22-micron in-line filter. Multiple dosing has not been studied.

Specific Patient Populations

Hepatic impairment: The manufacturer's labeling does not specify any dosage adjustments for patients with hepatic impairment.

Renal impairment: The manufacturer's labeling does not specify any dosage adjustments for renal impairment. Therefore, dosage adjustment of andexanet alfa is unlikely to be necessary.

Pregnancy considerations: Andexanet alfa has not been studied in pregnant women, and reproductive or developmental studies in animals are unavailable; thus, potential fetal risks remain unknown. Safety and efficacy of andexanet alfa during labor and delivery have not been established.

Breastfeeding considerations: No clinical data are available on the use of andexanet alfa during breastfeeding. As a large protein molecule (~40,000 Da), its concentration in milk is expected to be minimal, and absorption is unlikely due to potential degradation in the infant’s gastrointestinal tract. Until further data are available, caution is advised when administering andexanet alfa during breastfeeding, particularly in preterm or neonatal infants.[16]

Pediatric patients: The safety and efficacy of andexanet alfa have not been investigated in the pediatric population.

Older patients: No significant differences in safety or efficacy have been observed in older patients, although increased sensitivity in the geriatric population cannot be ruled out.

Adverse Effects

Adverse effects include deep vein thrombosis, arterial thrombosis, pulmonary embolism, ischemic stroke, acute myocardial infarction, and death. Additional adverse effects include cardiogenic shock, heart failure exacerbations, urinary tract infections, pneumonia, acute respiratory failure, and infusion-related reactions.

A 2018 interim report from the ANNEXA-4 clinical trial showed that 6 of 227 patients (2.6%) experienced thrombosis within 3 days, and 24 patients (11%) within 30 days. Twenty-seven of 227 (12%) patients died within 30 days. One hundred thirty-nine of 227 (61%) received andexanet alfa for intracranial hemorrhage, and 16 of these 139 patients (12%) died within 30 days. The mean age of patients in this trial was 77 years, and 78% of them had atrial fibrillation.[17]

A 2021 meta-analysis of 21 studies reported a 10.7% 30-day thromboembolism rate compared to 3.1% with PCC. 

Prompt reinitiation of anticoagulation therapy, as soon as clinically appropriate, is crucial to reduce the risk of thrombosis following andexanet alfa therapy. The ACC also emphasizes this risk and the importance of resuming anticoagulation in a timely manner. However, thrombosis may occur even after the reinitiation of anticoagulation.[18]

Drug-Drug and Drug-Laboratory Interactions

• Unfractionated heparin: Unresponsiveness to unfractionated heparin has been reported after administration of andexanet alfa, characterized by failure to prolong the activated clotting time and the need for increased heparin doses. This phenomenon may be attributable to competitive binding at the heparin-antithrombin complex or other unspecified mechanisms. Therefore, unfractionated heparin should not be used after administration of andexanet alfa; if anticoagulation is necessary, an alternative agent should be chosen.

• Interference with anti-FXa activity tests: Standard clinical anti–factor Xa activity assays are unreliable following the administration of andexanet alfa. Andexanet alfa binds reversibly to factor Xa inhibitors; during sample dilution in these assays, the inhibitor dissociates from andexanet alfa, falsely elevating measured anti–factor Xa activity. This results in an underestimation of the drug's reversal effect. Consequently, the results of anti–factor Xa activity should be interpreted with caution in this context.

Contraindications

No absolute contraindications are listed in the prescribing information. 

Box Warnings: Thromboembolic Risks, Cardiac Arrests, Ischemic Stroke, and Sudden Death

Treatment with andexanet alfa has been associated with severe, potentially fatal complications such as arterial and venous thromboembolism, cardiac arrest, ischemic stroke, myocardial infarction, and sudden death. These adverse effects may stem from the patient’s underlying thrombotic risk, as well as the transient nature of anticoagulation reversal.

Andexanet alfa causes a rapid reduction in factor Xa inhibitor activity; however, because it acts as a decoy rather than a permanent inhibitor, anti–factor Xa activity can increase again after the infusion ends if residual anticoagulant is still present. This transient reversal may leave patients vulnerable to recurrent anticoagulation or thrombosis.[19]

Close monitoring for thrombotic complications and cardiovascular instability is critical. Anticoagulation therapy should be resumed promptly once bleeding has been controlled. Andexanet alfa is not recommended for use before initiating unfractionated heparin therapy, as it may impair heparin responsiveness and increase thrombotic risk.

Warnings and Precautions

• Safety data: There is no clinical trial data on the use of andexanet alfa during pregnancy, labor, delivery, or lactation. Andexanet alfa's safety has not been evaluated in patients who experienced thrombosis or disseminated intravascular coagulation within 14 days prior to bleeding that required andexanet alfa treatment. Safety has also not been evaluated in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within 7 days prior to bleeding that required andexanet alfa treatment.[20]

• Heparin resistance: Unresponsiveness to unfractionated heparin, along with serious thrombotic events, has been reported with andexanet alfa. Andexanet alfa should not be used to reverse direct factor Xa inhibitors prior to heparin administration. If anticoagulation is required, an alternative to heparin should be selected. The safety and efficacy of andexanet alfa as an antidote to heparin have not been established.[21]

• Re-elevation/incomplete reversal of anti-FXa activity: Andexanet alfa produces a rapid, substantial reduction in anti–factor Xa activity during administration, with levels returning to placebo values approximately 2 hours after infusion completion. Subsequently, anti–factor Xa activity declines at a rate consistent with the clearance of factor Xa inhibitors. In patients anticoagulated with apixaban or rivaroxaban who had elevated baseline anti-FXa levels, andexanet alfa reduced anti-FXa activity by a median of 96% and 92%, respectively.

Monitoring

Drug effects of andexanet alfa can be measured by anti–factor Xa activity, free fraction of apixaban or rivaroxaban, and thrombin generation. Anti–factor Xa activity returns to placebo levels approximately 2 hours after the bolus or infusion ends, whereas tissue factor pathway inhibitors persist for approximately 22 hours after administration of the drug.[22] An increase in tissue-factor–initiated thrombin generation is sustained during the infusion and continues for approximately 22 hours afterward. Patients should be monitored for signs and symptoms of thrombosis.[20][23]

Toxicity

Signs and Symptoms of Overdose

Clinical experience with andexanet alfa overdose has not been reported. Based on its mechanism of action as a modified recombinant factor Xa decoy, a potential overdose may increase the risk of thromboembolic events from excessive anticoagulation reversal and could produce procoagulant effects.

Management of Overdose

In suspected overdose cases, monitor for clinical signs and symptoms of thromboembolism and relevant coagulation laboratory parameters. Provide supportive care as clinically indicated. Contact the poison control center for the most up-to-date information.

Enhancing Healthcare Team Outcomes

Reversing apixaban or rivaroxaban with andexanet alfa in patients experiencing anticoagulation therapy–related bleeding requires coordination among an interprofessional team. Licensed independent practitioners should promptly notify the pharmacy and nursing staff to coordinate the preparation and administration of the drug. Nurses play a vital role in monitoring patients for signs and symptoms of thrombosis. Patients should be informed that thrombotic events can occur within 30 days after andexanet alfa treatment.

Andexanet alfa reversal requires coordinated efforts from a multidisciplinary team. The hematologist guides anticoagulation reversal decisions, carefully weighing the risk of thrombosis. Emergency medicine physicians initiate rapid administration, while pharmacists ensure accurate dosing and monitor for adverse events. Critical care physicians manage acute bleeding and maintain hemodynamic stability. Advanced practice providers assess patients for andexanet alfa use, initiate reversal protocols, and monitor for complications.

When prescribing or ordering factor Xa inhibitors, clinicians should collaborate with pharmacy staff to ensure correct dosing, rule out drug interactions, and confirm the availability of andexanet alfa.[24] Nurses should be well-versed in the dosing of both the factor Xa inhibitor and andexanet alfa to administer anticoagulation effectively and respond quickly when reversal is required.

An interprofessional team approach and effective communication among physicians, advanced practice providers, pharmacists, and nurses are crucial to minimizing potential adverse effects and enhancing patient outcomes related to andexanet alfa therapy.