Factor Xa (also known as andexanet alfa) is a parenteral, recombinant modified human factor Xa protein indicated for reversal of apixaban or rivaroxaban anticoagulation in patients with life-threatening or uncontrolled bleeding. Guidelines also support off-label use for reversal of betrixaban or edoxaban anticoagulation. In clinical trials, anti-factor Xa activity decreased rapidly and substantially in response to the factor Xa bolus compared to baseline; decreased anti-factor Xa activity was sustained through the end of the factor Xa continuous infusion. An improvement in hemostasis has not been established. Factor Xa has been associated with serious and life-threatening adverse events including arterial and venous thromboembolism, myocardial infarction, ischemic stroke, cardiac arrest, and sudden death. To reduce thromboembolic risk, resume anticoagulant therapy as soon as medically appropriate after factor Xa treatment.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Reconstitution
-Reconstitute each vial with Sterile Water for Injection (SWFI) to a final concentration of 10 mg/mL; add 20 mL to each 200 mg vial using a 20-mL (or larger) syringe and a 20-gauge (or smaller in diameter, e.g., 21-gauge) needle. Slowly inject the SWFI, directing the solution onto the inside of the vial to minimize foaming.
-To ensure complete dissolution, gently swirl each vial. Do not shake. Typical dissolution time is approximately 3 to 5 minutes per vial. If dissolution is incomplete, do not use the product; discard the vial.
-For the bolus, use a 40-mL (or larger) syringe with a 20-gauge (or smaller in diameter, e.g., 21-gauge) needle to withdraw the reconstituted solution from each of the vials until the required dosing volume is achieved. Note the total volume withdrawn into the syringe.
-For the continuous IV infusion, multiple 40- to 60-mL syringes or an equivalent 100-mL syringe may be used for the transfer of the infusion volume to the IV bag. Note the total volume withdrawn into the syringe.
-Transfer the solutions for the bolus and the infusion from the syringes into separate empty polyolefin or polyvinyl chloride IV bags with a volume of 250 mL or less.
-Storage: Reconstituted vials are stable at room temperature for up to 8 hours or may be stored for up to 24 hours at 2 to 8 degrees C (36 to 46 degrees F). Reconstituted factor Xa in IV bags is stable at room temperature for up to 8 hours.
Administration
-Administer using a 0.2- or 0.22-micron in-line polyethersulfone or equivalent low protein-binding filter.
-Give the bolus at a target rate of approximately 30 mg/minute.
-Within 2 minutes after the bolus dose, administer the continuous IV infusion at a rate of 4 mg/minute (low dose) or 8 mg/minute (high dose) for 120 minutes.
Treatment with factor Xa has been associated with severe and life-threatening events, including arterial and venous thromboembolism, myocardial infarction, ischemic stroke, cardiac arrest, and sudden death. Thrombotic events occurred in 10.7% (45/419) of factor Xa-treated patients during clinical trials; the median time to the event was 10 days. In these patients (n = 45), cerebrovascular accident (42%), deep vein thrombosis (24%), acute myocardial infarction (20%), pulmonary embolism (11%), and transient ischemic attack (2%) were reported. This translates to an overall incidence (n = 419) of 4.5% for cerebrovascular accident, 2.6% for deep vein thrombosis, 2.1% for myocardial infarction, 1.2% for pulmonary embolism, and 0.2% for transient ischemic attack. Of the patients who were re-anticoagulated within 30 days of factor Xa treatment, 5.3% had a thrombotic or ischemic event after resumption. Of the patients who did not receive re-anticoagulation after factor Xa treatment, 20.3% had a thrombotic event. No patient had a thrombotic event after resumption of oral anticoagulation. Monitor patients receiving factor Xa for signs and symptoms of thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for signs and symptoms that precede cardiac arrest and provide treatment as needed. To reduce thromboembolic risk, resume anticoagulant therapy as soon as medically appropriate after factor Xa treatment.
Urinary tract infection and pneumonia both occurred in 5% or more of factor Xa-treated patients.
During the clinical trial, 2 of 419 (0.5%) patients treated with factor Xa developed infusion-related reactions, neither of which were deemed severe (1 mild; 1 moderate). Symptoms were transient and included rigors, chills, hypertension, oxygen desaturation, agitation, and confusion.
As with all therapeutic proteins, there is the potential for immunogenicity and antibody formation. Tests for antibodies to factor Xa as well as for antibodies cross-reacting with factor X (FX) and FXa were performed in 417 healthy subjects treated with factor Xa. The analysis of samples up to Day 48 from pooled healthy subjects found low incidence of anti-factor Xa (8.7% or less) and anti-FXa (0.8% or less) at all timepoints and no anti-FX antibody was detected. Similar results were observed in drug recipients with acute major bleeding in the ANNEXA-4 study. Of the 277 factor Xa-treated patients in ANNEXA-4 who had samples available at Day 30 or 45, 7.9% had antibodies against factor Xa, 0.4% had antibodies against FXa, and no patient had antibodies against FX. No neutralizing antibodies against factor Xa or cross-reacting with FX or FXa were detected in healthy subjects or in bleeding patients.
Laboratory assessment of coagulation does not necessarily correlate with or predict factor Xa hemostatic efficacy. Commercial clinical anti-factor Xa activity assays are not suitable for measuring factor Xa activity after factor Xa administration. Substantial underestimation of factor Xa reversal activity may occur.
Re-elevation or incomplete reversal of anti-factor Xa activity has been observed with factor Xa use. In patients receiving the factor Xa bolus, there is a rapid (within 2 minutes) and substantial decrease in anti-FXa activity (92% mean reduction for apixaban and 96% mean reduction for rivaroxaban). This decrease is sustained through the end of the factor Xa continuous infusion. Approximately 2 hours after completion of the factor Xa bolus or infusion, the anti-FXa activity returns to the placebo levels. Subsequently, the anti-FXa activity decreases at a rate similar to the clearance of the factor Xa inhibitors (apixaban or rivaroxaban).
Factor Xa has been associated with serious and life-threatening adverse events including arterial and venous thromboembolism, myocardial infarction, ischemic stroke, cardiac arrest, and sudden death. Monitor patients receiving factor Xa for signs and symptoms of thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for signs and symptoms that precede cardiac arrest and provide treatment as needed. To reduce thromboembolic risk, resume anticoagulant therapy as soon as medically appropriate after factor Xa treatment. The safety of factor Xa has not been evaluated in patients who experienced thromboembolic events or disseminated intravascular coagulation (DIC) within 2 weeks prior to the life-threatening bleeding event requiring factor Xa treatment. The safety of factor Xa has also not been evaluated in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within 7 days prior to the bleeding event. Factor Xa may cause unresponsiveness to heparin anticoagulation. Avoid use of factor Xa for the reversal of direct factor Xa inhibitors prior to heparinization. Use an alternative to heparin if anticoagulation is required. Use of factor Xa as an antidote for heparin has not been established.
There are no adequate and well-controlled studied of factor Xa in human pregnancy to inform patients of associated risks. Animal reproductive and developmental studies have not been conducted with factor Xa. The safety and effectiveness of factor Xa in labor and delivery have not been evaluated.
There are no data on the presence of factor Xa in human milk, the effects on the breast-fed child, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for factor Xa and any potential adverse effects on the breast-fed child from factor Xa or the underlying maternal condition.
For apixaban reversal, edoxaban reversal*, or rivaroxaban reversal in persons with life-threatening or uncontrolled bleeding:
NOTE: Dosing is based on the specific factor Xa inhibitor to be reversed, the dose of the factor Xa inhibitor, and the timing of the last dose of the factor Xa inhibitor prior to reversal.
Intravenous dosage (low dose):
Adults: 400 mg IV bolus, then 4 mg/minute continuous IV infusion for 120 minutes for reversal of apixaban 5 mg or less or rivaroxaban 10 mg or less given within 8 hours or unknown timing or for any dose of apixaban or rivaroxaban given 8 hours or more prior to reversal. The safety and efficacy of more than 1 dose have not been established. Resume anticoagulant therapy as soon as medically appropriate after factor Xa treatment.
Intravenous dosage (high dose):
Adults: 800 mg IV bolus, then 8 mg/minute continuous IV infusion for 120 minutes for reversal of apixaban more than 5 mg, rivaroxaban more than 10 mg, or unknown dose given within 8 hours or unknown timing prior to reversal and for reversal of edoxaban. The safety and efficacy of more than 1 dose have not been established. Resume anticoagulant therapy as soon as medically appropriate after factor Xa treatment.
Maximum Dosage Limits:
-Adults
1760 mg/event IV.
-Geriatric
1760 mg/event IV.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
Heparin: (Major) Avoid use of factor Xa for the reversal of direct factor Xa inhibitors prior to heparinization. Use an alternative to heparin if anticoagulation is required after factor Xa use. Factor Xa may cause unresponsiveness to heparin anticoagulation.
Factor Xa is a genetically modified variant of human factor Xa. Factor Xa binds and sequesters the factor Xa inhibitors, apixaban and rivaroxaban. Additionally, factor Xa binds and inhibits tissue factor pathway inhibitor (TFPI); the inhibition of TFPI activity can increase tissue factor-initiated thrombin generation. To remove potential anticoagulant effects, the active site serine was substituted with alanine, making the molecule unable to cleave and activate prothrombin and the gamma-carboxyglutamic acid (Gla) domain was removed, eliminating the protein's ability to assemble into the prothrombinase complex.
Factor Xa is administered intravenously. The Vd for factor Xa is 4.4 L for low dose and 3 L for high dose. Factor Xa clearance is approximately 4.4 L/hour for low dose and 3.1 L/hour for high dose. Elimination half-life ranges from 2.7 to 3.3 hours.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
A rapid decrease in anti-factor Xa activity and elevation of tissue factor-initiated thrombin generation above baseline occurs within 2 minutes after completion of the IV bolus and are maintained throughout the duration of the factor Xa continuous IV infusion. Anti-factor Xa activity returns to baseline approximately 2 hours are completion of a bolus or continuous infusion. There is an increase in anti-factor Xa activity, which peaks about 4 hours after the factor Xa infusion; after this peak, anti-factor Xa activity decreases at a rate similar to the clearance of the factor Xa inhibitors. The tissue factor-initiated thrombin generation is sustained for at least 22 hours after factor Xa administration.
-Special Populations
Geriatric
The pharmacokinetics of factor Xa in older (65 years or older) patients were not different from younger (18 to 45 years) patients.