安大略省汉密尔顿麦克马斯特大学健康科学医学系教授Stuart J. Connolly博士表示：“今天的批准是在病人护理方面向前迈出的重要一步，也是医学界热切期待的重要一步。Andexxa快速逆转利伐沙班及阿哌沙班的抗凝作用，将帮助临床医生去治疗危及生命的出血事件。”
本次Andexxa的批准基于两项临床3期研究ANNEXA（ANNEXA-R 与 ANNEXA-A）的试验数据，具体数据已刊登在《The New England Journal of Medicine》，研究评价了Andexxa逆转Xa因子抑制剂利伐沙班和阿哌沙班抗凝作用的安全性和有效性。结果显示，Andexxa可迅速而显著地逆转抗Xa因子的活性, 与基线相比，抗因子Xa活性的中位数下降了97%（利伐沙班），而阿哌沙班活性则下降了92%。
ANDEXXA®(coagulation factor Xa (recombinant), inactivated-zhzo) Lyophilized Powder for Solution For Intravenous Injection
THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, AND SUDDEN DEATHS
Treatment with ANDEXXA has been associated with serious and life-threatening adverse events, including: (WARNINGS AND PRECAUTIONS)
•Arterial and venous thromboembolic events
•Ischemic events, including myocardial infarction and ischemic stroke
Monitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for symptoms and signs that precede cardiac arrest and provide treatment as needed.
ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) is a sterile, white to off-white lyophilized powder available in single-use vials, containing 100 mg of coagulation factor Xa formulated with the inactive ingredients tromethamine (Tris), L-arginine hydrochloride, sucrose (2% w/v), mannitol (5% w/v), and polysorbate 80 (0.01% w/v) at pH 7.8. After reconstitution of the lyophilized powder with sterile Water for Injection for intravenous (IV) administration, the product is a clear, colorless to slightly yellow solution. ANDEXXA contains no preservatives.
The active ingredient in ANDEXXA is a genetically modified variant of human Factor Xa. The active site serine was substituted with alanine, rendering the molecule unable to cleave and activate prothrombin. The gamma-carboxyglutamic acid (Gla) domain was removed to eliminate the protein’s ability to assemble into the prothrombinase complex, thus removing the potential anti-coagulant effects.
No additives of human or animal origin are used in the manufacture of ANDEXXA. The recombinant protein is produced in a genetically engineered Chinese Hamster Ovary (CHO) cell expression system and has a molecular weight of approximately 41 kDa. The manufacturing process incorporates two validated virus clearance steps.
ANDEXXA is indicated for patients treated with rivaroxaban and 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 [see Clinical Studies]. 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.
Limitation 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 and rivaroxaban.
DOSAGE AND ADMINISTRATION
For intravenous use only.
There are two dosing regimens (see Table 1). The safety and efficacy of an additional dose has not been established.
Upon reconstitution, the parenteral drug product should be inspected visually for particulate matter and discoloration prior to administration.
•The reconstituted solution contains coagulation factor Xa (recombinant), inactivated-zhzo at a concentration of 10 mg/mL.
•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 ANDEXXA in IV bags is stable at room temperature for up to 8 hours, or may be stored for up to 16 hours at 2°C to 8°C.
IV Bolus Preparation
•Reconstitute each 100 mg vial of ANDEXXA (Figure A) using a 10-mL syringe and 20-gauge (or higher) needle. Slowly inject 10 mL Sterile Water for Injection (SWFI), USP, directing the solution onto the inside wall of the vial to minimize foaming (Figure A).
•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; shaking could lead to foaming (Figure B). Typical dissolution time for each vial is approximately 3 to 5 minutes. If dissolution is incomplete, discard the vial and do not use the product.
•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 (Figure C).
•Discard the syringe and needle.
•Discard the vials, including any unused portion.
Continuous IV Infusion Preparation
•Follow the same procedure outlined above for IV bolus preparation. Reconstitute the 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.
•Administer ANDEXXA 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 Antithrombotic 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.
Dosage Forms And Strengths
ANDEXXA is available as a lyophilized powder in single-use vials of 100 mg of coagulation factor Xa (recombinant), inactivated-zhzo.
ANDEXXA is supplied in cartons of 4 single-use vials each containing 100 mg of ANDEXXA as a white to off-white lyophilized cake or powder.
Storage And Handling
Unopened vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE