2018年5月3日，美国Portola制药宣布，美国FDA已批准Andexxa[凝血因子Xa(重组)inactivated-zhzo]作为首个及唯一一个凝血因子Xa抑制剂（利伐沙班、阿哌沙班）的解毒药物，用于当出现危及生命或无控制出血后的抗凝的逆转。此前有报道预测该药物即将获批，没想到好消息来的这么快。

　Andexxa的本次批准基于FDA加速批准，加速批准认定则是基于健康志愿者抗Xa因子活性的基线变化数据而获得，同时该药物获得了FDA的突破性疗法及孤儿药资格认定。该适应症的完全批准则可能取决于药物上市后的研究结果，需要证明病人的止血效果有所改善。
　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。”
　由于Xa因子抑制剂相比依诺肝素和华法林在预防和治疗血栓栓塞症[如卒中、肺栓塞和静脉血栓栓塞症（VTE）]中的良好疗效及安全性，使得Xa抑制剂的使用正在迅速增长。而这种使用的快速增长伴随着出血相关的入院和与死亡的增加，这也是抗凝治疗的主要并发症。仅在2016年，美国就有约11.7万例因xa抑制剂相关出血而住院的患者，每月有近2000人因出血而死亡。
　Portola制药首席执行官Bill Lis表示：“我们感谢参与临床试验的病人，临床试验合作者以及员工和FDA，他们帮助我们将这种新药推向市场，造福于与Xa因子相关的出血患者。为Andexxa是我们实验室发现的首创药物而感到自豪。除了Bevyxxa是第一种也是唯一一种被批准用于急性住院患者长期VTE预防的抗凝药物之外，Andexxa成为公司第二个获得FDA批准的产品，该药物具有拯救生命的潜力，将对全球公共卫生产生重大影响。我们仍然致力于在血栓形成和血液瘤领域的科学领导力。”
　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%。
　作为其审查和批准的一部分，FDA也评估了正在进行的ANNEXA-4单臂开放标签研究中对大出血患者治疗的中期数据。185例可评估患者的数据显示，Andexxa在给药时迅速而显著地逆转了抗Xa因子的活性，并在120分钟后持续逆转。与基线相比，利伐沙班和阿哌沙班的平均活性降幅分别为90%和93%。

附：药品使用说明
ANDEXXA®(coagulation factor Xa (recombinant), inactivated-zhzo) Lyophilized Powder for Solution For Intravenous Injection
WARNING
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
•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.
DESCRIPTION
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.
INDICATIONS
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.
Dose
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).
(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.
(Figure B)

•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).
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.
Administration
•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.
HOW SUPPLIED
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.
NDC 69853-0101-1
Storage And Handling
Unopened vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F). DO NOT FREEZE
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