Goodman & Gilman's: Annual FDA Approvals

[andexanet alfa] Andexxa^11,21

Direct-acting factor Xa (FXa) inhibitor antidote (FXa decoy)

Apixaban and rivaroxaban antidote for emergency reversal of anticoagulation^†

Andexanet alfa is the United States Adopted Name (USAN) and International Nonproprietary Name (INN) assigned to coagulation factor Xa (recombinant), inactivated-zhzo. Andexanet alfa is a genetically modified variant of human factor Xa (FXa) produced in Chinese hamster ovary cells. Andexanet alfa acts as a procoagulant FXa decoy⁸⁰ and is approved as an antidote for use in patients taking apixaban or rivaroxaban (but not betrixaban, edoxaban, or injectable FXa inhibitors), when rapid reversal of anticoagulation is needed.¹¹

Apixaban, betrixaban, edoxaban, and rivaroxaban are all direct-acting oral anticoagulants that act by binding to both free FXa in plasma and FXa attached to the prothrombinase complex. They prevent thrombin from being generated from prothrombin and are intended to reduce the risk of developing pathologic blood clots. Consistent with their mechanism of action, the therapeutic use of direct-acting oral anticoagulants is associated with an increased risk of clinically significant bleeding.

As a FXa decoy protein, andexanet alfa was specifically designed to be catalytically inactive within the coagulation cascade through two engineered structural modifications that render the drug (1) unable to assemble into the prothrombinase complex, and (2) unable to cleave and activate prothrombin.⁸¹ In addition to sequestering exogenous FXa inhibitors, andexanet alfa exerts an accessory procoagulant effect by inhibiting intrinsic tissue factor pathway inhibitor (TFPI) activity.¹¹ Through inhibition of TFPI, andexanet alfa indirectly drives tissue factor-initiated thrombin production.

Due to logistical difficulties and ethical concerns associated with studying patients in need of rapid FXa inhibitor reversal, FDA allowed randomized, placebo-controlled clinical trials in healthy volunteers as the basis for andexanet alfa’s approval. The pharmacodynamic and pharmacokinetic effects of andexanet alfa were measured in volunteers age 50–75 years using assays to detect changes in anti-factor Xa activity and thrombin generation following administration of either apixaban or rivaroxaban.¹¹ These studies demonstrated that andexanet alfa reduced anti–factor Xa activity by >90% and increased tissue factor–initiated thrombin generation within 2–5 minutes of the start of administration.¹¹ The effect on anti-FXa lasted ~2 hours, thrombin production remained elevated for ≥22 hours, and TFPI inhibition was judged to last ~96 hours.¹¹ In these premarket studies, andexanet alfa appeared to be well tolerated and the accumulated data did not signal excess immunogenic or prothrombotic safety concerns.⁸⁰ The drug is labeled with warnings regarding the possible development of thromboembolic events, ischemic stroke, myocardial infarction, cardiac arrest, and sudden death, but the occurrence of these outcomes attributable to drug administration is unknown. Due to the premarketing study design constraints, it also remains unknown if FXa inhibitor reversal by andexanet alfa will equate to a clinically meaningful reduction in bleeding.^80-83 In addition, there are insufficient data to recommend the use of andexanet for the reversal of FXa inhibitors other than apixaban or rivaroxaban. Further investigation of the benefits and risks of emergency andexanet alfa administration in patients with acute bleeding is underway.⁸⁰

Two dosing strategies for andexanet alfa are recommended depending on the timing and amount of direct-acting FXa inhibitor requiring reversal. The low-dose strategy consists of giving 400 mg IV as a bolus over 13–14 minutes followed by a 2-hour infusion delivering 4 mg of antidote per minute. The high-dose strategy doubles the bolus dose (800 mg) and doubles the rate of the follow-on 2-hour infusion (8 mg/min). The high-dose strategy is limited to use for apixaban or rivaroxaban doses >5 mg or >10 mg, respectively, when emergency reversal is necessary within 8 hours of the their last administration. Repeat doses of andexanet alfa for the clinical reversal of bleeding have not been studied. The average wholesale price listed for 100 mg of andexanet alfa is listed at $3300.00 (or nearly $30,000/bleed).⁸⁴

• Chapter 32. Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs > Andexanet Alfa

• eChapter 2018: The Goodman & Gilman Year in Review New and Noteworthy FDA Approvals