Andexanet Alfa

FDA Drug Information • Also known as: Andexxa

Brand Names: Andexxa
Dosage Form: LIQUID
Product Type: DRUG FOR FURTHER PROCESSING

⚠ Boxed Warning (Black Box)

WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, AND SUDDEN DEATHS Treatment with ANDEXXA has been associated with serious and life-threatening adverse events, including: ( 5.1 )

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. WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, and SUDDEN DEATHS See full prescribing information for complete boxed warning Treatment with ANDEXXA has been associated with serious and life-threatening adverse events, including: ( 5.1 )

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

11 DESCRIPTION ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) is a sterile, white to off-white lyophilized powder available in single-dose vials. Each 200 mg vial delivers 200 mg of coagulation factor Xa formulated with the inactive ingredients tromethamine (Tris base), Tris hydrochloride, L-arginine hydrochloride, sucrose (1% w/v), mannitol (2.5% w/v), and polysorbate 80 (0.01% w/v) at pH 7.8. After reconstitution of the lyophilized powder with SWFI for 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 FXa. 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 anticoagulant 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.

What Is Andexanet Alfa Used For?

1 INDICATIONS AND USAGE ANDEXXA is indicated for patients treated with rivaroxaban or 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 (14) ] . An improvement in hemostasis has not been established. Continued approval for this indication may be contingent upon the results of studies that demonstrate an improvement in hemostasis in patients. ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) is a recombinant modified human factor Xa (FXa) protein indicated for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. ( 1 ) This indication is approved under accelerated approval based on the change from baseline in anti-FXa activity in healthy volunteers. An improvement in hemostasis has not been established. Continued approval for this indication may be contingent upon the results of studies that demonstrate an improvement in hemostasis in patients. ( 1 , 14 ) Limitations 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 or rivaroxaban. ( 1 ) Limitations 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 or rivaroxaban.

Dosage and Administration

2 DOSAGE AND ADMINISTRATION For intravenous (IV) use only.

Dose ANDEXXA based on the specific FXa inhibitor, dose of FXa inhibitor, and time since the patient's last dose of FXa inhibitor. ( 2 )

Administer as an IV bolus, with a target rate of 30 mg/min, followed by continuous infusion for 120 minutes. ( 2.3 )

There are two dosing regimens: Dose The safety and effectiveness of more than one dose have not been evaluated. ( 2.1 ) Initial IV Bolus Follow-On IV Infusion Low Dose 400 mg at a target rate of 30 mg/min 4 mg/min for 120 minutes High Dose 800 mg at a target rate of 30 mg/min 8 mg/min for 120 minutes 2.1 Dose For intravenous (IV) use only. There are two dosing regimens (see Table 1 ). The safety and efficacy of an additional dose have not been established. Table 1: ANDEXXA Dosing Regimens Dose The safety and effectiveness of more than one dose have not been evaluated. Initial IV Bolus Follow-On IV Infusion Total Number of 200 mg Vials Low Dose 400 mg at a target rate of 30 mg/min 4 mg/min for 120 minutes (480 mg) 5 (2 vials bolus + 3 vials infusion) High Dose 800 mg at a target rate of 30 mg/min 8 mg/min for 120 minutes (960 mg) 9 (4 vials bolus + 5 vials infusion) The recommended dosing of ANDEXXA is based on the specific FXa inhibitor, dose of FXa inhibitor, and time since the patient's last dose of FXa inhibitor (see Table 2 ). Table 2: ANDEXXA Dose Based on Rivaroxaban or Apixaban Dose (Timing of Last Dose of FXa Inhibitor before ANDEXXA Initiation) FXa Inhibitor FXa Inhibitor Last Dose < 8 Hours or Unknown ≥ 8 Hours Rivaroxaban ≤ 10 mg Low Dose Low Dose > 10 mg or Unknown High Dose Apixaban ≤ 5 mg Low Dose > 5 mg or Unknown High Dose 2.2 Reconstitution

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 eight hours, or may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F).

Reconstituted ANDEXXA in IV bags is stable at room temperature for up to eight hours. IV Bolus Preparation Determine total number of vials required (see Table 1 ). 200 mg vials: Reconstitute the 200 mg vial of ANDEXXA with 20 mL of Sterile Water for Injection (SWFI). Use a 20-mL (or larger) syringe and 20-gauge (or smaller in diameter, e.g., 21-gauge) needle. Slowly inject the SWFI, directing the solution onto the inside wall of the vial to minimize foaming. 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 (A). Do not shake (B); shaking could lead to foaming. Typical dissolution time for each vial is approximately three to five minutes. If dissolution is incomplete, discard the vial, and do not use the product. Upon reconstitution, the parenteral drug product should be inspected visually for particulate matter and discoloration prior...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The most common adverse reactions (≥ 5%) in bleeding patients receiving ANDEXXA were urinary tract infections and pneumonia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most common adverse reactions (≥ 5%) in bleeding patients receiving ANDEXXA were urinary tract infections and pneumonia. In Study 3 (ANNEXA-4), four hundred and seventy-seven patients with acute major bleeding were enrolled and received ANDEXXA. Of these 477 patients, 419 patients were treated with apixaban (245/419; 58.5%) or rivaroxaban (174/419; 41.5%). Most patients had received apixaban or rivaroxaban as anticoagulation treatment for atrial fibrillation (348/419; 83%) or venous thromboembolism (65/419; 16%). In the majority of patients, ANDEXXA was used to reverse anticoagulant therapy following either an intracranial hemorrhage (289/419; 69%) or a gastrointestinal bleed (95/419; 23%), with the remaining patients (35/419; 8.4%) experiencing bleeding at other sites. Patients were assessed at a Day 30 follow-up visit following infusion with ANDEXXA. Deaths In the ANNEXA-4 study, of the 419 patients in the safety population who were treated with apixaban or rivaroxaban, there were 75 deaths (18%). There were 37 cardiovascular deaths related to bleeding, 19 deaths that were cardiovascular and not related to bleeding, 14 that were non-cardiovascular, and 5 deaths had an uncertain or unknown cause. The average time to death was 15 days after treatment. All patients died prior to Day 45. Of the 75 patients who died, the initial bleeding event was intracranial bleeding in 55 (73%), gastrointestinal bleeding in 14 (19%), and other bleeding types in 6 (8%)patients. Thromboembolic and Ischemic Events In the Study 3 (ANNEXA-4), 45/419 (10.7%) patients experienced one or more of the following thromboembolic events: cerebrovascular accident (CVA) (19/45; 42%), deep venous thrombosis (11/45; 24%), myocardial infarction (9/45; 20%), pulmonary embolism (5/45; 11%), and transient ischemic attack (1/45; 2%). The median time to event was ten days. A total of 38% of patients with thromboembolic events (17/45) experienced the thromboembolic event during the first three days. Of the 419 patients who received ANDEXXA, 282 (67.3%) received any form of re-anticoagulation within 30 days after treatment. Of these 282 patients, 16 received anticoagulation in response to a thrombotic event, while 266 received the anticoagulation as a prophylactic. Of these 266, 14 patients (5.3%) had a thrombotic event after resumption of anticoagulation; while of the 153 patients who did not receive anticoagulation as a prophylactic, 31 (20.3%) had a thrombotic event. No patient had a thrombotic event after resumption of oral anticoagulation [ see Warnings and Precautions (5.1) ]. Infusion-Related Reactions In the ANNEXA-4 study, 2/419 (0.5%) patients experienced an infusion-related reaction, neither of which were assessed as severe (1 moderate; 1 mild). Reported signs and symptoms were transient and included rigors, chills, hypertension, oxygen desaturation, agitation and confusion. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ANDEXXA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or stablish a causal relationship to drug exposure. General disorders and administration site conditions: heparin resistance [ see Unresponsiveness to Unfractionated Heparin (5.2) ] and [ see Use with Unfractionated Heparin (7.1) ].

Drug Interactions

7 DRUG INTERACTIONS Do not use unfractionated heparin following ANDEXXA administration due to unresponsiveness characterized by non-prolongation of activated clotting times ( 7.1 ). See full prescribing information for details on drug interactions. 7.1 Use with Unfractionated Heparin Unresponsiveness to unfractionated heparin has occurred following ANDEXXA administration, characterized by non-prolongation of activated clotting times and requirement for increased dosing of heparin. Do not use unfractionated heparin following ANDEXXA administration. 7.2 Interference with Anti-FXa Activity Test Current commercial clinical anti-FXa-activity assays are unsuitable for measuring FXa activity following administration of ANDEXXA. Due to the reversible binding of ANDEXXA to the FXa inhibitor, the high sample dilution currently used in commercial clinical assays promotes dissociation of the inhibitor from ANDEXXA, resulting in detection of erroneously elevated anti-FXa activity levels, thereby causing a underestimation of the reversal activity of ANDEXXA.

Contraindications

4 CONTRAINDICATIONS None. None. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies of ANDEXXA in pregnant women to inform patients of associated risks. Animal reproductive and developmental studies have not been conducted with ANDEXXA. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Labor or Delivery The safety and effectiveness of ANDEXXA during labor and delivery have not been evaluated.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) is a white to off-white lyophilized cake or powder supplied as single-dose vials in a carton. ANDEXXA is not made with natural rubber latex. ANDEXXA vials are provided as follows (see Table 5): Table 5: Presentation of ANDEXXA NDC Carton Configuration Vial Cap Color Packaging Color NDC 0310-3200-04 4 single use vials in a carton, each vial containing 200 mg of ANDEXXA Vials have a red flip-off cap. 1. Carton and vial label have a red to blue transition colored stripe across the front. 2. Carton and label have "200 mg/vial" in a blue graphic on the front panel. NDC 0310-3200-05 5 single use vials in a carton, each vial containing 200 mg of ANDEXXA Storage and Handling Prior to reconstitution Unopened vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F) until the expiration date indicated on the label. DO NOT FREEZE. Do not use ANDEXXA after the expiration date. After reconstitution

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 (36°F to 46°F).

Reconstituted ANDEXXA in IV bags is stable at room temperature for up to 8 hours.

Discard any unused portion of reconstituted solution.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.