Andexanet Alfa

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Intravenous [preservative free]:

Andexxa: 100 mg (1 ea); 200 mg (1 ea) [contains polysorbate 80]

Pharmacology

Mechanism of Action

Andexanet alfa binds and sequesters the FXa inhibitors rivaroxaban and apixaban. In addition, andexanet alfa inhibits the activity of Tissue Factor Pathway Inhibitor (TFPI), increasing tissue factor-initiated thrombin generation.

Pharmacokinetics/Pharmacodynamics

Distribution

V_ss:

Generation 1 product: Low dose: 5.1 (range: 3.2 to 13.8) L; High dose: 4.1 (range: 2.4 to 5.7) L

Generation 2 product: Low dose: 4.4 (range: 3.3 to 5.7) L; High dose: 3 (range 2.2 to 5) L

Onset of Action

Rapid (Lu 2013)

Half-Life Elimination

Note: Clinical trials have shown that when andexanet alfa is administered to patients taking apixaban or rivaroxaban, anti-factor Xa activity increases to placebo levels ~2 hours after completion of the infusion (Connolly 2016; Siegel 2015). However, elevation of tissue factor-initiated thrombin generation above pretreatment baseline occurs within 2 minutes after administration and is sustained above placebo for at least 22 hours after administration.

Pharmacokinetic half-life:

Generation 1 product: Low dose: 4.3 (range: 3.3 to 11.9) hours; High dose: 4 (range: 2 to 5.7) hours

Generation 2 product: Low dose: 3.3 (range: 2.3 to 4) hours; High dose: 2.7 (range: 1.9 to 3.4) hours

Pharmacodynamic half-life: ~1 hour (Siegal 2015).

Use: Labeled Indications

Reversal of anticoagulation from apixaban or rivaroxaban: Reversal of anticoagulation in patients treated with apixaban or rivaroxaban experiencing life-threatening or uncontrolled bleeding

Use: Off Label

Reversal of anticoagulation from direct and indirect factor Xa inhibitorsc

Data from a limited number of patients suggest that andexanet alfa may be beneficial for the reversal of anticoagulation from the factor Xa inhibitor direct oral anticoagulants (DOAC) edoxaban and betrixaban Crowther 2016, Crowther 2014. Andexanet alfa may also be beneficial for the reversal of anticoagulation from enoxaparin, an indirect factor Xa inhibitor Connolly 2016.

Clinical experience also suggests the utility of andexanet alfa for reversal of factor Xa inhibitor DOACs and enoxaparin Garcia 2018. Specific dosing for this off-label use has not been established at this time.

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosage and Administration

Dosing: Adult

Reversal of anticoagulation from apixaban or rivaroxaban: IV: Note: Some experts recommend administration of andexanet alfa for life-threatening bleeding when use of a factor Xa inhibitor DOAC (eg, apixaban, rivaroxaban, edoxaban [off-label], betrixaban [off-label]) is confirmed and only after other hemostatic measures (eg, antifibrinolytic therapy [eg, tranexamic acid or aminocaproic acid] and drug removal with activated charcoal) have been shown to be ineffective or when patients are at imminent risk of death from bleeding (used in conjunction with other hemostatic measures) or for those who are in need of emergent surgery (Garcia 2018).

Andexanet alfa dosing regimens: Note: The andexanet alfa dosing regimen (low dose or high dose) is based on the specific factor Xa inhibitor given, the factor Xa inhibitor dose, and time since it was last taken. Safety and efficacy of >1 dose of andexanet alfa has not been established. Resume anticoagulant therapy as soon as medically appropriate following treatment.

IV:

Low dose: 400 mg IV bolus administered at a rate of ~30 mg/minute, followed within 2 minutes by an IV infusion of 4 mg/minute for up to 120 minutes

High dose: 800 mg IV bolus administered at a rate of ~30 mg/minute, followed within 2 minutes by an IV infusion of 8 mg/minute for up to 120 minutes

Table has been converted to the following text.

Andexanet alfa Dose Based on Apixaban or Rivaroxaban Dose:

If apixaban dose was ≤5 mg and administered <8 hours or unknown before andexanet alfa initiation, then use low dose.

If apixaban dose was >5 mg or unknown and administered <8 hours or unknown before andexanet alfa initiation, then use high dose.

If apixaban was administered ≥8 hours before andexanet alfa initiation, then use low dose.

If rivaroxaban dose was ≤10 mg and administered <8 hours or unknown before andexanet alfa initiation, then use low dose.

If rivaroxaban dose was >10 mg or unknown and administered <8 hours or unknown before andexanet alfa initiation, then use high dose.

If rivaroxaban was administered ≥8 hours before andexanet alfa initiation, then use low dose.

Dosing: Geriatric

Refer to adult dosing.

Reconstitution

Note: Reconstitute the number of vials needed based on the vial concentration and dose requirements:

100 mg vial:

Low dose = 4 vials for bolus dose + 5 vials for infusion dose (total number of vials = 9)

High dose = 8 vials for bolus dose + 10 vials for infusion dose (total number of vials = 18)

200 mg vial:

Low dose = 2 vials for bolus dose + 3 vials for infusion dose (total number of vials = 5)

High dose = 4 vials for bolus dose + 5 vials for infusion dose (total number of vials = 9)

To reduce the total reconstitution time, reconstitute all required vials in succession.

Reconstitute each 100 mg vial with 10 mL SWFI or each 200 mg vial with 20 mL SWFI using a ≥20 mL syringe and ≥20 gauge needle; slowly inject SWFI onto the inside wall of the vial to minimize foaming. Gently swirl vial until complete dissolution of powder. Do not shake. Typical dissolution time 3 to 5 minutes; if dissolution is incomplete, discard vial and do not use. Reconstituted solution contains andexanet alfa at a concentration of 10 mg/mL.

IV bolus: Use a ≥60 mL syringe with a ≥20 gauge needle to withdraw reconstituted solution from the vial and transfer the solution into an empty polyolefin or polyvinyl chloride IV bag with a volume of ≤250 mL.

Continuous IV infusion: Use the same procedure described above. May use more than one 40 to 60 mL syringe or a 100 mL syringe to transfer reconstituted solution to IV bag.

Administration

IV: For IV administration. Initiate bolus at a target rate of ~30 mg/minute. For IV infusion, use of a 0.2 or 0.22 micron in-line polyethersulfone or equivalent low protein-binding filter is required.

Storage

Store intact vials at 2°C to 8°C (36°F to 46°F). Do not freeze. Reconstituted vials are stable at room temperature ≤8 hours, or may be stored ≤24 hours at 2°C to 8°C. Reconstituted solution in IV bags is stable at room temperature ≤8 hours. Discard any unused portion.

Drug Interactions

There are no known significant interactions.

Adverse Reactions

>10%:

Immunologic: Antibody development (6% to 17%)

Miscellaneous: Infusion related reaction (18%)

1% to 10%:

Cardiovascular: Deep vein thrombosis (6%), ischemic stroke (5%), acute myocardial infarction (3%), pulmonary embolism (3%), cardiogenic shock (2%), cardiac failure (1%)

Genitourinary: Urinary tract infection (≥5%)

Respiratory: Pneumonia (≥5%), acute respiratory failure (1%)

Frequency not defined: Cardiovascular: Arterial thromboembolism, venous thromboembolism

<1%, postmarketing, and/or case reports: Coronary thrombosis, intracardiac thrombus, nonsustained ventricular tachycardia

Warnings/Precautions

Concerns related to adverse effects:

• Anti-FXa activity re-elevation: There is a rapid and substantial decrease in anti-FXa activity corresponding to the bolus dose, which is sustained during the continuous infusion. Anti-FXa activity returns to placebo levels ~2 hours after completion of bolus or continuous infusion; thereafter, anti-FXa activity decreases at a rate similar to the clearance of FXa inhibitors.
• Thromboembolic and ischemic risks: Arterial and venous thromboembolic events, ischemic events, and cardiac events (including sudden death) were observed within 30 days post-administration (median time to first event: 6 days). Monitor patients for signs and symptoms of arterial and venous thromboembolic events, ischemic events, and cardiac arrest. To reduce thromboembolic risk, resume anticoagulant therapy as soon as medically appropriate following treatment with andexanet alfa. Safety has not been evaluated in patients with thromboembolic events or disseminated intravascular coagulation within 2 weeks prior to the bleeding event or in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within 7 days prior to the bleeding event.

Monitoring Parameters

Signs/symptoms of arterial and venous thromboembolic events, ischemic events, or cardiac arrest

Signs/symptoms of hemostasis; if available, the preferred test to rule out clinically significant serum concentrations and quantify anticoagulant effect is anti-Xa activity individually calibrated to each specific factor Xa inhibitor (undetectable anti-Xa activity likely excludes clinically relevant drug concentrations). An anti-Xa activity assay calibrated for low molecular weight heparin can rule out clinically relevant drug concentrations of a factor Xa inhibitor DOAC, but is not useful for quantification (ACC [Tomaselli 2017]; AHA [Raval 2017]).

Pregnancy

Pregnancy Considerations

Animal reproduction studies have not been conducted.

Patient Education

What is this drug used for?

• It is used to undo the effects of a certain blood thinner.

Frequently reported side effects of this drug

• Flushing
• Sensation of warmth
• Change in taste

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Urinary tract infection like blood in the urine, burning or painful urination, passing a lot of urine, fever, lower abdominal pain, or pelvic pain
• Persistent cough
• Severe dizziness
• Passing out
• Severe nausea
• Vomiting
• Sweating a lot
• Severe cerebrovascular disease like change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes
• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.