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Andexanet Alfa

Medically reviewed by Drugs.com. Last updated on Aug 18, 2020.

Pronunciation

(an DEX a net AL fa)

Index Terms

  • Coagulation Factor Xa (Recombinant), Inactivated zhzo
  • PRT064445

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]

Brand Names: U.S.

  • Andexxa

Pharmacologic Category

  • Antidote

Pharmacology

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

Distribution

Vss:

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

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

Off Label Uses

Life-threatening bleeding associated with edoxaban or betrixaban

Data from a limited number of patients suggest that andexanet alfa may be beneficial for the reversal of anticoagulation from the factor Xa inhibitors 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, although specific dosing has not been well established [Connolly 2016].

Based on the Reversal of Direct Oral Anticoagulants: Guidance from the Anticoagulation Forum, andexanet alfa may be effective for life-threatening bleeding associated with edoxaban or betrixaban and should be considered for use if treatment with other supportive measures are ineffective [Cuker 2019].

Contraindications

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

Dosing: Adult

Life-threatening bleeding associated with factor Xa inhibitors: Note: Generally used for life-threatening bleeding or bleeding into a critical organ that is not controlled with maximal supportive measures (eg, activated charcoal [if ingestion is within ~2 to 4 hours], antifibrinolytic agent) (ACC [Tomaselli 2020]; Baugh 2019; Cuker 2019).

Life-threatening bleeding associated with edoxaban or betrixaban (off-label use): IV: 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 (ACC [Tomaselli 2020]; Baugh 2019; Cuker 2019).

Life-threatening bleeding associated with apixaban or rivaroxaban: Note: 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.

Andexanet alfa Dose Based on Apixaban or Rivaroxaban Dose

Factor Xa Inhibitor

Factor Xa Inhibitor Last Dose

Timing of Factor Xa Inhibitor Last Dose Before Andexanet alfa Initiation

<8 Hours or Unknown

≥8 Hours

Apixaban

≤5 mg

Low dose

Low dose

>5 mg or unknown

High dose

Rivaroxaban

≤10 mg

Low dose

>10 mg or unknown

High 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

ALERT: U.S. Boxed Warning

Thromboembolic risks, ischemic risks, cardiac arrest, and sudden deaths:

Treatment with andexanet alfa has been associated with serious and life-threatening adverse events, including: Arterial and venous thromboembolic events, ischemic events (including myocardial infarction and ischemic stroke), cardiac arrest, and 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.

Warnings/Precautions

Concerns related to adverse effects:

• Anti-factor Xa activity re-elevation: There is a rapid and substantial decrease in anti-factor Xa activity corresponding to the bolus dose, which is sustained during the continuous infusion. Anti-factor Xa activity returns to placebo levels ~2 hours after completion of bolus or continuous infusion; thereafter, anti-factor Xa activity decreases at a rate similar to the clearance of factor Xa inhibitors.

• Thromboembolic and ischemic risks: Arterial and venous thromboembolic events, ischemic events, and cardiac events (including sudden death) were observed within 3 to 30 days postadministration (median time to first event: 7 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-factor Xa activity individually calibrated to each specific factor Xa inhibitor (undetectable anti-factor Xa activity likely excludes clinically relevant drug concentrations). An anti-factor 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 2020]; AHA [Raval 2017]).

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.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Flushing

• Sensation of warmth

• Change in taste

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• 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

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• 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 an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

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