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Factor Xa (recombinant), Inactivated-zhzo

Class: Antihemorrhagic Agents, Miscellaneous
Chemical Name: Recombinant inactivated Factor Xa containing Gla-domain deletion and S290A mutation
Molecular Formula: C1750H2727N489O539S27
CAS Number: 1262449-58-0
Brands: Andexxa

Medically reviewed by Drugs.com on Oct 14, 2019. Written by ASHP.

Warning

    Thromboembolic Risks, Ischemic Risks, Cardiac Arrest, and Sudden Death
  • Treatment with factor Xa (recombinant), inactivated-zhzo has been associated with serious and life-threatening adverse effects (e.g., arterial and venous thromboembolic events, ischemic events [MI and ischemic stroke], cardiac arrest, sudden death).

  • Monitor for manifestations of thromboembolic events and initiate anticoagulation when medically appropriate.

  • Monitor for signs and symptoms that precede cardiac arrest and provide appropriate medical treatment. (See Thromboembolic Risks, Ischemic Risks, Cardiac Arrest, and Sudden Death under Cautions.)

Introduction

Specific reversal agent for anticoagulant effects of apixaban or rivaroxaban; a recombinant modified human factor Xa protein. Also known as andexanet alfa.

Uses for Factor Xa (recombinant), Inactivated-zhzo

Reversal of Apixaban or Rivaroxaban Anticoagulation

Used for the reversal of apixaban or rivaroxaban anticoagulation in patients with life-threatening or uncontrolled bleeding; designated an orphan drug by FDA for this use.

Accelerated approval of factor Xa (recombinant), inactivated-zhzo for this indication based on the change from baseline in anti-factor Xa activity following administration in healthy individuals; an improvement in hemostasis has not been established. Continued FDA approval for this indication may be contingent on the results of studies demonstrating an improvement in hemostasis in patients receiving the drug.

Manufacturer states that safety and efficacy of factor Xa (recombinant), inactivated-zhzo not established in, and the drug is not indicated for, the treatment of bleeding related to any factor Xa inhibitor other than apixaban or rivaroxaban.

Factor Xa (recombinant), Inactivated-zhzo Dosage and Administration

General

  • Resume anticoagulant therapy as soon as medically appropriate following treatment with factor Xa (recombinant), inactivated-zhzo.

  • Dosage based upon the specific factor Xa inhibitor, dosage of the factor Xa inhibitor, and time since the patient's last dose of the factor Xa inhibitor. (See Table 1.)

  • Safety and efficacy of additional doses of factor Xa (recombinant), inactivated-zhzo not established.

Table 1. Factor Xa (Recombinant), Inactivated-zhzo Dosage Based on Apixaban or Rivaroxaban Dose and Timing

Factor Xa Inhibitor

Factor Xa Inhibitor Last Dose

Timing of Last Dose of Factor Xa Inhibitor

<8 Hours or Unknown

≥8 Hours

Apixaban

≤5 mg

Low dose

Low dose

>5 mg or unknown

High dose

Low dose

Rivaroxaban

≤10 mg

Low dose

Low dose

>10 mg or unknown

High dose

Low dose

Administration

IV Administration

Administer as a direct IV (“bolus”) injection followed by a continuous infusion.

Initiate continuous infusion within 2 minutes after the direct IV injection of the drug.

Reconstitution

Reconstitute vials containing 100 or 200 mg of factor Xa (recombinant), inactivated-zhzo with 10 or 20 mL of sterile water for injection, respectively, using a 20-mL (or larger) syringe and a 20-gauge (or higher) needle to provide a solution containing 10 mg/mL.

Gently swirl vials (do not shake) to aid reconstitution (typical dissolution time for each vial is 3–5 minutes).

Reconstitute all required vials for a dose in succession to reduce total reconstitution time.

Direct IV injection: Transfer appropriate amount of solution from the reconstituted vial(s), using a 60-mL (or larger) syringe with a 20-gauge (or higher) needle, into an empty polyolefin or PVC IV bag (≤250 mL).

Continuous IV infusion: Transfer appropriate amount of solution from the reconstituted vial(s), using more than one 40- to 60-mL syringe or an equivalent 100-mL syringe with a 20-gauge (or higher) needle, into an empty polyolefin or PVC IV bag (≤250 mL).

Administer drug IV using an inline 0.2- or 0.22-μm polyethersulfone or equivalent low protein-binding filter.

Rate of Administration

Direct IV injection: Target rate 30 mg/minute.

Continuous IV infusion low-dose regimen: 4 mg/minute.

Continuous IV infusion high-dose regimen: 8 mg/minute.

Dosage

Adults

Reversal of Apixaban or Rivaroxaban Anticoagulation
IV

Low-dose regimen: Direct IV injection of 400 mg followed within 2 minutes by a continuous IV infusion of 4 mg/minute for up to 120 minutes (480 mg).

High-dose regimen: Direct IV injection of 800 mg followed within 2 minutes by a continuous IV infusion of 8 mg/minute for up to 120 minutes (960 mg).

Safety and efficacy of additional doses of factor Xa (recombinant), inactivated-zhzo not established.

Special Populations

Renal Impairment

No specific dosage recommendations at this time.

Hepatic Impairment

No specific dosage recommendations at this time.

Cautions for Factor Xa (recombinant), Inactivated-zhzo

Contraindications

  • Manufacturer states none.

Warnings/Precautions

Warnings

Thromboembolic Risks, Ischemic Risks, Cardiac Arrest, and Sudden Death

Life-threatening thromboembolic and ischemic complications, including sudden death, reported following administration of factor Xa (recombinant), inactivated-zhzo.

Safety of factor Xa (recombinant), inactivated-zhzo not established in patients who have experienced a thromboembolic event or disseminated intravascular coagulation (DIC) within 2 weeks prior to the life-threatening bleeding event requiring treatment with the drug.

Safety of factor Xa (recombinant), inactivated-zhzo also not established in patients who have received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within 7 days prior to the bleeding event.

Monitor patients for manifestations of arterial and venous thromboembolic events, ischemic events, and cardiac arrest. Initiate anticoagulation when medically appropriate. Provide appropriate treatment for cardiac arrest as needed.

Reversing effects of factor Xa inhibitor therapy increases the risk of thromboembolic events; resume anticoagulant therapy as soon as medically appropriate following treatment with factor Xa (recombinant), inactivated-zhzo.

Other Warnings and Precautions

Re-elevation or Incomplete Reversal of Anti-factor Xa Activity

A rapid and substantial decrease in anti-factor Xa activity corresponding to a direct IV (“bolus”) injection dose of the drug observed. This decrease was sustained throughout continuous IV infusion of the drug; anti-factor Xa activity returned to placebo concentrations approximately 2 hours after completion of a direct IV injection or continuous IV infusion. Thereafter, the anti-factor Xa activity decreased at a rate similar to the clearance of the factor Xa inhibitor. Tissue factor pathway inhibitor (TFPI) activity in plasma returned to pretreatment levels approximately 96 hours following factor Xa (recombinant), inactivated-zhzo administration.

Safety and efficacy of repeat doses of factor Xa (recombinant), inactivated-zhzo not established.

Immunogenicity

Potential for immunogenicity with use of all therapeutic proteins, including factor Xa (recombinant), inactivated-zhzo. Low titers of anti-factor Xa (recombinant), inactivated-zhzo antibodies observed in patients receiving the drug (generation 1 product). None of these anti-factor Xa (recombinant), inactivated-zhzo antibodies were neutralizing. Development of antibodies cross-reacting with factor X or factor Xa not observed.

Specific Populations

Pregnancy

No adequate and well-controlled studies of factor Xa (recombinant), inactivated-zhzo in pregnant women. Animal reproductive and developmental studies with factor Xa (recombinant), inactivated-zhzo lacking. Safety and efficacy of the drug during labor and delivery not established.

Lactation

Not known whether factor Xa (recombinant), inactivated-zhzo is distributed into human milk. Consider benefits of breast-feeding and the clinical need for factor Xa (recombinant), inactivated-zhzo in the woman along with any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No overall differences in efficacy or safety between geriatric and younger patients; however, increased sensitivity of some older individuals cannot be ruled out.

Common Adverse Effects

Adverse effects reported in patients in clinical trials: Urinary tract infections, pneumonia.

Adverse effects reported in healthy individuals: Infusion-related reactions (e.g., flushing, feeling hot, cough, dysgeusia, dyspnea).

Interactions for Factor Xa (recombinant), Inactivated-zhzo

Specific Drugs

Drug

Interaction

Factor Xa inhibitors (i.e., apixaban, rivaroxaban)

No effect on pharmacokinetics of factor Xa (recombinant), inactivated-zhzo

Factor Xa (recombinant), Inactivated-zhzo Pharmacokinetics

Differences in manufacturing processes resulted in a generation 1 and generation 2 drug product. These products are from the same cell line and FDA has determined the 2 products to be bioequivalent.

Absorption

Onset

Rapidly reduces anti-factor Xa activity (within 2–5 minutes).

Distribution

Extent

Not known whether distributed into milk.

Elimination

Half-life

Low-dose regimen (generation 1 product): 4.3 hours (range: 3.3–11.9 hours).

Low-dose regimen (generation 2 product): 3.3 hours (range 2.3–4 hours).

High-dose regimen (generation 1 product): 4 hours (range 2–5.7 hours).

High-dose regimen (generation 2 product): 2.7 hours (range 1.9–3.4 hours).

Stability

Storage

Parenteral

Powder for injection, unopened vials: 2–8°C; do not freeze.

Reconstituted vials: Stable at room temperature for ≤8 hours; stable at 2–8°C for ≤24 hours.

Reconstituted drug solution in IV bags: Stable at room temperature for ≤8 hours.

Actions

  • Recombinant modified human factor Xa protein; decoy protein that binds to and sequesters factor Xa inhibitors (e.g., apixaban, rivaroxaban) with high affinity in a stoichiometric ratio of 1:1, thereby restoring the activity of native factor Xa.

  • Has a similar affinity for factor Xa inhibitors as native factor Xa without having intrinsic anticoagulant or procoagulant activity; the drug is unable to cleave and activate prothrombin and cannot assemble into the prothrombinase complex.

  • Binds to and inhibits the activity of tissue factor pathway inhibitor (TFPI), a protein that normally binds to native factor Xa. Inhibition of TFPI activity can increase tissue factor-initiated thrombin generation.

Advice to Patients

  • Importance of informing patients that reversing the effects of factor Xa inhibitor therapy increases the risk of thromboembolic events; arterial and venous thromboembolic events, including ischemic events, cardiac events, and sudden death, have been observed within 30 days following administration of factor Xa (recombinant), inactivated-zhzo.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Factor Xa (Recombinant), Inactivated-zhzo

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use only

100 mg

Andexxa

Portola

200 mg

Andexxa

Portola

AHFS DI Essentials™. © Copyright 2021, Selected Revisions October 14, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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