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 is based on the change from baseline in anti-factor Xa activity following administration in healthy individuals; improvement in hemostasis not established. Continued FDA approval for this indication may be contingent on results of studies demonstrating improvement in hemostasis.

Rapidly reverses the anticoagulant effects of apixaban or rivaroxaban (as measured by anti-factor Xa activity, unbound anticoagulant concentration, and thrombin generation).

Not indicated for treatment of bleeding related to other factor Xa inhibitors; safety and efficacy not established.

Management of bleeding complications in patients receiving direct oral anticoagulants (DOACs) should be individualized according to severity and location of hemorrhage. Reversal agents should generally be reserved for patients with severe and life-threatening bleeding. Experts state that reversal agents should only be administered when clinically relevant DOAC concentrations are documented or expected. If a reversal agent is warranted in patients with rivaroxaban- or apixaban-associated major bleeding, factor Xa (recombinant), inactivated-zhzo may be used.

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

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 200 mg of factor Xa (recombinant), inactivated-zhzo with 20 mL of sterile water for injection 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

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.)

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.

Resume anticoagulant therapy as soon as medically appropriate.

Special Populations

Renal Impairment

No specific dosage recommendations.

Hepatic Impairment

No specific dosage recommendations.

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. (See Boxed Warning.)

Safety 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.

Safety 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 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.

Interference with Effects of Heparin

May interfere with the anticoagulant effect of heparin. (See Specific Drugs under Interactions.)

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 in pregnant women. Animal reproductive and developmental studies lacking. Safety and efficacy 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 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

Patients with major bleeding: Urinary tract infections, pneumonia.

Healthy individuals: Infusion-related reactions (e.g., flushing, feeling hot, cough, dysgeusia, dyspnea).

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 200 mg of factor Xa (recombinant), inactivated-zhzo with 20 mL of sterile water for injection 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

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.)

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.

Resume anticoagulant therapy as soon as medically appropriate.

Special Populations

Renal Impairment

No specific dosage recommendations.

Hepatic Impairment

No specific dosage recommendations.

Specific Drugs