coagulation factor Xa recombinant, inactivated-zhzo (Rx)

>10%

Infusion-related reactions (18%)

Thromboembolic events

• Note: 33% of patients were on antithrombotic therapy at time of event
• Deep vein thrombosis (33%)
• Ischemic stroke (24%)
• Acute myocardial infarction (15%)
• Pulmonary embolism (15%)

Deaths due to bleeding <30 days postdose

• 25 deaths (14%)

• By bleeding type, patient deaths

  • Intracranial bleeding (14%)
  • GI bleeding (10%)
  • Other bleeding types (19%)

1-10%

Thromboembolic events

• Note: 33% of patients were on antithrombotic therapy at time of event
• Cardiogenic shock (9%)
• Sudden death (6%)
• CHF (6%)
• Acute respiratory failure (6%)
• Cardiac arrest (3%)
• Cardiac thrombus (3%)
• Embolic stroke (3%)
• Iliac artery thrombosis (3%)
• Nonsustained ventricular tachycardia (3%)

Contraindications

None

Cautions

Thromboembolic and ischemic risks

• 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 therapy
• Safety not evaluated in patients who experienced thromboembolic events or disseminated intravascular coagulation within two weeks prior to life-threatening bleeding event requiring treatment with this drug
• Safety also not evaluated in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within seven days prior to the bleeding event

Reelevation or incomplete reversal of anti-FXa activity

• Compared wtih baseline, the ANNEXA-4 clinical trial observed a rapid and substantial decrease in anti-FXa activity corresponding to the IV bolus that was sustained through the end of the continuous infusion
• Following the infusion, there was an increase in anti-FXa activity, which peaked 4 hr after infusion
• After this peak, the antiFXa activity decreased at a rate similar to the clearance of the FXa inhibitors
• ~50% of patients experience >90% decrease from baseline anti-FXa activity after administration

Pregnancy

Data are not available in pregnant women to inform patients of associated risks

Safety during labor and delivery has not been evaluated

Animal reproductive and development studies have not been conducted

Lactation

Data are not available regarding the presence in human milk, the effects on the breastfed child, or the effects on milk production

The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed child or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Exerts its procoagulant effect by binding and sequestering the FXa inhibitors, rivaroxaban and apixaban

Another observed procoagulant effect is its ability to bind and inhibit the activity of tissue factor pathway inhibitor (TFPI); inhibiting TFPI activity can increase tissue factor-initiated thrombin generation

Distribution

Vd: 5 L; ~equivalent to blood volume

Elimination

Half-life: 5-7 hr

Clearance: 4.3 L/hr

IV Preparation

Reconstitution

• Reconstitute each 100-mg vial using a 10-mL syringe and ≥20-gauge needle
• Slowly inject 10 mL sterile water for injection; direct solution onto the inside wall of the vial to minimize foaming
• Resulting concentration is 10 mg/mL
• To reduce the total reconstitution time needed during preparation, reconstitute all required vials in succession
• Low dose requires 4 vials for bolus and 5 vials for infusion
• High dose requires 8 vials for bolus and 10 vials for infusion
• Ensure dissolution by gently swirling each vial; do not shake (may lead to foaming); typical dissolution time is 3 minutes; discard vial if dissolution is incomplete
• Upon reconstitution, visually inspect solution for particulate matter and discoloration prior to administration; solution should appear clear, colorless to slightly yellow

IV bolus preparation

• Use ≥60-mL syringe with ≥20-gauge needle to withdraw the reconstituted solution from each vial until the required dosing volume is achieved
• Note the total volume withdrawn into the syringe
• Transfer solution from the syringe into an empty polyolefin or PVC IV bag with a volume of ≤250 mL
• Discard syringe, needle, and vials, including any unused portion of drug

Continuous IV infusion preparation

• Follow the same procedure outlined above for reconstitution and IV bolus preparation
• More than one 40- to 60-mL syringe, or an equivalent 100-mL syringe, may be used for transfer of reconstituted solution to the IV bag

IV Administration

Administer intravenously, using a 0.2- or 0.22-micron in-line polyether sulfone or equivalent low protein-binding filter

Start the bolus at a target rate of ~30 mg/minute

Within 2 minutes following the bolus dose, administer the continuous IV infusion for up to 120 minutes

Storage

Does not contain preservatives

Unopened vials

• Refrigerate at 2-8°C (36-46°F)
• Do not freeze

Reconstituted solution

• In vials

  • Room temperature for up to 8 hr, or
  • Refrigerate at 2-8°C for up to 24 hr

• In IV bags

  • Room temperature for up to 8 hr, or
  • Refrigerate at 2-8°C for up to 16 hr