General

High Alert Medication: This medication bears a heightened risk of causing significant patient harm when it is used in error.

Pronunciation:
a-pix-a-ban

Trade Name(s)

• Eliquis
• Eliquis Sprinkle

Ther. Class.

anticoagulants

Pharm. Class.

factor xa inhibitors

Indications

• Reduction in risk of stroke/systemic embolism associated with nonvalvular atrial fibrillation.
• Prevention of deep vein thrombosis (DVT) that may lead to pulmonary embolism (PE) following knee or hip replacement surgery.
• Treatment of and reduction in risk of recurrence of DVT or PE.

Action

Acts as a selective, reversible site inhibitor of factor Xa, inhibiting both free and bound factor. Does not affect platelet aggregation directly but does inhibit thrombin-induced platelet aggregation. Decreases thrombin generation and thrombus development.

Therapeutic Effect(s):

Treatment and prevention of thromboembolic events.

Pharmacokinetics

Absorption: 50% absorbed following oral administration.

Distribution: Unknown.

Metabolism and Excretion: Primarily metabolized by the liver by the CYP3A4 isoenzyme; excreted in urine and feces. Biliary and direct intestinal excretion account for fecal elimination.

Half-life: 6 hr (12 hr after repeated dosing due to prolonged absorption).

TIME/ACTION PROFILE (effect on hemostasis)

Contraindication/Precautions

Contraindicated in:

• Previous severe hypersensitivity reactions;
• Active pathological bleeding;
• Severe hepatic impairment;
• Prosthetic heart valves;
• PE with hemodynamic instability or requiring thrombolysis or pulmonary embolectomy;
• Triple-positive antiphospholipid syndrome (↑ risk of thrombosis);
• Lactation:  Lactation.

Use Cautiously in:

• Black Box:  Neuroaxial spinal anesthesia or spinal puncture, especially if concurrent with an indwelling epidural catheter; drugs affecting hemostasis; or history of traumatic/repeated spinal puncture or spinal deformity (↑ risk of epidural or spinal hematoma);
• Surgery;
• Renal impairment (dose ↓ may be required);
• Moderate hepatic impairment (↑ risk of bleeding);
• Rep:   Women of reproductive potential;
• OB:  Use during pregnancy only if potential maternal benefit justifies potential fetal risk.

Adverse Reactions/Side Effects

Hemat: BLEEDING

Misc: HYPERSENSITIVITY REACTIONS (including anaphylaxis)

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

• ↑ risk of bleeding with other  anticoagulants,  aspirin,  clopidogrel,  ticagrelor,  prasugrel,  fibrinolytics,  NSAIDs,  SNRIs, or  SSRIs.
•  Strong CYP3A4 and P-glycoprotein (P-gp) inhibitors, including  itraconazole,  ketoconazole, and  ritonavir, ↑ levels and risk of bleeding; may need to ↓ apixaban dose or avoid concurrent use.
•  Strong CYP3A4 and P-gp inducers, including  carbamazepine,  phenytoin, and  rifampin, may ↓ levels and ↑ risk of thromboses; avoid concurrent use.

Drug-Natural Products:

 St. John's wort  may ↓ levels and ↑ risk of thromboses; avoid concurrent use.

Route/Dosage

Reduction in Risk of Stroke/Systemic Embolism in Nonvalvular Atrial Fibrillation

PO (Adults): 5 mg twice daily;  Any 2 of the following: age ≥80 yr, weight ≤60 kg, serum creatinine ≥1.5 mg/dL:  2.5 mg twice daily;  Concurrent use of strong CYP3A4 and P-gp inhibitors:  2.5 mg twice daily; if patient already taking 2.5 mg twice daily, avoid concurrent use.

Renal Impairment 
PO (Adults): Hemodialysis:  5 mg twice daily;  Hemodialysis and either age ≥80 yr or weight ≤60 kg:  2.5 mg twice daily.

Prevention of Deep Vein Thrombosis Following Knee or Hip Replacement Surgery

PO (Adults): 2.5 mg twice daily, initiated 12–24 hr postoperatively (when hemostasis is achieved); continued for 35 days after hip replacement or 12 days after knee replacement;  Concurrent use of strong CYP3A4 and P-gp inhibitors:  Avoid concurrent use.

Treatment of Deep Vein Thrombosis or Pulmonary Embolism

PO (Adults): 10 mg twice daily for 7 days; then 5 mg twice daily;  Concurrent use of strong CYP3A4 and P-gp inhibitors:  2.5 mg twice daily

PO (Children  ≥35 kg): 10 mg twice daily for 7 days; then 5 mg twice daily.

PO (Children  25–<35 kg): 8 mg twice daily for 7 days; then 4 mg twice daily.

PO (Children  18–<25 kg): 6 mg twice daily for 7 days; then 3 mg twice daily.

PO (Children  12–<18 kg): 4 mg twice daily for 7 days; then 2 mg twice daily.

PO (Children  9–<12 kg): 3 mg twice daily for 7 days; then 1.5 mg twice daily.

PO (Children  6–<9 kg): 2 mg twice daily for 7 days; then 1 mg twice daily.

PO (Children  4–<6 kg): 1 mg twice daily for 7 days; then 0.5 mg twice daily.

PO (Children  2.6–<4 kg): 0.3 mg twice daily for 7 days; then 0.15 mg twice daily.

Reduction in Risk of Recurrence of Deep Vein Thrombosis or Pulmonary Embolism

PO (Adults): 2.5 mg twice daily after ≥6 mo of treatment of DVT or PE;  Concurrent use of strong CYP3A4 and P-gp inhibitors:  Avoid concurrent use.

Availability (generic available)

Tablets: 2.5 mg, 5 mg

Tablets for oral suspension: 0.5 mg

Sprinkle capsules: 0.15 mg

Assessment

• Assess patient for symptoms of stroke, DVT, PE, bleeding, or peripheral vascular disease periodically during therapy.  If pathological hemorrhage occurs,  discontinue apixaban and provide appropriate treatment.
• Monitor frequently for signs and symptoms of neurological impairment in patients with indwelling epidural or intrathecal catheters and after removal.  If neurological compromise occurs,  treat immediately.

Antidote is andexanet alfa, indicated for adults only. Effects persist for ≥24 hr after last dose. Oral activated charcoal also ↓ apixaban plasma concentrations. Other agents and hemodialysis do not have a significant effect.

Implementation

• High Alert: Do not confuse apixaban with axitinib.
• Black Box:  If apixaban is discontinued for a reason other than bleeding or completion of a course of therapy, consider coverage with another anticoagulant because of ↑ risk of thromboembolism when apixaban is prematurely discontinued.
• When  converting from warfarin , discontinue warfarin and start apixaban when INR <2.0.
• When  converting from apixaban to warfarin , apixaban affects INR, so INR measurements may not be useful for determining appropriate dose of warfarin. If continuous anticoagulation is necessary, discontinue apixaban and begin both a parenteral anticoagulant and warfarin at time of next dose of apixaban. Discontinue parenteral anticoagulant when INR reaches acceptable range.
• When  switching between apixaban and anticoagulants other than warfarin , discontinue one being taken and begin the other at the next scheduled dose.
• For surgery , discontinue apixaban ≥48 hr before invasive or surgical procedures with a moderate or high risk of unacceptable or clinically significant bleeding or ≥24 hr prior to procedures with a low risk of bleeding or where the bleeding would be noncritical and easily controlled.
• For indwelling epidural or intrathecal catheters, do not remove within 24 hr after the last dose of apixaban; do not administer next dose <5 hr after catheter removal.  If traumatic or repeated puncture occurs,  delay dose for 48 hr.
• PO Administer twice daily without regard to food.
  • For adults and children weighing ≥35 kg who cannot swallow a tablet, 5 mg and 2.5 mg tablets can be crushed; suspended in water, D5W, or apple juice; or mixed with applesauce and administered immediately orally. May also be suspended in 60 mL of water or D5W and promptly administered through a 12 French nasogastric tube.
  • For children weighing <35 kg,  capsules  must be opened and entire contents sprinkled in water or infant formula, mixed as described in Instructions for Use (IFU). Administer within 2 hr. Do not swallow capsule. For 0.5 mg  tablet for oral suspension,  mix with water, infant formula, apple juice, or applesauce as described in IFU. Administer mixture within 2 hr or immediately when mixed in applesauce. Each packet is for single use only. Liquid mixtures may be delivered through a 5–12 French nasogastric or gastrostomy tube.

Patient/Family Teaching

• Black Box:  Explain purpose and side effects of medication. Advise patient to read  Patient Information  before starting therapy and to take missed dose as soon as remembered on the same day; then resume twice daily; do not double doses. Do not discontinue without consulting health care provider.
• Advise patient to store apixaban at room temperature.
• Advise patient to notify health care provider immediately if signs of bleeding (easy bruising, discolored urine, red or tarry stools, coughing or vomiting blood, pain or swelling of joints, headache, dizziness, weakness, recurring nosebleed, bleeding from gums, ↑ menstrual bleeding, dyspepsia, abdominal pain, epigastric pain) occur or if injury occurs, especially head injury.
• Caution patient to notify health care provider if skin rash or signs of severe allergic reaction (chest pain or tightness, swelling of face or tongue, trouble breathing or wheezing, feeling dizzy or faint) occur.
• Advise patient to notify health care provider of medication regimen prior to treatment or surgery.
• Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care provider before taking any new medications, especially St. John's wort. Risk of bleeding is ↑ with aspirin, NSAIDs, warfarin, heparin, SSRIs, or SNRIs.
• Black Box:  Inform patient having had neuraxial anesthesia or spinal puncture to watch for signs and symptoms of spinal or epidural hematoma (numbness or weakness of legs, bowel or bladder dysfunction). Notify health care provider immediately if symptoms occur.
• Rep:  Advise women of reproductive potential to notify health care provider if pregnancy is planned or suspected and to avoid breastfeeding during therapy. May ↑ risk of uterine bleeding in pregnant women, fetus, and neonate; advise patient to notify health care provider if significant uterine bleeding occurs.

Evaluation/Desired Outcomes

Reduction in the risk and treatment of stroke and systemic embolism.