Adverse Effects

• Bleeding

to Warfarin

• Stop Apixaban
• If continuous anticoagulation (AC) needed, start Warfarin with parenteral anticoagulant at next scheduled dose

to Heparin (CI)

• Stop Apixaban
• Start CI Heparin without a bolus at next scheduled dose

to LMWH

• Stop Apixaban
• Start LMWH at next scheduled dose

to Dabigatran

• Stop Apixaban
• Start Dabigatran at next scheduled dose

to Apixaban

• N/A

to Rivaroxaban

• Stop Apixaban
• Start Rivaroxaban <2 hours before next scheduled dose

to Edoxoban

• Stop Apixaban
• Start Edoxaban at time of next scheduled dose

*Note: Dabigatran, Rivaroxaban, Edoxaban, and Apixaban affect the INR; measuring the INR during coadministration with warfarin therapy may not be useful for determining an appropriate dose of warfarin. To minimize this effect, check INR at trough level of respective medication

Purpose
To provide details about apixaban use, an orally available factor Xa inhibitor, at IHTC during hospital admission or as outpatient

Indication

Apixaban was approved in 2025 for treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth and older after at least 5 days of initial anticoagulant treatment. Do not use in patients with triple positive antiphospholipid antibody syndrome or prosthetic heart valves.

Dosage Forms
Apixaban is available as oral tablet or capsule.

Tablets for oral use	5 mg, 2.5 mg
Tablet for oral suspension	0.5 mg
Capsule for oral suspension	0.15 mg

Eliquis was approved as a 0.5 mg tablet for oral suspension and a 0.15 mg capsule for oral suspension for patients weighing less than 35 kg. However, availability might be limited.  

Patient assistance program for drug: Bristol Myers Squibb

Initiating Therapy
Minimum Monitoring Requirements: Prior to initiation of therapy, but no longer than 48 hours before, the following labs should be checked: CBC, coagulation profile (PT, PTT, fibrinogen activity), hepatic function panel, creatinine, urine pregnancy if applicable

Administration:
Adult and pediatric patients weighing greater than or equal to 35 kg:
Splitting/crushing	If unable to swallow as a whole, tablets may be split or crushed and mixed in water, D5W, or apple juice, or mixed with applesauce; administer immediately. Crushed tablets are stable in water, D5W, apple juice, and apple sauce for up to 4 hours
Nasogastric/gastric feeding tube	Crushed tablets may be suspended in 60 mL of water or D5W followed by immediate delivery. Following administration of the dose, the nasogastric tube should be flushed with an additional 20 mL of water or D5W. Crushed tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours. Absorption occurs primarily in the small intestine.
Pediatric patients weighing less than 35 kg *
0.5 mg oral tablet	The 0.5 mg ELIQUIS tablet comes in a packet for oral suspension and should be mixed with water, infant formula, apple juice, or apple sauce. The liquid mixtures with water, infant formula or apple juice should be administered within 2 hours and the mixture in apple sauce should be administered immediately.
0.15 mg capsule	The 0.15 mg ELIQUIS SPRINKLE capsule must be opened, and the entire contents sprinkled in water or infant formula, mixed, and administered within 2 hours.

Pharmacokinetics

Half-life	12 h (adult)
Time to peak	2 hours in pediatrics, 3 to 4 h in adults
Absorption	Primarily proximal small intestine and some gastric absorption
Oral availability	~50%; prolonged absorption
Excretion	75% primarily cleared via Hepatic degradation via the cytochrome P450 pathway ~ 25% Renal elimination
Protein binding	~90%

Safety Precautions

In pediatric patients equal to or greater than 2 years of age, ELIQUIS is not recommended in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 body surface area (BSA)  

 In patients less than 2 years of age, ELIQUIS is not recommended in patients with inadequate renal function defined by sex and postnatal age as used in the pediatric VTE trial for ELIQUIS (see Table  below).  

 To estimate GFR, the pediatric VTE trial for ELIQUIS used the updated Schwartz formula, eGFR (ml/min/1.73m2 ) = 0.413 * height (cm)/serum creatinine (mg/dL) for serum creatinine measured by an enzymatic creatinine method calibrated to be traceable to isotope dilution mass spectrometry (IDMS)

Inadequate renal function by sex and post-nasal age in pediatric patients <2 years of age as defined in the pediatric VTE trial for ELIQUIS
Postnatal age (gender)	Threshold eGFR used to define inadequate renal function (mL/min/1.73 m2)
1 week (males and females)	<8
2-8 weeks (males and females)	<12
>8 weeks to <2 years (males and females)	<22

Renal impairment: In adults, if serum creatinine ≥ 1.5 mg/dL and patient is either ≥ 80 years of age or weighs ≤ 60 kg dose, reduce to 2.5 mg PO BID. If serum creatinine ≥ 2.5 mg/dL or CrCl <25 mL/min, avoid use. Consider on individual basis in consultation with hematology, nephrology and pharmacy for patients with CrCl < 30 mL/minute.

Hepatic impairment: For mild hepatic impairment (Child-Pugh A), no adjustment necessary. For moderate hepatic impairment (Child-Pugh B), no adjustments provided by the manufacturer. For severe hepatic impairment (Child-Pugh C), avoid use.

Drug-Drug interactions:

• Substrate of p-glycoprotein
  • Strong dual P-glycoprotein and CYP3A4 Inhibitors (ex. rifampin, phenytoin, phenobarbital or carbamazepine):  If recommended apixaban dose is >5 mig BID, reduce apixaban dose by 50%. If recommended apixaban dose is 2.5 mg BID, avoid concomitant use.
  • Strong dual P-glycoprotein and CYP3A4 Inducers (ex. ketoconazole, itraconazole, posaconazole, ritonavir and all HIV protease inhibitors, erythromycin), avoid concomitant use.
  • Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the anticoagulant effect of Anticoagulants

Dosing
Dose Recommendation in Pediatric Patients from Birth to less than 18 Years of Age for the Treatment of VTE and Reduction in the Risk of Recurrent VTE

		Days 1-7	Days 8 and beyond
Presentation	Body weight (kg)	Dosing schedule	Dosing schedule
Power in Capsule 0.15 mg For pediatric use	2.6 to less than 4	0.3 mg twice daily	0.15 mg twice daily
Tablet 0.5 mg For pediatric use	4 to less than 6	1 mg twice daily	0.5 mg twice daily
	6 to less than 9	2 mg twice daily	1 mg twice daily
	9 to less than 12	3 mg twice daily	1.5 mg twice daily
	12 to less than 18	4 mg twice daily	2 mg twice daily
	18 to less than 25	6 mg twice daily	3 mg twice daily
	25 to less than 35	8 mg twice daily	4 mg twice daily
Tablets 2.5 mg and 5 mg	greater than or equal to 35	10 mg twice daily	5 mg twice daily

ELIQUIS is not recommended for use in pediatric patients less than 2.6 kg because ELIQUIS was not studied in these patients. 

• Apixaban should be used with caution with severe renal dysfunction or with moderate hepatic impairment and avoided in patients with severe hepatic impairment

Anticoagulation Monitoring Parameters and Reference Range
Routine coagulation testing is not required for monitoring of apixaban. If monitoring is indicated, apixaban anti-Xa activity assay is the preferred test to extrapolate apixaban concentrations in ng/ml. Therapeutic range not defined. Dose adjustment based on results not yet established. Observed peak and trough concentrations in patients exposed to therapeutic dosing have been reported.

Perioperative Management

• Decision making regarding whether apixaban needs to be held depends on type of surgery and balance of bleeding versus thrombosis risk. The duration for withholding is based upon the estimated apixaban’s half-life times 2 to 3 half-lives for low procedural bleeding risk and 4 to 5 drug half-lives for high procedural bleeding risk. If it is indicated, apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant bleeding, and should be discontinued for at least 24 hours prior to elective surgery or invasive procedures with low bleeding risk or where the bleeding would be non-critical in location easily controlled.
• In CrCl < 30 mL/minute, for low bleeding risk procedure, discontinue apixaban therapy ≥36 hours prior. If Cr < 15 mL/min for low bleeding risk procedure., consider measuring apixaban anti-Xa level and/or withholding ≥48 hours.
• In CrCl < 30 mL/minute, for moderate or high risk procedure, discontinue apixaban therapy ≥48 hours prior. If Cr < 15 mL/min for moderate or high risk procedure, consider measuring apixaban anti-Xa level and/or withholding ≥72 hours.
• Epidural or spinal hematomas have occurred in patients treated with DOACs who are receiving neuraxial anesthesia or undergoing spinal puncture. Optimal timing between the administration of rivaroxaban and neuraxial procedures is not known. Consider holding for 72 hours prior to lumbar punctures for these reasons above.
• In rare cases, in patients with very high risk of thrombosis, bridging with unfractionated heparin may be required to limit the time off anticoagulation.
• Restart apixaban after the procedure as soon as adequate hemostasis has been established and once cleared by the surgeon or interventionalist. If oral medication cannot be taken after the procedure, consider switching to a parenteral anticoagulant.

Bleeding Precautions & Warnings

• While on anticoagulation avoid aspirin, ibuprofen, or other anti-platelet drugs unless specifically indicated as anti-platelet therapy.
• Try to avoid IM injections and arterial punctures. Apply pressure after venipuncture until bleeding has ceased.

Reversal Information

• Andexanet alfa is FDA indicated for reversal of apixaban, but is NOT currently on formulary at St. Vincent. It is recommended for life-threatening bleeding, bleeding into a critical organ. It is a modified human factor Xa decoy protein that binds and sequesters factor Xa inhibitors, but also TFPI. Anti FXa assay results rapidly decrease within 2 minutes after bolus and this is maintained throughout the duration of the continuous infusion. Anti Xa levels returned to placebo levels approximately 2 hours after completion of bolus or infusion. Andexanet alfa is associated with pro-thrombotic risks.
  • Recommended Adult dose:
    

    Apixaban last dose	Timing of apixaban last dose before Andexxa initiation
    	< 8 hrs or Unknown	< 8 hrs or Unknown
    ≤ 5 mg	Low dose: Initial IV Bolus 400 mg at a target rate of 30 mg/min; Follow-on IV Infusion: 4 mg/min for up to 120 minutes (480 mg)	Low dose: Initial IV Bolus 400 mg at a target rate of 30 mg/min; Follow-On IV Infusion: 4 mg/min for up to 120 minutes
    > 5 mg or Unknown	High dose: Initial IV Bolus: 800 mg at a target rate of 30 mg/min; Follow-on IV Infusion: 8 mg/min for up to 120 minutes (960 mg)

  • Andexanet Alpha Pediatric dosing: NO published pediatric dosing is available. Recommend considering the following dosing in patients
    < 40kg:
    • Bolus: 20 mg/kg (max 800 mg)
    • Infusion: 0.2 mg/kg/min for up to 120 minutes
  • Critical site bleeds: Intracranial hemorrhage, including intraparenchymal, subdural, epidural, and subarachnoid hemorrhages; Other CNS hemorrhage, including intraocular, intra- or extra-axial spinal hemorrhages; Pericardial tamponade; Airway, including posterior epistaxis; Hemothorax, intraabdominal bleeding, and retroperitoneal hemorrhage; Extremity bleeds, including intramuscular and intraarticular bleeding concerning for compartment syndrome, bleeding associated with hemodynamic instability, bleeding in a noncompressible vessel (e.g., subclavian)

• Kcentra (prothrombin complex concentrate) 25-50 units/kg for severe bleeding or NovoSeven (rFVIIa) 90 mcg/kg. FEIBA (activated PCC) 50 units/kg would be a last resort due to higher thrombosis risk. They are on formulary at PMCH but are not labeled by the manufacturer for reversal of apixaban.
• In the setting of overdose, also consider administration of activated charcoal (50 g) if within 2 hours of dose.
• Apixaban is NOT dialyzable because it is mostly protein bound.
• Repeat monitoring tests for anticoagulant and platelets, PT, PTT, and fibrinogen after infusing a reversal agent and q 4-6 hours until severe bleeding risk has passed. Determine if and when anticoagulation should be reinitiated and what agent. Monitor patient for thrombosis and bleeding.

Transition Information

• A bridge anticoagulant is not necessary when transitioning from another anticoagulant to apixaban therapy. See separate anticoagulant-specific Clinical Case Manual for transitioning from another specific anticoagulant to apixaban.
• See table for switching from apixaban to another anticoagulant

From	To	Action
Apixaban	Argatroban/Bivalirudin/Enoxaparin/Fondaparinux/Heparin	Discontinue apixaban and give the first dose of the other anticoagulant at the time that next apixaban dose would be due. In cases of high bleeding risk, consider omitting initial bolus when transitioning to heparin infusion.
	Betrixaban,Dabigatran, Edoxaban, or Rivaroxaban	Discontinue apixaban and give the first dose of the other anticoagulant at the time that the next apixaban dose would have been taken.
	Warfarin	Limited data available on switching DOACs to warfarin. Consider coadministering DOAC and warfarin therapy until INR is therapeutic, or stopping DOAC and bridging warfarin with LMWH or UFH if bridging patient is clinically indicated (e.g., start UFH or therapeutic LMWH and warfarin when next dose of dabigatran would have been taken). All DOACs affect INR so that initial INR during the transition may not be useful for determining the appropriate dose of warfarin. Consider starting warfarin and stopping apixaban 3 days later.

Pregnancy
Currently, only Lovenox (enoxaparin) and unfractionated heparin are advised for use in pregnant women. Females of childbearing age must be counseled that DOACs are not approved for use during pregnancy and referred for appropriate contraception if needed.

Patient Education and Ongoing Management
Discharging IHTC physician/APP is responsible for ensuring adequate follow-up for anticoagulation management has been scheduled prior to patient leaving the hospital.

References

1. Eliqus® (apixaban) tablet [Prescribing Information]. Pfizer, Bristol-Myers Squib; April 2021.
2. Andexxa (coagulation factor Xa (recombinant), inactivated-zhzo) [Prescribing information]; San Francisco, CA: Portola Pharmaceuticals; February 2023.
3. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart.
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10. Daniels PR. Peri-procedural management of patients taking oral anticoagulants. Bmj 2015;351:h2391.
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