What are the stability and interaction considerations for patients taking Eliquis (apixaban)?

Stability and Drug Interactions with Eliquis (Apixaban)

Medication Stability

Apixaban tablets are stable for up to 4 hours when crushed and suspended in water, 5% dextrose in water (D5W), apple juice, or mixed with applesauce. 1

• The drug has a half-life of approximately 12 hours, with pharmacodynamic effects persisting for at least 24 hours (approximately two half-lives) after the last dose 1, 2
• Apixaban reaches maximum plasma concentration 3-4 hours after oral administration 2
• The drug exhibits dose-proportional exposure for oral doses up to 10 mg 2

Critical Drug Interactions Requiring Dose Adjustment or Avoidance

Strong Dual P-glycoprotein (P-gp) and CYP3A4 Inhibitors

For patients taking apixaban 5 mg or 10 mg twice daily, reduce the dose by 50% when combined with strong dual P-gp and CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin). 3, 1

• For patients already taking apixaban 2.5 mg twice daily, avoid coadministration with these strong dual inhibitors entirely 3, 1
• A retrospective study demonstrated that clarithromycin (a strong dual inhibitor) was associated with higher rates of hospitalization for major bleeding compared to azithromycin (P-gp inhibitor only) in patients taking DOACs 3

Strong P-gp and CYP3A4 Inducers

Avoid apixaban use with strong inducers such as rifampin, carbamazepine, phenytoin, and St. John's wort, as these markedly reduce apixaban plasma levels and increase thrombotic risk. 3

• Pharmacokinetic studies show rifampin significantly decreases apixaban area under the curve (AUC), potentially leading to treatment failure 3
• The reduced drug exposure from inducers creates unacceptable stroke and thromboembolism risk 3

Moderate Inhibitors and Clinical Context

Rate and Rhythm Control Medications

Diltiazem causes a 40% increase in apixaban plasma concentrations but generally does not require dose adjustment unless combined with other risk factors (age ≥80 years, weight ≤60 kg, creatinine ≥1.5 mg/dL, or multiple bleeding risk factors). 3

• Verapamil has variable effects on apixaban depending on formulation, but specific interaction data are limited; exercise caution when combining 3
• Amiodarone and dronedarone are moderate P-gp inhibitors that warrant caution but typically do not require empiric dose reduction for apixaban 3
• Post-hoc analysis from the ARISTOTLE trial showed that combined moderate CYP3A4 and P-gp inhibitors did not significantly affect clinical outcomes compared to patients without interacting medications 3

Key Distinction in Apixaban Metabolism

CYP3A4 interactions may play a greater role than P-gp interactions in affecting apixaban metabolism, unlike dabigatran which is highly P-gp dependent. 3

• This explains why apixaban shows less pronounced effects with P-gp inhibitors that only moderately inhibit CYP3A4 3
• Only 27% of apixaban clearance occurs via renal excretion, with the majority through metabolism, biliary excretion, and direct intestinal excretion 3, 2

Renal Function Considerations

Dose reduction to 2.5 mg twice daily is required if patients meet at least 2 of the following criteria: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL. 3

• Unlike dabigatran (80% renal excretion), apixaban has only 27% renal clearance, making it less sensitive to renal impairment 3, 4
• No dose adjustment is needed for mild-to-moderate hepatic impairment (Child-Pugh A or B) 3
• Apixaban is not substantially removed by hemodialysis 1

Antiplatelet Agent Combinations

Concomitant use of antiplatelet agents (aspirin, clopidogrel, prasugrel, ticagrelor) with apixaban increases bleeding risk and should be limited to situations where dual or triple therapy is absolutely necessary. 3, 1

• Consider discontinuing antiplatelet agents when bleeding occurs, particularly irreversible agents like aspirin and clopidogrel (effects persist for days) 3
• Ticagrelor is an exception as a reversible platelet inhibitor with a 7-9 hour half-life, allowing more rapid offset of effect 3

Perioperative Management

Discontinue apixaban at least 48 hours before elective surgery or procedures with moderate-to-high bleeding risk; discontinue at least 24 hours before low-bleeding-risk procedures. 5, 1

• For patients with impaired renal function, consider extending the discontinuation period beyond 48 hours 5
• Bridging anticoagulation during the 24-48 hours after stopping apixaban is not generally required and may increase bleeding risk 5, 1
• Resume apixaban when adequate hemostasis is established: as early as 6 hours post-procedure for low bleeding risk, or delay 48-72 hours for high bleeding risk 5

Reversal Strategies for Major Bleeding

Andexanet alfa is the FDA-approved specific reversal agent for apixaban-associated life-threatening bleeding. 3

• Low-dose regimen: 400 mg IV bolus at 30 mg/min followed by 4 mg/min infusion for up to 120 minutes (for last dose taken ≥8 hours ago or unknown timing) 3
• High-dose regimen: 800 mg IV bolus at 30 mg/min followed by 8 mg/min infusion for up to 120 minutes (for last dose taken <8 hours ago or dose >5 mg) 3
• If andexanet alfa is unavailable, four-factor prothrombin complex concentrate (4F-PCC) or activated PCC may be considered, though not specifically studied for apixaban reversal 3, 1
• Activated charcoal reduces apixaban absorption if given within 2-4 hours of ingestion 3, 1

Common Pitfalls to Avoid

• Do not use PT, INR, aPTT, or anti-Xa levels to guide reversal therapy with PCCs—these tests are not useful for monitoring apixaban reversal 3
• Do not empirically reduce apixaban doses when combined with moderate CYP3A4 inhibitors alone—dose reduction is only indicated for strong dual P-gp and CYP3A4 inhibitors 3
• Do not assume all P-gp inhibitors require dose adjustment—the magnitude of CYP3A4 inhibition is more clinically relevant for apixaban 3
• Avoid unnecessary prolonged anticoagulation—use apixaban only for the duration when anticoagulation is strictly required to minimize bleeding risk 6