Which class of medications can increase apixaban (a Factor Xa inhibitor) levels, particularly in patients with impaired renal function?

Medications That Increase Apixaban Levels

Combined strong CYP3A4 and P-glycoprotein (P-gp) inhibitors are the primary class of medications that significantly increase apixaban levels, requiring dose reduction or avoidance of concomitant use. 1

Primary Mechanism: Dual CYP3A4 and P-gp Inhibition

Apixaban is metabolized by CYP3A4 (approximately 25% of elimination) and is a substrate of the P-glycoprotein efflux transporter. 1, 2 When both pathways are inhibited simultaneously, apixaban exposure increases substantially, elevating bleeding risk. 1

Strong Dual Inhibitors (Avoid or Reduce Dose)

The following medications inhibit both CYP3A4 and P-gp, causing clinically significant increases in apixaban levels:

• Ketoconazole and other azole antifungals (itraconazole, voriconazole) more than double apixaban plasma concentrations 1
• Ritonavir and cobicistat (HIV protease inhibitors) significantly increase both Cmax and AUC 1
• Clarithromycin increases apixaban exposure and has been associated with higher rates of major bleeding requiring hospitalization in retrospective studies 1

For patients on standard doses of 5-10 mg twice daily, reduce apixaban by 50% when combined with strong dual inhibitors. 1 Do not use this combination in patients already on the reduced 2.5 mg twice daily dose. 1

Moderate Inhibitors: Context-Dependent Risk

P-gp Inhibitors with Moderate CYP3A4 Activity

These medications cause modest increases in apixaban levels but are generally safer than strong dual inhibitors:

• Verapamil increases apixaban exposure but can be co-administered if no other risk factors for drug accumulation exist 1
• Amiodarone is a less potent P-gp inhibitor and can be used with DOACs when renal function is preserved 1
• Dronedarone is a strong P-gp inhibitor that should generally be avoided with all DOACs 1
• Quinidine modestly increases apixaban plasma concentrations 1

Post-hoc analysis of the ARISTOTLE trial found no differences in safety or efficacy outcomes when apixaban was combined with moderate CYP3A4 and P-gp inhibitors, which comprised most drug interactions in that study. 1

Critical Consideration: Renal Impairment Amplifies Risk

The risk of drug interactions is substantially magnified in patients with impaired renal function. 1 Since apixaban has 27% renal clearance, P-gp inhibition in the setting of CKD can lead to excessive drug accumulation. 1, 3

• Avoid strong dual inhibitors entirely in patients with CrCl <50 mL/min 1
• Even moderate inhibitors may require dose adjustment or alternative anticoagulation in moderate-to-severe renal impairment 1

Common Pitfalls to Avoid

Do not assume P-gp inhibition alone requires dose adjustment in patients with normal renal function. Research suggests CYP3A4 interactions may play a greater role than P-gp interactions in affecting apixaban metabolism. 1 Moderate P-gp inhibitors that only weakly inhibit CYP3A4 have less pronounced effects on apixaban exposure. 1

Do not overlook the cumulative effect of multiple moderate inhibitors. A patient taking both a moderate P-gp inhibitor and experiencing declining renal function faces compounded risk. 1

Avoid empiric dose reduction for all interacting medications. The 2014 AHA/ACC/HRS guidelines specifically note that dose adjustments are primarily indicated for strong dual inhibitors, particularly in the setting of CKD. 1

Practical Algorithm

1. Identify if the medication is a strong dual CYP3A4 and P-gp inhibitor (ketoconazole, ritonavir, clarithromycin) 1
2. Assess renal function using Cockcroft-Gault method 1
3. If CrCl >50 mL/min and strong dual inhibitor needed: Reduce apixaban dose by 50% if on 5-10 mg twice daily 1
4. If CrCl <50 mL/min and strong dual inhibitor needed: Avoid combination or consider alternative anticoagulation 1
5. For moderate inhibitors with normal renal function: Generally safe to continue standard dosing 1
6. Reassess renal function at least annually or when clinically indicated 1