Is apixaban (Eliquis) safe to use together with fluoxetine in an otherwise healthy adult?

Apixaban (Eliquis) and Fluoxetine: Safe to Use Together

Yes, apixaban and fluoxetine can be safely co-prescribed in otherwise healthy adults without dose adjustment, as fluoxetine does not significantly affect the CYP3A4 or P-glycoprotein pathways that metabolize apixaban. 1

Why This Combination Is Safe

No Metabolic Interaction

• Unlike strong CYP3A4 and P-glycoprotein inhibitors (such as ketoconazole, clarithromycin, or ritonavir), fluoxetine does not significantly affect apixaban metabolism through these pathways, so dose adjustment of apixaban based on drug-drug interaction is not required. 1
• Apixaban is primarily metabolized via CYP3A4 (with some CYP3A5 involvement) and is a P-glycoprotein substrate, but only strong dual inhibitors or inducers of both pathways cause clinically significant interactions. 2, 3
• Standard SSRIs like fluoxetine do not inhibit or induce CYP3A4 or P-gp at clinically relevant levels. 1

Important Bleeding Risk Considerations

Pharmacodynamic Interaction

• While there is no pharmacokinetic interaction, SSRIs like fluoxetine can impair platelet function by depleting intraplatelet serotonin, which theoretically increases bleeding risk when combined with anticoagulants. 1, 4
• The combination of anticoagulants with agents affecting platelet function, such as SSRIs, may increase bleeding risk, though specific data for apixaban-fluoxetine is limited. 1

Risk Stratification Before Prescribing

• Carefully assess individual bleeding risk factors including age ≥75 years, weight <60 kg, serum creatinine ≥1.5 mg/dL, and any history of bleeding before initiating this combination. 1
• Patients with renal impairment have prolonged apixaban half-life (17 hours versus 12 hours in normal renal function), increasing bleeding risk. 1
• Comorbidities including thrombocytopenia, uremia, or liver disease further elevate bleeding risk. 1

Critical Medications to Avoid Adding

• Avoid adding antiplatelet agents (especially aspirin) to this combination unless there is a clear indication for acute vascular disease, as bleeding events increase without clear benefit for stroke prevention. 1, 5
• The most reported adverse drug reaction triplet in global pharmacovigilance data was apixaban-aspirin-gastrointestinal hemorrhage. 4

Standard Apixaban Dosing Applies

No Dose Adjustment Needed for the Interaction

• Standard apixaban dosing is 5 mg twice daily for atrial fibrillation. 2, 1
• Reduce to 2.5 mg twice daily only if any 2 of the following are present: age ≥80 years, serum creatinine ≥1.5 mg/dL, or body weight ≤60 kg. 2, 1
• This dose reduction is based on patient characteristics, not the fluoxetine co-administration. 1

Renal Function Monitoring

• Monitor renal function at least annually and when clinically indicated, as apixaban requires dose adjustment when creatinine clearance falls below certain thresholds. 1
• For CrCl 15-50 mL/min, reduce apixaban to 2.5 mg twice daily if used for atrial fibrillation. 2

Management of Bleeding Events

If Major Bleeding Occurs

• Stop apixaban immediately when major bleeding occurs, as the drug effect will diminish over 24-48 hours in patients with normal renal function. 1
• Reserve reversal agents like andexanet alfa for life-threatening bleeding, bleeding at critical sites, or hemodynamically unstable patients—not for routine bleeding events. 1, 5
• Concurrent SSRIs should also be stopped when major bleeding occurs. 1

Reversal Agent Dosing

• Andexanet alfa dosing: low-dose regimen of 400 mg IV bolus at 30 mg/min followed by 4 mg/min infusion for up to 120 minutes, or high-dose regimen of 800 mg IV bolus at 30 mg/min followed by 8 mg/min infusion for up to 120 minutes. 5
• If andexanet alfa is unavailable, four-factor prothrombin complex concentrate (4F-PCC) may be considered. 5

Common Pitfalls to Avoid

• Do not confuse fluoxetine with strong CYP3A4 inhibitors like fluconazole—fluoxetine does not require apixaban dose adjustment. 1, 5
• Do not routinely add proton pump inhibitors "for GI protection" without clear indication, as the bleeding risk increase from SSRIs is modest and PPIs have their own risks. 1
• Avoid switching to warfarin solely because of the SSRI combination, as warfarin carries similar or higher bleeding risk and requires INR monitoring. 2