What are the risks of using Eliquis (apixaban) and fluoxetine concomitantly?

Concomitant Use of Eliquis (Apixaban) and Fluoxetine

The combination of apixaban and fluoxetine can be used together with caution, as fluoxetine increases bleeding risk through impaired platelet function rather than through significant pharmacokinetic drug interactions, and does not require apixaban dose adjustment. 1, 2

Mechanism of Interaction

Pharmacokinetic Considerations

• Fluoxetine is a weak to moderate CYP3A4 inhibitor, and while apixaban is partially metabolized through CYP3A4, fluoxetine does not significantly affect apixaban metabolism through CYP3A4 or P-glycoprotein pathways to a degree that requires dose adjustment 2
• Unlike strong dual CYP3A4 and P-gp inhibitors (such as ketoconazole or ritonavir), escitalopram—a related SSRI—does not significantly affect apixaban metabolism, and this principle applies similarly to fluoxetine 1

Pharmacodynamic Risk

• The primary concern is pharmacodynamic: SSRIs including fluoxetine impair serotonin-mediated platelet function, which creates an additive bleeding risk when combined with anticoagulants 2, 3
• This antiplatelet effect is distinct from the anticoagulant mechanism of apixaban, creating synergistic bleeding potential 3

Clinical Management Approach

Before Initiating the Combination

• Assess baseline bleeding risk factors including age ≥75 years, weight <60 kg, serum creatinine ≥1.5 mg/dL, history of bleeding, thrombocytopenia, uremia, or liver disease 1
• Avoid adding antiplatelet agents (especially aspirin or NSAIDs) to this combination unless there is a clear indication for acute vascular disease, as bleeding events increase substantially 1
• Monitor renal function at baseline and at least annually, as apixaban requires dose adjustment when creatinine clearance falls below certain thresholds 1

Apixaban Dosing

• No dose adjustment of apixaban is required based solely on the addition of fluoxetine 1, 2
• Standard apixaban dosing remains 5 mg twice daily for atrial fibrillation, with dose reduction 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 1

Ongoing Monitoring

• Educate patients about signs of bleeding (unusual bruising, blood in urine/stool, prolonged bleeding from cuts, severe headache) 4
• Monitor for bleeding complications more vigilantly than with apixaban alone, particularly in the first weeks after initiating fluoxetine 3
• Patients with renal impairment require heightened surveillance, as apixaban half-life increases from 12 to 17 hours with renal dysfunction 1

Management of Bleeding Events

If Major Bleeding Occurs

• Stop both apixaban and fluoxetine immediately when major bleeding occurs 1
• Apixaban 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 (intracranial, spinal, intraocular, pericardial), or hemodynamically unstable patients—not for routine bleeding events 1

Important Caveats

Comparison to Other SSRIs

• Among SSRIs, fluoxetine and fluvoxamine appear to carry the highest drug interaction risk with warfarin, but this concern is less relevant for DOACs like apixaban where the interaction is primarily pharmacodynamic rather than pharmacokinetic 2
• The American Heart Association recommends escitalopram and sertraline as better alternatives to fluvoxamine and fluoxetine when selecting an SSRI for patients taking anticoagulants, though this recommendation was made in the context of warfarin 5

Patient Education Gap

• Approximately 66% of patients are uncertain or incorrect about the potential for increased bleeding from combining medications with apixaban, highlighting the need for explicit counseling 4
• Less knowledge about potentially interacting products is associated with greater use of such products, creating a dangerous cycle 4

Avoid Concurrent Antiplatelet Agents

• The combination of apixaban with fluoxetine should not be further complicated by adding aspirin or NSAIDs (ibuprofen, naproxen) unless there is a compelling acute vascular indication, as this substantially increases bleeding risk without clear benefit for stroke prevention 1