What are the side effects and interactions of apixaban (Eliquis)?

Side Effects and Interactions of Apixaban (Eliquis)

The most significant side effect of apixaban is bleeding risk, and it has important drug interactions with strong CYP3A4 and P-glycoprotein inhibitors/inducers that require dose adjustments or avoidance. 1

Major Side Effects

Bleeding Complications

• Major bleeding: Primary safety concern with apixaban
  • Lower risk compared to warfarin (0.6% vs 1.8% in the AMPLIFY trial) 2
  • Increased risk when combined with antiplatelet agents (3.4% per year with aspirin vs 1.8% without) 1
  • Higher bleeding rates with dual antiplatelet therapy (5.9% per year) 1

Other Side Effects

• Skin rash or severe allergic reactions 1
• Signs of hypersensitivity:
  • Chest pain or tightness
  • Facial or tongue swelling
  • Breathing difficulties or wheezing
  • Dizziness or fainting 1

Major Drug Interactions

CYP3A4 and P-glycoprotein (P-gp) Interactions

• Apixaban is metabolized via CYP3A4 (liver) and is a substrate for P-gp transport 2, 1

Strong CYP3A4 and P-gp Inhibitors

• Require dose adjustment:
  • For patients on 5-10mg twice daily: Reduce dose by 50% 2, 1
  • For patients on 2.5mg twice daily: Avoid co-administration 2, 1
• Examples: ketoconazole, itraconazole, ritonavir 1
• Exception: Clarithromycin (despite being a strong inhibitor) does not require dose adjustment based on pharmacokinetic data 1

Strong CYP3A4 and P-gp Inducers

• Avoid co-administration due to reduced apixaban exposure and increased thrombotic risk 2, 1
• Examples: rifampin, carbamazepine, phenytoin, St. John's wort 2, 1

Antiplatelet and Anticoagulant Interactions

• Significantly increased bleeding risk when combined with:
  • Antiplatelet agents (especially dual antiplatelet therapy)
  • Fibrinolytics
  • Heparin
  • Aspirin
  • Chronic NSAID use 1
• P2Y12 inhibitors (e.g., clopidogrel) increase major bleeding risk nearly 6-fold 3
• Most common reported adverse interaction in VigiBase: apixaban-aspirin-gastrointestinal hemorrhage 4

Special Populations and Considerations

Renal Impairment

• Approximately 27% of apixaban is eliminated via kidneys 2, 5
• Avoid in severe renal impairment (CrCl <15 mL/min) 2, 6
• Use with caution in moderate renal impairment 6
• Higher bleeding risk observed in patients with acute kidney injury 3

Hepatic Impairment

• Avoid in patients with:
  • Transaminases >2 times upper limit of normal
  • Total bilirubin >1.5 times upper limit of normal 2
• Not recommended in moderate hepatic impairment (Child-Pugh B) 2

Other Considerations

• Not recommended during pregnancy or lactation 6
• Use caution in elderly patients (≥80 years), low body weight (≤60 kg), or elevated serum creatinine (≥1.5 mg/dL) 6
• Half-life is approximately 12 hours 2, 5

Monitoring Recommendations

1. Regular assessment for bleeding signs:

   • Unexplained bruising
   • Blood in urine or stool
   • Unusual headaches or dizziness 6

2. Periodic evaluation of:

   • Renal function
   • Hepatic function
   • Signs of thrombosis or bleeding 6

3. Consider proton pump inhibitors to reduce gastrointestinal bleeding risk in high-risk patients 6

Clinical Pearls

• Apixaban has a more favorable bleeding profile compared to warfarin, but bleeding risk remains the primary safety concern 7
• Approximately 67% of drug-drug interactions with apixaban reported in global databases are not well described or understood 4
• The pharmacodynamic effect of apixaban correlates closely with plasma concentration 5
• Unlike warfarin, apixaban does not require routine coagulation monitoring 5
• In patients with cancer, apixaban may not be the preferred anticoagulant due to limited data in this population 2, 6

When prescribing apixaban, always assess the patient's bleeding risk using tools like the HAS-BLED score, and carefully evaluate concomitant medications for potential interactions that could increase bleeding risk 2.