What to do in case of accidental overdosing of Eliquis (apixaban) 15 mg?

Management of Accidental Apixaban 15 mg Overdose

In the case of an accidental 15 mg apixaban overdose (triple the standard 5 mg dose), adopt a conservative "wait-and-see" approach with supportive care and close monitoring, as this represents a modest overdose that rarely causes clinically significant bleeding in patients without active hemorrhage. 1, 2

Immediate Assessment and Initial Management

Risk Stratification

• Assess timing of ingestion: If the overdose occurred within the last 2 hours, consider administering activated charcoal 30-50 g orally to reduce absorption, though clinical efficacy data are limited 1
• The FDA label confirms that activated charcoal given 2 hours after a 20 mg dose reduced apixaban absorption by 50%, and by 27% when given at 6 hours 2
• Evaluate for active bleeding: Perform a focused physical examination looking for signs of bleeding (petechiae, ecchymoses, mucosal bleeding, hematemesis, melena, hematuria, or neurological changes suggesting intracranial hemorrhage) 1
• Check baseline laboratories: Obtain CBC with platelets, PT/INR, aPTT, creatinine, and calculate creatinine clearance using Cockcroft-Gault equation to estimate drug elimination 1

Patient-Specific Factors Affecting Risk

• Renal function is critical: Apixaban has 27% renal clearance, so patients with impaired kidney function (CrCl <50 mL/min) will have prolonged drug exposure and slower elimination 1
• Age considerations: Elderly patients (≥80 years) have reduced drug clearance and may require longer observation 1
• Concomitant medications: Patients taking P-glycoprotein inhibitors or strong CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin) will have elevated apixaban levels 1

Conservative Management Strategy

Observation Without Reversal

• The European Heart Rhythm Association explicitly recommends a "wait-and-see" strategy for NOAC overdoses without active bleeding, given the relatively short plasma half-life of 12 hours for apixaban 1
• Clinical trial data demonstrate that apixaban doses up to 50 mg daily for 3-7 days in healthy subjects produced no clinically relevant adverse effects 2
• A case report documented a patient who ingested 300-350 mg of apixaban (60-70 tablets) with peak blood concentration of 4,000 ng/mL (therapeutic range 91-321 ng/mL) who experienced no bleeding events with supportive care alone 3

Monitoring Protocol

• Admit for observation for at least 24 hours (two half-lives of apixaban in patients with normal renal function) 1
• Serial monitoring: Check hemoglobin/hematocrit every 6-8 hours for the first 24 hours to detect occult bleeding 1
• Neurological checks: Perform serial neurological assessments every 4 hours to detect intracranial hemorrhage, particularly in elderly patients or those with fall risk 1
• Avoid invasive procedures: Defer elective procedures, intramuscular injections, and neuraxial anesthesia until drug clearance is complete 1

When to Consider Reversal Agents

Indications for Andexanet Alfa

• Active life-threatening bleeding: Intracranial hemorrhage, gastrointestinal bleeding with hemodynamic instability, or bleeding into critical anatomical spaces 1, 4
• Urgent surgery required: When emergency surgery cannot be delayed and was performed within 12 hours of the last apixaban dose (assuming normal renal function) 1, 4
• Catastrophic bleeding with unknown timing: When the timing of the last dose is uncertain and the patient presents with major hemorrhage 4

Andexanet Alfa Dosing

• For apixaban overdose, use the low-dose regimen: 400 mg IV bolus at 30 mg/min, followed by 4 mg/min infusion for up to 120 minutes 1
• The FDA granted accelerated approval for andexanet alfa specifically for reversal of apixaban and rivaroxaban in life-threatening bleeding 4

Alternative Hemostatic Support (If Andexanet Unavailable)

• Four-factor prothrombin complex concentrate (4F-PCC): Consider 25-50 units/kg IV if andexanet alfa is unavailable and bleeding is life-threatening, though this is off-label and carries prothrombotic risk 1
• The European guidelines note that 4F-PCC returned endogenous thrombin potential to baseline within 4 hours after apixaban administration, but caused sustained elevation (34-51% above baseline) at 21 hours, with unknown clinical significance 2

Critical Pitfalls to Avoid

Do Not Routinely Use Reversal Agents

• Prophylactic reversal is not indicated: The European Heart Rhythm Association explicitly states that "balancing the benefit of normalizing coagulation in a non-bleeding patient needs to be carefully weighed against a possibly strong prothrombotic effect" 1
• Reversal agents carry thrombotic risk: Andexanet alfa and 4F-PCC can precipitate thrombotic events (stroke, MI, DVT/PE), particularly in patients with atrial fibrillation who require anticoagulation 1

Avoid Unnecessary Laboratory Monitoring

• PT/INR and aPTT are not useful: These tests are minimally prolonged by apixaban and do not correlate with bleeding risk or guide management 1
• Anti-factor Xa activity may not correlate with clinical outcomes: One case report showed hybrid anti-factor Xa activity did not correlate with blood apixaban concentrations 3

Do Not Skip the Next Scheduled Dose Unnecessarily

• For a single accidental double dose (10 mg instead of 5 mg), the European guidelines recommend continuing the normal twice-daily schedule without skipping doses 1
• For the 15 mg overdose (three times the normal dose), consider holding the next scheduled dose and resuming normal dosing 24 hours after the overdose 1

Resumption of Anticoagulation

Timing Considerations

• Resume normal apixaban dosing once the risk of bleeding has resolved and at least 24-48 hours have elapsed since the overdose 1
• In patients with atrial fibrillation, prolonged interruption increases stroke risk: The FDA label warns that stopping apixaban without adequate alternative anticoagulation increases stroke risk 2
• Do not use bridging anticoagulation: There is no role for heparin bridging in the setting of apixaban overdose recovery 1