What is the management of Apixaban (Direct Oral Anticoagulant) overdose?

From the Guidelines

Management of apixaban overdose requires prompt medical attention and supportive care, with the specific reversal agent andexanet alfa being the most effective treatment option. For patients with suspected apixaban overdose, discontinue the medication immediately and assess for bleeding. Activated charcoal may be administered within 2-6 hours of ingestion to reduce absorption, as suggested by 1. Laboratory tests including complete blood count, coagulation studies, renal and liver function should be obtained. For minor bleeding, local hemostatic measures are often sufficient. For severe bleeding, administer intravenous fluids and blood products as needed.

• The specific reversal agent for apixaban is andexanet alfa, given as an IV bolus followed by a 2-hour infusion, with dosing based on the apixaban dose and time since last intake, as shown in studies such as 1.
• For patients on 5 mg or less, use the low-dose regimen (400 mg bolus at 30 mg/min, followed by 4 mg/min for 120 minutes).
• For higher doses or unknown amounts, use the high-dose regimen (800 mg bolus followed by 8 mg/min infusion).
• If andexanet alfa is unavailable, prothrombin complex concentrate at 25-50 units/kg can be considered.
• Hemodialysis is ineffective for removing apixaban due to its high protein binding, as noted in 1.
• Monitor the patient closely for at least 24 hours, as apixaban's half-life is 12 hours in patients with normal renal function but can be longer in renal impairment or the elderly.

From the FDA Drug Label

10 OVERDOSAGE Overdose of apixaban tablets increases the risk of bleeding [see Warnings and Precautions (5.2)]. In controlled clinical trials, orally administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) had no clinically relevant adverse effects. In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion. An agent to reverse the anti-factor Xa activity of apixaban is available.

The management of apixaban overdose may include:

• Administration of activated charcoal to reduce apixaban absorption
• Use of an agent to reverse the anti-factor Xa activity of apixaban 2

From the Research

Management of Apixaban Overdose

• The management of apixaban overdose is a critical concern, and several studies have investigated the effectiveness of various reversal agents 3, 4, 5, 6, 7.
• In a case report, a 76-year-old man who ingested 60-70 apixaban pills was treated with activated charcoal and fresh frozen plasma, and his apixaban concentration decreased over time without any bleeding events 3.
• The use of prothrombin complex concentrate (PCC), activated PCC (aPCC), and recombinant activated factor VII (rFVIIa) has been studied as potential reversal agents for apixaban 4, 6, 7.
• A study found that aPCC was more effective than PCC and rFVIIa in reversing the anticoagulant effect of apixaban in vitro 4.
• Another study found that rFVIIa, PCC, and fibrinogen concentrate failed to reverse apixaban-induced bleeding in a rabbit model, although they improved some laboratory parameters 6.
• A retrospective study found that aPCC was effective in achieving clinical hemostasis in patients with major bleeding associated with apixaban or rivaroxaban, although the safety of the drug was a concern 7.
• The use of specific anti-Xa tests has been recommended to assess apixaban levels, as standard coagulation assays may not be reliable 5.

Reversal Agents

• Activated prothrombin complex concentrates (aPCCs) have been studied as a potential reversal agent for apixaban 4, 7.
• Recombinant activated factor VII (rFVIIa) has also been investigated as a reversal agent, although its effectiveness is uncertain 4, 6.
• Prothrombin complex concentrate (PCC) has been studied as a potential reversal agent, although its effectiveness is also uncertain 4, 6.
• Fibrinogen concentrate has been studied as a potential reversal agent, although it may increase the risk of bleeding 6.

Laboratory Tests

• Specific anti-Xa tests are recommended to assess apixaban levels, as standard coagulation assays may not be reliable 5.
• The use of prothrombin time/international normalized ratio and anti-Xa assays may be useful in certain situations, although their reliability is uncertain 5.