Apixaban

1. Drug Name

• Generic Name: Apixaban

• Brand Names: Eliquis

2. Drug Classification

• Class: Anticoagulant

• Subclass: Direct Factor Xa Inhibitor

3. Mechanism of Action

Apixaban is a selective, reversible, and direct inhibitor of Factor Xa, a key enzyme in the coagulation cascade. By inhibiting Factor Xa, apixaban decreases thrombin generation, which reduces fibrin formation and prevents the development of thrombi. Apixaban acts independently of antithrombin and does not directly affect platelet aggregation, although it inhibits thrombin-induced platelet aggregation indirectly.

4. Pharmacokinetics

• Absorption: Apixaban has an oral bioavailability of approximately 50%. Peak plasma concentrations are achieved 3-4 hours after ingestion.

• Distribution: The volume of distribution (Vd) is around 21 liters, with approximately 87% protein binding, primarily to albumin.

• Metabolism: Apixaban undergoes hepatic metabolism via CYP3A4, along with minor contributions from other cytochrome P450 enzymes. Additionally, it is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

• Excretion: The elimination half-life is around 12 hours, allowing for twice-daily dosing. About 27% of the drug is excreted renally, with the remainder eliminated through the hepatobiliary route.

• Special Considerations:

  • Renal Impairment: Apixaban dose adjustments are advised in patients with severe renal impairment.

  • Hepatic Impairment: Avoid in patients with severe hepatic impairment, as it can lead to altered drug metabolism and increased bleeding risk.

5. Indications

• Primary Indications:

  • Non-Valvular Atrial Fibrillation: For reducing the risk of stroke and systemic embolism.

  • Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE): For treatment and reduction of recurrent DVT and PE risk.

  • Postoperative Venous Thromboembolism (VTE) Prophylaxis: For patients undergoing hip or knee replacement surgery.

• Off-Label Uses: Limited, but may be used in specific thromboembolic disorders as directed by a specialist.

• Specific Populations: Suitable for patients requiring an alternative to warfarin who have difficulty maintaining therapeutic INR levels or who prefer not to undergo routine blood monitoring.

6. Dosage and Administration

• General Adult Dosing:

  • Non-Valvular Atrial Fibrillation: 5 mg orally twice daily. For patients with at least two of the following criteria (age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL), reduce dose to 2.5 mg twice daily.

  • DVT and PE Treatment: Initial dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily.

  • VTE Prophylaxis After Hip/Knee Replacement: 2.5 mg twice daily, starting 12-24 hours post-surgery, and continued for 12 days (knee replacement) or 35 days (hip replacement).

• Administration: Apixaban tablets can be taken with or without food and should be swallowed whole.

7. Contraindications

• Absolute Contraindications:

  • Active pathological bleeding.

  • Severe hypersensitivity reaction to apixaban or any component of the formulation.

• Relative Contraindications:

  • Severe hepatic impairment (due to potential accumulation and increased bleeding risk).

  • Pregnancy and lactation, due to insufficient safety data.

8. Warnings and Precautions

• Bleeding Risk: Apixaban increases the risk of bleeding and is not recommended for patients with active bleeding or high bleeding risk. Caution is advised in patients undergoing procedures with high bleeding risk.

• Spinal/Epidural Hematoma: Patients receiving neuraxial anesthesia or undergoing spinal puncture may be at risk of developing spinal or epidural hematoma, potentially resulting in long-term paralysis.

• Discontinuation Warning: Abrupt discontinuation increases the risk of thrombotic events. If apixaban is discontinued temporarily, other anticoagulants may be used to maintain anticoagulation.

9. Adverse Effects

• Common Adverse Effects (≥10%):

  • Bleeding complications, including minor bleeding like epistaxis and hematoma.

• Less Common but Clinically Significant Side Effects:

  • Gastrointestinal bleeding, particularly in elderly patients or those with other bleeding risks.

  • Anemia and hemorrhagic events that may require medical attention.

• Rare/Serious Adverse Reactions:

  • Severe bleeding, such as intracranial hemorrhage or life-threatening gastrointestinal hemorrhage.

10. Drug Interactions

• Major Drug Interactions:

  • CYP3A4 and P-gp Inhibitors (e.g., ketoconazole, itraconazole): These drugs increase apixaban plasma concentrations, increasing bleeding risk. Dosage adjustments may be necessary.

  • CYP3A4 and P-gp Inducers (e.g., rifampin, carbamazepine): These drugs reduce apixaban concentrations, which may reduce efficacy.

• Food-Drug Interactions: None significant, though it may be taken with food if gastrointestinal tolerance is an issue.

• Interactions with Lab Tests: Apixaban may affect coagulation test results, although routine monitoring is not required.

11. Clinical Pharmacology

• Pharmacodynamics: Apixaban rapidly achieves anticoagulant effects by inhibiting Factor Xa, significantly reducing thrombin formation and fibrin clot generation. It has a favorable safety profile compared to warfarin, with lower rates of major bleeding in atrial fibrillation.

12. Special Populations

• Pregnancy: Due to limited safety data, apixaban use in pregnancy is generally avoided, as the potential for bleeding poses risks to both mother and fetus.

• Lactation: It is unknown if apixaban is excreted in breast milk; breastfeeding is generally not recommended.

• Geriatrics: Age-related decline in renal function may necessitate monitoring, though dosage adjustments are generally unnecessary.

• Pediatrics: Safety and efficacy have not been established for pediatric patients.

13. Therapeutic Uses

• Primary Use: Apixaban is used primarily for stroke prevention in atrial fibrillation and in the treatment and prevention of thromboembolic conditions, such as DVT and PE.

• Combinational Therapy: May be combined with antiplatelet agents in some cardiovascular settings, although bleeding risk increases.

14. Monitoring and Follow-Up

• Renal Function Tests: Monitor renal function periodically, especially in elderly or renally-impaired patients.

• Signs of Bleeding: Regularly assess for bleeding symptoms, including unexplained bruising, blood in stools or urine, and decreased hemoglobin levels.

15. Overdose Management

• Symptoms of Overdose: Overdose primarily results in increased bleeding risk, including life-threatening bleeding events.

• Treatment Protocols:

  • Andexanet Alfa (Andexxa): A reversal agent approved for life-threatening or uncontrolled bleeding with apixaban.

  • Supportive Measures: Activated charcoal may be considered if the overdose was recent, and supportive measures, such as fluid resuscitation, may be used to manage hemorrhage.

16. Patient Counseling Information

• Key Points:

  • Take apixaban as directed, and do not discontinue use abruptly without consulting a healthcare provider due to risk of thrombosis.

  • Report any signs of bleeding, such as blood in stools, urine, or unexpected bruising.

  • Inform healthcare providers and dentists about apixaban use prior to any procedure.

• Seek Immediate Medical Attention: If patients experience significant or persistent bleeding, dizziness, or signs of severe blood loss, they should seek urgent medical care.