Apixaban

Apixaban is a direct oral anticoagulant that selectively and reversibly inhibits coagulation factor Xa (FXa), preventing the conversion of prothrombin to thrombin and thereby interrupting the amplification of the coagulation cascade. Unlike heparins, apixaban does not require antithrombin III as a cofactor, and unlike warfarin it does not act through vitamin K-dependent clotting factor synthesis.

Mechanism of Action

• Direct, reversible inhibition of factor Xa: apixaban binds the active site of factor Xa with high affinity and selectivity, inhibiting both the free enzyme and FXa bound within the prothrombinase complex on activated platelet surfaces. This dual inhibition is clinically relevant because clot-associated FXa is protected from antithrombin-dependent inhibitors such as heparin.
• Downstream effects: because a single FXa molecule generates a large number of thrombin molecules, selective FXa inhibition produces a potent reduction in thrombin generation while preserving residual hemostatic thrombin activity better than direct thrombin inhibitors.
• No effect on platelet function directly: apixaban does not inhibit platelet aggregation, although bleeding-time prolongation may occur secondary to reduced thrombin generation.

Pharmacokinetics

• Absorption: oral bioavailability approximately 50% (range 43–46% in some studies); peak plasma concentration reached within 3–4 hours. Absorption is not clinically affected by food.
• Volume of distribution: approximately 21 L — relatively limited tissue distribution.
• Protein binding: 92–94%, primarily to plasma albumin.
• Metabolism: hepatic, primarily via CYP3A4/5 with minor contributions from CYP1A2, CYP2C8, CYP2C9, CYP2C19, and CYP2J2. The main metabolite, O-demethyl apixaban sulfate, is pharmacologically inactive. Approximately 50% of an oral dose is excreted unchanged.
• Half-life: approximately 12 hours, supporting twice-daily dosing.
• Excretion: multiple pathways — approximately 27% renal (the lowest renal dependence among the DOACs), with the remainder biliary and intestinal. This balanced elimination is clinically important in patients with impaired renal function.
• Transporters: substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP/ABCG2); combined strong P-gp and CYP3A4 inhibitors or inducers can significantly alter apixaban exposure.

• Non-valvular atrial fibrillation (NVAF): prevention of stroke and systemic embolism in adult patients with one or more risk factors (such as prior stroke or TIA, age ≥75 years, hypertension, diabetes, symptomatic heart failure).
• Deep vein thrombosis (DVT) and pulmonary embolism (PE): treatment of acute DVT and PE, and prevention of recurrent DVT and PE following initial therapy.
• Postoperative VTE prophylaxis: prevention of venous thromboembolism in adult patients who have undergone elective hip or knee replacement surgery.

• Hypersensitivity to apixaban or any of the excipients.
• Active clinically significant bleeding.
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.
• Lesions or conditions at significant risk of major bleeding (e.g., current or recent gastrointestinal ulceration, malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent surgery to the brain, spine, or eye, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms, or major intraspinal or intracerebral vascular abnormalities).
• Concomitant treatment with any other anticoagulant agent, with the exception of switching therapy or when unfractionated heparin is given at doses necessary to maintain a central venous or arterial catheter.

Common (≥1/100 to <1/10): anaemia; haemorrhage — eye (including conjunctival), gastrointestinal, rectal, gingival, urogenital tract; epistaxis; nausea; contusion (bruising); gamma-glutamyltransferase increased; haematuria; post-procedural haemorrhage.

Uncommon (≥1/1,000 to <1/100): thrombocytopenia; hypersensitivity, allergic oedema, anaphylaxis; pruritus, alopecia; intracranial haemorrhage; haemoptysis; intra-abdominal haemorrhage, haemorrhoidal haemorrhage, mouth haemorrhage, haematochezia; hypotension (including procedural); liver function tests abnormal — AST, alkaline phosphatase, bilirubin increased.

Rare (<1/1,000): respiratory tract haemorrhage; retroperitoneal haemorrhage; muscle haemorrhage.

Not known: angioedema.

Bleeding risk: as expected from its mechanism, the principal safety concern is haemorrhage. In the pivotal ARISTOTLE trial (apixaban vs warfarin in NVAF), apixaban demonstrated lower rates of major bleeding and intracranial haemorrhage than warfarin while reducing stroke and systemic embolism.

• Strong dual CYP3A4 and P-gp inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole, ritonavir): contraindicated or to be avoided — significantly increase apixaban exposure.
• Strong dual CYP3A4 and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital, St John’s Wort): substantially decrease apixaban exposure; co-administration should be avoided.
• Other anticoagulants and antiplatelet agents (heparins, low-molecular-weight heparins, fondaparinux, direct thrombin inhibitors, vitamin K antagonists, dual antiplatelet therapy): increase bleeding risk; combination requires careful clinical justification.
• NSAIDs, including selective COX-2 inhibitors: increased bleeding risk.
• SSRIs and SNRIs: may modestly increase bleeding risk.
• Grapefruit juice: contains CYP3A4 inhibitors; large quantities may increase exposure.

Apixaban tablets are taken orally with or without food, swallowed whole with water. For patients unable to swallow whole tablets, apixaban tablets may be crushed and suspended in water, 5% dextrose in water, or apple juice, or mixed with apple puree and administered immediately.

Non-valvular Atrial Fibrillation

• Standard dose: 5 mg twice daily.
• Reduced dose (2.5 mg twice daily): in patients with at least two of the following criteria — age ≥80 years, body weight ≤60 kg, serum creatinine ≥1.5 mg/dL (133 µmol/L). Also in patients with severe renal impairment (CrCl 15–29 mL/min).

Treatment of DVT/PE

• Initial: 10 mg twice daily for 7 days.
• Maintenance: 5 mg twice daily.
• Extended prevention of recurrence (after at least 6 months of standard treatment): 2.5 mg twice daily.

VTE Prophylaxis after Hip or Knee Replacement

• Dose: 2.5 mg twice daily, starting 12–24 hours after surgery.
• Duration: 32–38 days following hip replacement; 10–14 days following knee replacement.

Renal Impairment

• CrCl ≥30 mL/min: no dose adjustment for VTE indications.
• CrCl 15–29 mL/min: use with caution; reduced doses apply in NVAF.
• CrCl <15 mL/min or dialysis: not recommended.

Hepatic Impairment

• Mild (Child-Pugh A): no dose adjustment.
• Moderate (Child-Pugh B): use with caution.
• Severe (Child-Pugh C): not recommended.

Missed Dose

Take the missed dose as soon as remembered on the same day, then resume twice-daily dosing as before. Do not double the next dose.

Bleeding Management

There is no routine coagulation monitoring requirement, but anti-FXa assays calibrated for apixaban can be used in emergencies. The specific reversal agent andexanet alfa is approved for life-threatening or uncontrolled bleeding on apixaban; non-specific options include four-factor prothrombin complex concentrate (4F-PCC), activated charcoal (within 2–6 hours of overdose), and supportive measures.

Surgical and Invasive Procedures

Apixaban should generally be discontinued at least 48 hours before procedures with a moderate or high risk of bleeding, and at least 24 hours before procedures with low bleeding risk. Restart timing depends on the bleeding risk of the procedure and adequacy of haemostasis.

Spinal/Epidural Anaesthesia

Risk of spinal or epidural haematoma — careful timing of neuraxial procedures relative to apixaban dosing is essential. Patients should be monitored for signs of neurological impairment.

Pregnancy and Lactation

• Pregnancy: not recommended; safer alternatives (e.g., LMWH) should be used.
• Breastfeeding: discontinue breastfeeding or apixaban based on the risk-benefit assessment.

Elderly

No specific dose adjustment for age alone, but apply the dose-reduction criteria above for NVAF. Increased fall risk, polypharmacy, and renal decline warrant heightened bleeding-risk vigilance.

Effect on Driving

Apixaban has no or negligible influence on the ability to drive and use machines.

This medicinal product does not require any special storage conditions. Keep in the original packaging.

Typically 3 years for the film-coated tablets. Do not use after the expiry date printed on the packaging.

Prescription required (Rx).