Apixaban

Registered South African indications:

• Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery
• Prevention of stroke and systemic embolism and death in patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors
• Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
• Prevention of recurrent DVT and PE

Registered South African contraindications

• Hypersensitivity to the active substance or to any of the excipients
• Clinically significant active bleeding
• Apixaban is not recommended in patients with severe renal disease (CrCl<15ml/min)
• Apixaban is not recommended in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk
• Apixaban should not be administered with antiplatelet medicines other than aspirin
• Patients with antiphospholipid syndrome (APS) with persistent positivity for all three antiphospholipid antibodies (patients with triple positive APS)

Contraindications registered in other jurisdictions

• Hypersensitivity to the active substance or to any of the excipients
• Active clinically significant bleeding
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk
• Lesion or condition if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, 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 e.g., unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation

• Pregnancy
• Breastfeeding
• Severe renal impairment (Recommendations in other jurisdictions)
• Hepatic impairment
• Elderly (Prevention of stroke and systemic embolism in patients with NVAF)
• Increased risk of haemorrhage
• Prosthetic heart valves
• Antiphospholipid syndrome
• Temporary discontinuation of therapy
• Pulmonary embolism (in patients who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy)
• Acute ischaemic stroke
• Use 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding
• Use 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding (See additional prescribing points)
• Active cancer
• Low body weight (<60kg)
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Prevention of venous thromboembolism events in adult patients who have undergone elective hip or knee replacement surgery

• Oral (fct): Initial: 2.5mg, 12-24hrs after surgery; Then: 2.5mg, twice dly; Treatment duration: Hip replacement surgery: 32-38 days, knee replacement surgery: 10-14 days

Prevention of stroke, systemic embolism and death in patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors

• Oral (fct): 5mg, twice dly

- In patients with at least 2 of the following characteristics, age ≥80 years, body weight ≤60kg, or serum creatinine ≥1.5mg/dL (133 micromol/l)

• Oral (fct): 2.5mg, twice dly

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)

• Oral (fct): Initial: 10mg, twice dly for 7 days; Followed by: 5mg, twice dly; Treatment duration: At least 6 months

Prevention of recurrent DVT and PE

• Oral (fct): 2.5mg, twice dly after at least 6 months of treatment for DVT or PE

Nonvalvular atrial fibrillation (NVAF) patients undergoing cardioversion
- Not previously treated with anticoagulants

• Oral (fct): Standard dose: 5mg, twice dly OR Reduced dose: 2.5mg, twice dly for eligible patients; At least 5 doses should be given before cardioversion to ensure adequate anticoagulation

- When cardioversion is required before 5 doses of apixaban can be administered

• Oral (fct): Loading dose: 10mg, admin. at least 2hrs before cardioversion; Followed by: 5mg, twice dly OR Reduced dose: Loading dose: 5mg, admin. at least 2hrs before cardioversion; Followed by 2.5mg, twice dly if the patient meets the criteria for dose reduction

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Missed dose: If a dose is missed, the patient should take apixaban immediately and then continue with twice daily administration as before

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Apixaban can be taken with or without food. For patients who are unable to swallow whole tablets, apixaban tablets may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, or mixed with applesauce and promptly administered orally. Alternatively, the tablets may be crushed and suspended in 60ml of water or D5W and promptly delivered through a nasogastric tube. Crushed tablets are stable in water, D5W, apple juice, and applesauce for up to 4 hours

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Apixaban can be initiated or continued in NVAF patients who may require cardioversion. Confirmation should be sought prior to cardioversion that the patient has taken apixaban as prescribed. Decisions on initiation and duration of treatment should take established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion into account

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See additional prescribing points

Not established for use in children below 18 years

Pregnancy

• Caution
• There are no data from the use of apixaban in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. Apixaban is not recommended during pregnancy

Breastfeeding

• Caution
• It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in animals have shown excretion of apixaban in milk. In rat milk, a high milk to maternal plasma ratio (C^max about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to newborns and infants cannot be excluded
• A decision must be made to either discontinue breastfeeding or to discontinue/abstain from apixaban therapy

Fertility

• Studies in animals dosed with apixaban have shown no effect on fertility

South African recommendations

Prevention of VTE: elective hip or knee replacement surgery
Treatment of VTE

• CrCl ≥15ml/min: No dose adjustment recommended
• CrCl <15ml/min: Contraindicated
• Those undergoing dialysis: Not recommended

Prevention of stroke and systemic embolism: NVAF

CrCl (ml/min)	Dose (mg)
≥30	No dose adjustment recommended; except in patients with at least 2 of the following characteristics, age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5mg/dL (133 micromol/l): 2.5mg, twice dly
15-29
<15	Contraindicated
Those undergoing dialysis	Not recommended

Recommendations in other jurisdictions

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt)

• Mild to moderate (CrCl 30-80ml/min): No dose adjustment recommended
• Severe (CrCl 15-29ml/min): Caution; no dose adjustment recommended
• CrCl <15ml/min or in patients undergoing dialysis: Not recommended
  There is no clinical experience in such patients, therefore apixaban is not recommended

Prevention of stroke and systemic embolism in patients with NVAF

• Mild to moderate (CrCl 30-80ml/min): No dose adjustment recommended
  Except, if serum creatinine ≥1.5mg/dL (133 micromol/l) associated with age ≥80 years or body weight ≤60kg, a dose reduction is necessary; Oral (fct): 2.5mg, twice daily
• Severe (CrCl 15-29ml/min): Caution; dose adjustment recommended
  Oral (fct): 2.5mg, twice dly
• CrCl <15ml/min or in patients undergoing dialysis: Not recommended
  There is no clinical experience in such patients, therefore apixaban is not recommended

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate (Child-Pugh class A and B): Caution; no dose adjustment recommended
• Severe (Child-Pugh class C): Not recommended
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk: Contraindicated

Recommendations below are applicable to South Africa and other jurisdictions

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE

• No dose adjustment recommended

Prevention of stroke and systemic embolism in patients with NVAF

• Caution; dose adjustment recommended
  See adult dosages for criteria on dose reduction, if required

Central Nervous System Disorders

• Brain haemorrhage (including all intracranial or intraspinal haemorrhages)

Cardiovascular Disorders

• Hypotension (including procedural hypotension)

Respiratory Disorders

• Epistaxis
• Haemoptysis
• Respiratory tract haemorrhage

Gastrointestinal Disorders

• Intra-abdominal haemorrhage
• Gastrointestinal haemorrhage
• Haemorrhoidal haemorrhage
• Mouth haemorrhage
• Rectal haemorrhage
• Retroperitoneal haemorrhage
• Nausea
• Haematochezia

Hepatobiliary Disorders

• Abnormal liver function test
• Increased aspartate aminotransferase
• Increased blood alkaline phosphatase
• Increased blood bilirubin
• Increased gamma-glutamyltransferase
• Increased alanine aminotransferase

Genitourinary Disorders

• Haematuria
• Abnormal vaginal haemorrhage
• Urogenital haemorrhage

Musculoskeletal Disorders

• Muscle haemorrhage

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Skin rash
• Alopecia
• Contusion

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Thrombocytopenia
• Hypersensitivity
• Allergic oedema
• Anaphylaxis
• Haemorrhage
• Haematoma

Sensory Disorders

• Eye haemorrhage (including conjunctival haemorrhage)
• Gingival bleeding

Others

• Positive occult blood
• Application site bleeding
• Postprocedural haemorrhage (including post-procedural haematoma, wound haemorrhage, vessel puncture site haematoma and catheter site haemorrhage)
• Wound secretion
• Incision site haemorrhage (including incision site haematoma)
• Operative haemorrhage
• Traumatic haemorrhage

• Strong inhibitors of CYP3A4 and P-gp
  - Azole-antimycotics (e.g. ketoconazole, itraconazole, voriconazole and posaconazole) 
  - HIV protease inhibitors (e.g. ritonavir) 
• Strong inducers of CYP3A4 and P-gp
  - Rifampicin
  - Phenytoin
  - Carbamazepine
  - Phenobarbital
• Antiplatelets
• Anticoagulants
  - Unfractionated heparin
  - Low molecular weight heparins (e.g enoxaparin, dalteparin)
  - Heparin derivatives (e.g fondaparinux)
  - Oral anticoagulants (e.g warfarin, rivaroxaban, dabigatran)
• Non-steroidal anti-inflammatory drugs
  - Acetylsalicylic acid
• Thrombolytic agents
• GPIIb/IIIa receptor antagonists
• Thienopyridines (e.g. Clopidogrel)
• Dipyridamole
• Dextran
• Sulfinpyrazone
• Selective serotonin reuptake inhibitors
• Serotonin-norepinephrine reuptake inhibitors 

Other interactions

• St. John's Wort
• Activated charcoal

None routine. Specific cases may require 

• Full blood count
• Renal function
• Hepatic function
• Activated partial thromboplastin time
• Prothrombin time
• Anti-Factor Xa assay

Converting from or to parenteral anticoagulants

• Generally, switching treatment from parenteral anticoagulants to apixaban (and vice versa) can be done at the next scheduled dose

Converting from or to warfarin or other vitamin K antagonists (VKA)

• When converting patients from warfarin or other VKA therapy to apixaban, discontinue warfarin or other VKA therapy and start apixaban when the international normalised ratio (INR) is below 2.0
• When converting from apixaban to warfarin or other VKA therapy, continue apixaban for 48 hours after the first dose of warfarin or other VKA therapy

Other platelet aggregation inhibitors or other antithrombotic medicines

• Other platelet aggregation inhibitors or other antithrombotic medicines are not recommended concomitantly with apixaban following surgery
• In patients with atrial fibrillation and a condition that warrants chronic use of aspirin, apixaban may be used with due regard to increased risk of major bleeding

Surgery and invasive procedures

• Apixaban should be discontinued 2 to 3 days prior to elective surgery or invasive procedures such as neuraxial regional anaesthesia
• If surgery or invasive procedures cannot be delayed, exercise appropriate caution taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention

Temporary discontinuation

• Discontinue apixaban, in the presence of active bleeding, elective surgery, or invasive procedures that place patients at an increased risk of haemorrhage. Restart therapy 12 - 24 hours after the danger of haemorrhage has ceased

Concomitant administration of medicines associated with serious bleeding

• Medicines associated with serious bleeding are not recommended concomitantly with apixaban, such as: unfractionated heparins and heparin derivatives (including low molecular weight heparins (LMWH)), FXa inhibiting oligosaccharides (e.g. fondaparinux), direct thrombin II inhibitors (e.g., desirudin), thrombolytic medicines, GPIIb/IIIa receptor antagonists, dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists, and other oral anticoagulants
• It should be noted that unfractionated heparin can be administered at doses necessary to maintain a patent central venous or arterial catheter

Apixaban is a direct, potent, reversible and highly selective active site inhibitor of factor Xa. It inhibits free and clot-bound factor Xa, and prothrombinase activity. Apixaban does not require antithrombin III for antithrombotic activity and has no direct effects on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban prevents thrombin generation and thrombus development.

Film-coated tablet 2.5mg

• Eliquis 2.5mg (Pfizer) Originator

Film-coated tablet 5mg

• Eliquis 5mg (Pfizer) Originator