Drugs List

Therapeutic Indications

Uses

Deep vein thrombosis - prophylaxis
Deep vein thrombosis - treatment
Nonvalvular atrial fibrillation; prevention of stroke and systemic embolism
Prevention of VTE in patients undergoing hip replacement surgery
Prevention of VTE in patients undergoing knee replacement surgery
Pulmonary embolism - prophylaxis
Pulmonary embolism - treatment

Prevention of venous thromboembolic events in adult patients who have undergone elective hip replacement surgery.

Prevention of venous thromboembolic events in adult patients who have undergone elective knee replacement surgery.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age equal to or greater than 75 years, hypertension, diabetes mellitus, symptomatic heart failure (NYHA class equal to or greater than II).

Treatment and prevention of recurrent deep vein thrombosis (DVT).

Treatment and prevention of recurrent pulmonary embolism (PE).

Contraindications

Children under 18 years
Haemorrhage
Arteriovenous malformation
Breastfeeding
Coagulopathy due to hepatic disorder
Galactosaemia
Gastrointestinal ulcer
History of gastrointestinal ulceration
Neoplasm with increased bleeding risk
Oesophageal varices
Pregnancy
Recent central nervous system surgery
Recent central nervous system trauma
Recent intracranial haemorrhage
Recent ocular surgery
Renal dialysis
Renal impairment - creatinine clearance below 15ml/minute
Severe hepatic impairment
Vascular disorder

Precautions and Warnings

Elderly
Risk of haemorrhage
Spinal/epidural anaesthesia
Weight below 60kg
Antiphospholipid syndrome
Elevated serum transaminases - greater than twice the upper limit of normal
Glucose-galactose malabsorption syndrome
Hepatic impairment
Lactose intolerance
Renal impairment - creatinine clearance 15-29ml/minute
Serum bilirubin above 1.5 times upper limit of normal

Not recommended for anticoagulation with prosthetic heart valves
Not all available strengths are licensed for all indications
Contains lactose
Administer at least 5 hours after removal of epidural catheter
Increased risk of spinal haematoma with post-op insitu epidural catheter
Monitor for bleeding during treatment
Monitor patients undergoing spinal or epidural anaesthesia closely
Reversal agent available
May affect results of some laboratory tests
Discontinue if severe haemorrhage occurs
Discontinue prior to surgery
Advise patient not to take NSAIDs unless advised by clinician
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Advise patient of risk of bleeding
Remind patient of importance of carrying Alert Card with them at all times

Although treatment with apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-FXa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery. An agent to reverse the anti-factor Xa activity of apixaban is available.

Apixaban has not been studied in patients undergoing hip fracture surgery, therefore apixaban is not recommended in these patients.

Patients undergoing spinal or epidural anaesthesia or puncture while being treated with apixaban are at risk of developing an epidural or spinal haematoma which could result in long term or permanent paralysis. This risk is increased by the post-operative use of indwelling epidural catheters or other drugs affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of apixaban. Traumatic or repeated epidural or spinal puncture will also increase the risk. Patients must be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). Urgent diagnosis and treatment is required if neurological compromise is observed. Prior to neuraxial intervention the potential risks should be weighted against the benefits in patients currently anticoagulated or planned to be anticoagulated for thromboprophylaxis.

There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. When there is such a need, a time interval of 20 to 30 hours (2 times the half life) between the last dose of apixaban and catheter withdrawal is required and at least one dose should be omitted before catheter withdrawal. The next apixaban dose is not to be administered earlier than 5 hours after the removal of the catheter.

Use with caution when using apixaban in the presence of neuraxial blockade.

There is very limited experience with the use of thrombolytic agents for the treatment of acute ischaemic stroke.

Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding.
If surgery cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.

Discontinuing apixaban, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thromboses. Lapses in therapy should be avoided and if anticoagulation with apixaban must be temporarily discontinued for any reason, therapy should be restarted as soon as possible provided the clinical situation allows and adequate haemostasis has been established.

Direct acting Oral Anticoagulants (DOACs) including apixaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein 1 antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Pregnancy and Lactation

Pregnancy

Apixaban is contraindicated during pregnancy.

At the time of writing, there is limited published experience concerning the use of apixaban during pregnancy. Animal studies have not indicated direct or indirect harmful effects with respect to reproductive toxicity. The manufacturer does not recommend the use of apixaban during pregnancy.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Apixaban is contraindicated during breastfeeding.

At the time of writing, there is limited published experience concerning the use of apixaban during breastfeeding. Animal studies haven shown the excretion of apixaban in milk. In rat milk, a high milk to maternal plasma ratio was found, possibly due to active transport in the milk. However, it is unknown whether apixaban or its metabolites are excreted in human milk. A risk to newborns and infants cannot be excluded. A decision must be made whether to discontinue apixaban or breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Side Effects

Anaemia
Anaphylactic reaction
Bleeding (surgical site)
Conjunctival haemorrhage
Contusion
Elevation of liver enzymes
Epistaxis
Gastro-intestinal haemorrhage
Gingival bleeding
Haematochezia
Haematoma
Haematuria
Haemoptysis
Haemorrhage
Haemorrhoidal bleeding
Hypersensitivity reactions
Hypotension
Intracranial bleeding
Melaena
Mouth haemorrhage
Muscle haemorrhage
Nausea
Ocular haemorrhage
Pulmonary haemorrhage
Rash
Rectal haemorrhage
Reduced platelet count
Retroperitoneal bleeding
Serum bilirubin increased
Thrombocytopenia
Urethral bleeding
Vaginal haemorrhage

Presentation

Oral formulations of apixaban.

Drugs List

Therapeutic Indications

Uses

Deep vein thrombosis - prophylaxis
Deep vein thrombosis - treatment
Nonvalvular atrial fibrillation; prevention of stroke and systemic embolism
Prevention of VTE in patients undergoing hip replacement surgery
Prevention of VTE in patients undergoing knee replacement surgery
Pulmonary embolism - prophylaxis
Pulmonary embolism - treatment

Prevention of venous thromboembolic events in adult patients who have undergone elective hip replacement surgery.

Prevention of venous thromboembolic events in adult patients who have undergone elective knee replacement surgery.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age equal to or greater than 75 years, hypertension, diabetes mellitus, symptomatic heart failure (NYHA class equal to or greater than II).

Treatment and prevention of recurrent deep vein thrombosis (DVT).

Treatment and prevention of recurrent pulmonary embolism (PE).

Dosage

Adults

Elderly

Patients with Renal Impairment

Additional Dosage Information

Contraindications

Children under 18 years
Haemorrhage
Arteriovenous malformation
Breastfeeding
Coagulopathy due to hepatic disorder
Galactosaemia
Gastrointestinal ulcer
History of gastrointestinal ulceration
Neoplasm with increased bleeding risk
Oesophageal varices
Pregnancy
Recent central nervous system surgery
Recent central nervous system trauma
Recent intracranial haemorrhage
Recent ocular surgery
Renal dialysis
Renal impairment - creatinine clearance below 15ml/minute
Severe hepatic impairment
Vascular disorder

Precautions and Warnings

Elderly
Risk of haemorrhage
Spinal/epidural anaesthesia
Weight below 60kg
Antiphospholipid syndrome
Elevated serum transaminases - greater than twice the upper limit of normal
Glucose-galactose malabsorption syndrome
Hepatic impairment
Lactose intolerance
Renal impairment - creatinine clearance 15-29ml/minute
Serum bilirubin above 1.5 times upper limit of normal

Not recommended for anticoagulation with prosthetic heart valves
Not all available strengths are licensed for all indications
Contains lactose
Administer at least 5 hours after removal of epidural catheter
Increased risk of spinal haematoma with post-op insitu epidural catheter
Monitor for bleeding during treatment
Monitor patients undergoing spinal or epidural anaesthesia closely
Reversal agent available
May affect results of some laboratory tests
Discontinue if severe haemorrhage occurs
Discontinue prior to surgery
Advise patient not to take NSAIDs unless advised by clinician
Advise patient not to take St John's wort concurrently
Advise patient grapefruit products may increase plasma level
Advise patient of risk of bleeding
Remind patient of importance of carrying Alert Card with them at all times

Although treatment with apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-FXa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g. overdose and emergency surgery. An agent to reverse the anti-factor Xa activity of apixaban is available.

Apixaban has not been studied in patients undergoing hip fracture surgery, therefore apixaban is not recommended in these patients.

Patients undergoing spinal or epidural anaesthesia or puncture while being treated with apixaban are at risk of developing an epidural or spinal haematoma which could result in long term or permanent paralysis. This risk is increased by the post-operative use of indwelling epidural catheters or other drugs affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of apixaban. Traumatic or repeated epidural or spinal puncture will also increase the risk. Patients must be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). Urgent diagnosis and treatment is required if neurological compromise is observed. Prior to neuraxial intervention the potential risks should be weighted against the benefits in patients currently anticoagulated or planned to be anticoagulated for thromboprophylaxis.

There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. When there is such a need, a time interval of 20 to 30 hours (2 times the half life) between the last dose of apixaban and catheter withdrawal is required and at least one dose should be omitted before catheter withdrawal. The next apixaban dose is not to be administered earlier than 5 hours after the removal of the catheter.

Use with caution when using apixaban in the presence of neuraxial blockade.

There is very limited experience with the use of thrombolytic agents for the treatment of acute ischaemic stroke.

Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding.
If surgery cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. This risk of bleeding should be weighed against the urgency of intervention.

Discontinuing apixaban, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thromboses. Lapses in therapy should be avoided and if anticoagulation with apixaban must be temporarily discontinued for any reason, therapy should be restarted as soon as possible provided the clinical situation allows and adequate haemostasis has been established.

Direct acting Oral Anticoagulants (DOACs) including apixaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein 1 antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Pregnancy and Lactation

Pregnancy

Apixaban is contraindicated during pregnancy.

At the time of writing, there is limited published experience concerning the use of apixaban during pregnancy. Animal studies have not indicated direct or indirect harmful effects with respect to reproductive toxicity. The manufacturer does not recommend the use of apixaban during pregnancy.

The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Lactation

Apixaban is contraindicated during breastfeeding.

At the time of writing, there is limited published experience concerning the use of apixaban during breastfeeding. Animal studies haven shown the excretion of apixaban in milk. In rat milk, a high milk to maternal plasma ratio was found, possibly due to active transport in the milk. However, it is unknown whether apixaban or its metabolites are excreted in human milk. A risk to newborns and infants cannot be excluded. A decision must be made whether to discontinue apixaban or breastfeeding.

Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1

Counselling

For patients who are unable to swallow whole tablets, apixaban tablets may be crushed and suspended in water, or 5% dextrose in water (D5W), or apple juice or mixed with apple puree and immediately administered orally. Alternatively, apixaban tablets may be crushed and suspended in 60 ml of water or D5W and immediately delivered through a nasogastric tube.
Advise patient not to take NSAIDs unless advised by clinician.
Advise patient not to take St John's wort concurrently.
Advise patient grapefruit products may increase plasma level.

Side Effects

Anaemia
Anaphylactic reaction
Bleeding (surgical site)
Conjunctival haemorrhage
Contusion
Elevation of liver enzymes
Epistaxis
Gastro-intestinal haemorrhage
Gingival bleeding
Haematochezia
Haematoma
Haematuria
Haemoptysis
Haemorrhage
Haemorrhoidal bleeding
Hypersensitivity reactions
Hypotension
Intracranial bleeding
Melaena
Mouth haemorrhage
Muscle haemorrhage
Nausea
Ocular haemorrhage
Pulmonary haemorrhage
Rash
Rectal haemorrhage
Reduced platelet count
Retroperitoneal bleeding
Serum bilirubin increased
Thrombocytopenia
Urethral bleeding
Vaginal haemorrhage

Effects on Laboratory Tests

The manufacturer states clotting tests (e.g. Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT) and International Normalised Ratio (INR)) are affected as expected by the mechanism of action of apixaban. Changes observed in these clotting tests at the expected therapeutic dose are small and subject to a high degree of variability.

Overdosage

It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.

The following number will direct the caller to the relevant local centre (0844) 892 0111

Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).

Further Information

Last Full Review Date: April 2015

Reference Sources

Martindale: The Complete Drug Reference (online) London: Brayfield A (ed). Pharmaceutical Press Accessed on 20 April 2015.

Summary of Product Characteristics: Eliquis 2.5mg film-coated tablets. Bristol-Myers Squibb - Pfizer. Revised October 2019.
Summary of Product Characteristics: Eliquis 5mg film-coated tablets. Bristol-Myers Squibb - Pfizer. Revised October 2019.

HPRA Safety Notices May 2019
Available at: https://www.hpra.ie
Lasr accessed: 07 June 2019

MHRA Drug Safety Update October 2013
Available at: https://www.mhra.gov.uk
Last accessed: 20 April, 2015

MHRA Drug Safety Update June 2020
Available at: https://www.mhra.gov.uk
Last accessed: 06 November 2020

NICE Evidence Services Available at: www.nice.org.uk Last accessed: 18 July 2018