Apixaban
Apixaban 2.5 & 5 mg F.C. tablet
Category:
Antithrombotic agents, direct factor Xa inhibitors
(Medicines.org.uk)
Chemistry:
It is chemically described as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl) phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4c] pyridine-3-carboxamide. Its molecular formula is C25H25N5O4, which corresponds to a molecular weight of 459.5. It has the following structural formula:
(Rxlist)
Pharmacokinetics:
Absorption
The absolute bioavailability of apixaban is ~ 50% for doses up to 10 mg. rapidly absorbed with maximum concentrations (Cmax) appearing 3 to 4 hours after tablet intake and it can be taken with or without food.
Distribution
Plasma protein binding in humans is ~ 87%. The volume of distribution (Vss) is ~ 21 litres.
Metabolism
O-demethylation and hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. Apixaban is metabolised mainly via CYP3A4/5 with minor contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. It is a substrate of transport proteins, P-gp and breast cancer resistance protein.
Elimination
~ 25% was recovered as metabolites, with the majority recovered in faeces. Renal excretion accounts for approximately 27% of total clearance.
Apixaban has a total clearance of about 3.3 L/h and a half-life of ~12 hours.
(Medicines.org.uk)
Indications:
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II).
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.
(Medicines.org.uk, BNF)
Contraindications:
- 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.
- Concomitant treatment with any other anticoagulant agent 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.
(Medicines.org.uk)
Warnings & Precautions:
- It is recommended to be used with caution in conditions with increased risk of haemorrhage.
- Care is to be taken if patients are treated concomitantly with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or non-steroidal anti-inflammatory medicinal products (NSAIDs), including acetylsalicylic acid.
- 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 I antibodies).
- Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding and at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding.
-If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised. This risk of bleeding should be weighed against the urgency of intervention.
- Apixaban should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established.
- For patients undergoing catheter ablation for atrial fibrillation, apixaban treatment does not need to be interrupted.
- When apixaban is considered for DVT or PE treatment in cancer patients, a careful assessment of the benefits against the risks should be made.
- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), apixaban is to be used with caution in patients with severe renal impairment (creatinine clearance 15-29 mL/min).
- For the prevention of stroke and systemic embolism in patients with NVAF, patients with severe renal impairment (creatinine clearance 15-29 mL/min), and patients with serum creatinine ≥ 1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg should receive the lower dose of apixaban ,2.5 mg twice daily.
- In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore apixaban is not recommended.
- It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). Prior to initiating apixaban, liver function testing should be performed.
- The use of apixaban is not recommended in patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp, such as azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir).
- In patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) the following recommendations apply:
for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE, apixaban should be used with caution; for the treatment of DVT and treatment of PE, apixaban should not be used since efficacy may be compromised.
(Medicines.org.uk)
Pregnancy and Breast – feeding:
Pregnancy
As a precautionary measure, it is preferable to avoid the use of apixaban during pregnancy.
Breast-feeding
A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from apixaban therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
(Medicines.org.uk, BNF)
Drug Interactions:
azole-antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir), phenytoin, carbamazepine, phenobarbital or St. John's Wort, rifampicin, SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors, dipyridamole, dextran or sulfinpyrazone, activated charcoal.
(Medicines.org.uk)
Adverse Reactions:
Anaemia, Thrombocytopenia, Eye haemorrhage (including conjunctival haemorrhage), Haemorrhage, haematoma, Epistaxis, Nausea, Gastrointestinal haemorrhage, Mouth and Rectal haemorrhage, gingival bleeding, Gamma-glutamyltransferase increased, Skin rash, Haematuria, Abnormal vaginal, urogenital haemorrhage, Contusion, Hypotension (including procedural hypotension), Alanine aminotransferase increased.
(Medicines.org.uk, BNF)
OVERDOSE:
Symptoms: bleeding.
Treatment: In the event of haemorrhagic complications, treatment must be discontinued and the source of bleeding investigated. The initiation of appropriate treatment, e.g., surgical haemostasis, the transfusion of fresh frozen plasma or the administration of a reversal agent for factor Xa inhibitors should be considered. administration of activated charcoal 2 and 6 hours after ingestion of apixaban.
Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings.
(Medicines.org.uk)
DOSAGE AND ADMINISTRATION:
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF)
The recommended dose of apixaban is 5 mg taken orally twice daily.
The recommended dose of apixaban is 2.5 mg taken orally twice daily in patients with NVAF and at least two of the following characteristics: age ≥ 80 years, body weight ≤ 60 kg, or serum creatinine ≥ 1.5 mg/dL (133 micromole/L).
Therapy should be continued long-term.
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt)
The recommended dose of apixaban for the treatment of acute DVT and treatment of PE is 10 mg taken orally twice daily for the first 7 days followed by 5 mg taken orally twice daily. As per available medical guidelines, short duration of treatment (at least 3 months) should be based on transient risk factors (e.g., recent surgery, trauma, immobilisation).
The recommended dose of apixaban for the prevention of recurrent DVT and PE is 2.5 mg taken orally twice daily. following completion of 6 months of treatment with apixaban 5 mg twice daily or with another anticoagulant. The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding.
Prophylaxis of venous thromboembolism following knee and hip replacement surgery
2.5 mg twice daily for 10-14 days after knee surgery and for 32-38 days after hip surgery, to be started 12-24 hours after surgery.
Switching from vitamin K antagonist (VKA) therapy to apixaban
When converting patients from vitamin K antagonist (VKA) therapy to apixaban, warfarin or other VKA therapy should be discontinued and apixaban started when the international normalised ratio (INR) is < 2.
Switching from apixaban to VKA therapy
When converting patients from apixaban to VKA therapy, administration of apixaban should be continued for at least 2 days after beginning VKA therapy. After 2 days of coadministration of apixaban with VKA therapy, an INR should be obtained prior to the next scheduled dose of apixaban. Coadministration of apixaban and VKA therapy should be continued until the INR is ≥ 2.
Patients undergoing cardioversion
Apixaban can be initiated or continued in NVAF patients who may require cardioversion.
For patients initiating treatment with apixaban, 5 mg should be given twice daily for at least 2.5 days (5 single doses) before cardioversion to ensure adequate anticoagulation. The dosing regimen should be reduced to 2.5 mg apixaban given twice daily for at least 2.5 days (5 single doses) if the patient meets the criteria for dose reduction.
If cardioversion is required before 5 doses of apixaban can be administered, a 10 mg loading dose should be given, followed by 5 mg twice daily. The dosing regimen should be reduced to a 5 mg loading dose followed by 2.5 mg twice daily if the patient meets the criteria for dose reduction. The administration of the loading dose should be given at least 2 hours before cardioversion.
For all patients undergoing 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.
- The safety and efficacy of apixaban in children and adolescents below age 18 have not been established.
- If a dose is missed, the patient should take apixaban immediately and then continue with twice daily intake as before.
- Apixaban should be swallowed with water, with or without food.
For patients who are unable to swallow whole tablets, apixaban tablets may be crushed and suspended in water, or 5% glucose in water (G5W), 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 G5W and immediately delivered through a nasogastric tube.
Crushed tablets are stable in water, G5W, apple juice, and apple puree for up to 4 hours.
(Medicines.org.uk, BNF)
Storage:
Store below 30˚ C and keep away from humidity & light.
How supplied:
Apixaban 2.5 & 5 mg F.C. tablets contain 2.5 & 5 mg Apixaban and are available as round yellow-coated 2.5 mg tablets and pink-coated 5 mg tablets, in transparent colorless blister of 10 at boxes of 30 tablets with leaflet, manufactured at Tehran darou pharmaceutical Co.
References:
1) medicines.org.uk 2021
2) RXlist 2021
3) BNF 81