Posology : מינונים

4.2   Posology and method of administration
Posology
Prevention of VTE (VTEp): elective hip or knee replacement surgery
The recommended dose of apixaban is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery.

Physicians may consider the potential benefits of earlier anticoagulation for VTE prophylaxis as well as the risks of post-surgical bleeding in deciding on the time of administration within this time window.

In patients undergoing hip replacement surgery
The recommended duration of treatment is 32 to 38 days.

In patients undergoing knee replacement surgery:
The recommended duration of treatment is 10 to 14 days.
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.

Dose reduction
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. When prevention of recurrent DVT and PE is indicated, the 2.5 mg twice daily dose should be initiated following completion of 6 months of treatment with apixaban 5 mg twice daily or with another anticoagulant, as indicated in Table 1 below (see also section 5.1).

Table 1: Dose recommendation (VTEt)
Dosing schedule                                  Maximum daily dose



Treatment of DVT or PE               10 mg twice daily for the first 7 days   20 mg  followed by 5 mg twice daily             10 mg

Prevention of recurrent DVT          2.5 mg twice daily                       5 mg and/or PE following completion of
6 months of treatment for DVT or
PE

The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4).


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

Switching
Switching treatment from parenteral anticoagulants to apixaban (and vice versa) can be done at the next scheduled dose (see section 4.5). These agents should not be administered simultaneously.

Switching from vitamin K antagonist (VKA) therapy to apixaban
When converting patients from vitamin K antagonist (VKA) therapy to apixaban, discontinue warfarin or other VKA therapy and start apixaban when the international normalised ratio (INR) is < 2.0.

Switching from apixaban to VKA therapy
When converting patients from apixaban to VKA therapy, continue administration of apixaban for at least 2 days after beginning VKA therapy. After 2 days of coadministration of apixaban with VKA therapy, obtain an INR prior to the next scheduled dose of apixaban. Continue coadministration of apixaban and VKA therapy until the INR is ≥ 2.0.

Switching between apixaban and anticoagulants other than warfarin: Discontinue one being taken and begin the other at the next scheduled dose.

Elderly
VTEp and VTEt – No dose adjustment required (see sections 4.4 and 5.2).

NVAF – No dose adjustment required, unless criteria for dose reduction are met (see Dose reduction at the beginning of section 4.2).

Renal impairment

In patients with mild or moderate renal impairment, the following recommendations apply: 

- for the prevention of VTE in elective hip or knee replacement surgery (VTEp), for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt), no dose adjustment is necessary (see section 5.2).

- for the prevention of stroke and systemic embolism in patients with NVAF and serum creatinine ≥ 1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg, a dose reduction is necessary and described above. In the absence of other criteria for dose reduction (age, body weight), no dose adjustment is necessary (see section 5.2).


In patients with severe renal impairment (creatinine clearance 15-29 mL/min) the following recommendations apply (see sections 4.4 and 5.2):

- for the prevention of VTE in elective hip or knee replacement surgery (VTEp).
-for the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) apixaban is to be used with caution;

-for the prevention of stroke and systemic embolism in patients with NVAF, patients 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 (see sections 4.4 and 5.2).

Hepatic impairment apixaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3).

It is not recommended in patients with severe hepatic impairment (see sections 4.4. and 5.2).

It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment (see sections 4.4 and 5.2).

Patients with elevated liver enzymes alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) >2 x ULN or total bilirubin ≥1.5 x ULN were excluded in clinical studies. Therefore, apixaban should be used with caution in this population (see sections 4.4 and 5.2). Prior to initiating apixaban, liver function testing should be performed.

Body weight
VTEp and VTEt - No dose adjustment required (see sections 4.4 and 5.2).
NVAF - No dose adjustment required, unless criteria for dose reduction are met (see Dose reduction at the beginning of section 4.2).

Gender
No dose adjustment required (see section 5.2).

Cardioversion (NVAF)
Patients can stay on apixaban while being cardioverted.
Paediatric population
The safety and efficacy of apixaban in children and adolescents below age 18 have not been established. Currently available data on thromboembolism prevention are described in section 5.1 but no recommendation on a posology can be made.

Method of administration
Oral use.
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 (see section 5.2). Alternatively, apixaban tablets may be crushed and suspended in 60 mL of water or G5W and immediately delivered through a nasogastric tube (see section 5.2).
Crushed apixaban tablets are stable in water, G5W, apple juice, and apple puree for up to 4 hours.