Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Bristol-Myers Squibb/Pfizer EEIG, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex, UB8 1DH, United Kingdom
Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery.
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 (see section 4.4 for haemodynamically unstable PE patients).
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.
The recommended duration of treatment is 32 to 38 days.
The recommended duration of treatment is 10 to 14 days.
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.
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:
| 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 and/or PE following completion of 6 months of treatment for DVT or PE | 2.5 mg twice daily | 5 mg |
The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4).
If a dose is missed, the patient should take Eliquis immediately and then continue with twice daily intake as before.
Switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose (see section 4.5). These medicinal products should not be administered simultaneously.
When converting patients from vitamin K antagonist (VKA) therapy to Eliquis, warfarin or other VKA therapy should be discontinued and Eliquis started when the international normalised ratio (INR) is <2.
When converting patients from Eliquis to VKA therapy, administration of Eliquis should be continued for at least 2 days after beginning VKA therapy. After 2 days of coadministration of Eliquis with VKA therapy, an INR should be obtained prior to the next scheduled dose of Eliquis. Coadministration of Eliquis and VKA therapy should be continued until the INR is ≥2.
In patients with mild or moderate renal impairment, the following recommendations apply:
In patients with severe renal impairment (creatinine clearance 15-29 mL/min) the following recommendations apply (see sections 4.4 and 5.2):
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).
Eliquis 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 trials. Therefore Eliquis should be used with caution in this population (see sections 4.4 and 5.2). Prior to initiating Eliquis, liver function testing should be performed.
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).
No dose adjustment required (see section 5.2).
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).
Apixaban can be initiated or continued in NVAF patients who may require cardioversion.
For patients not previously treated with anticoagulants, at least 5 doses of apixaban 5 mg twice daily (2.5 mg twice daily in patients who qualify for a dose reduction (see above sections Dose reduction and Renal impairment)) should be given before cardioversion to ensure adequate anticoagulation (see section 5.1).
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 (see above sections Dose reduction and Renal impairment). The administration of the loading dose should be given at least 2 hours before cardioversion (see section 5.1).
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 Eliquis in children and adolescents below age 18 have not been established. No data are available.
Oral use.
Eliquis should be swallowed with water, with or without food.
For patients who are unable to swallow whole tablets, Eliquis 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 (see section 5.2). Alternatively, Eliquis tablets may be crushed and suspended in 60 mL of water or D5W and immediately delivered through a nasogastric tube (see section 5.2).
Crushed Eliquis tablets are stable in water, D5W, apple juice, and apple puree for up to 4 hours.
There is no antidote to Eliquis. Overdose of apixaban may result in a higher risk of bleeding. 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 or the transfusion of fresh frozen plasma should be considered.
In controlled clinical trials, orally-administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days (25 mg twice daily (bid) for 7 days or 50 mg once daily (od) for 3 days) had no clinically relevant adverse effects.
In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of a 20 mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively, and had no impact on Cmax. Mean half-life of apixaban decreased from 13.4 hours when apixaban was administered alone to 5.3 hours and 4.9 hours, respectively, when activated charcoal was administered 2 and 6 hours after apixaban. Thus, administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion.
If life-threatening bleeding cannot be controlled by the above measures, administration of prothrombin complex concentrates (PCCs) or recombinant factor VIIa may be considered. Reversal of Eliquis pharmacodynamic effects, as demonstrated by changes in the thrombin generation assay, was evident at the end of infusion and reached baseline values within 4 hours after the start of a 4-factor PCC 30 minute infusion in healthy subjects. However, there is no clinical experience with the use of 4-factor PCC products to reverse bleeding in individuals who have received Eliquis. Currently there is no experience with the use of recombinant factor VIIa in individuals receiving apixaban. Re-dosing of recombinant factor VIIa could be considered and titrated depending on improvement of bleeding.
Depending on local availability, a consultation of a coagulation expert should be considered in case of major bleedings.
Haemodialysis decreased apixaban AUC by 14% in subjects with end-stage renal disease (ESRD), when a single dose of apixaban 5 mg was administered orally. Therefore, haemodialysis is unlikely to be an effective means of managing apixaban overdose.
3 years.
This medicinal product does not require any special storage condition.
Alu-PVC/PVdC blisters. Cartons of 10, 20, 60, 168 and 200 film-coated tablets.
Alu PVC/PVdC perforated unit dose blisters of 60x1 and 100x1 film-coated tablets.
Not all pack sizes may be marketed.
No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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