The following risk minimisation materials have been developed for Eliquis(apixaban) for the 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):
•Prescriber Guide – for healthcare professionals
•Patient Alert Card – for patients (to be given by the healthcare professional)
•Summary of Product Characteristics (SmPC, 5mg and 2.5mg) – for healthcare professionals
Please ensure that you are familiar with these educational materials before prescribing Eliquis as they contain important safety information. In particular, they are aimed at increasing awareness about the potential risk of bleeding during treatment with Eliquis and providing guidance on how to manage that risk.
Please click on this link to view the materials.
Table of Contents
1. Name of the medicinal product
2. Qualitative and quantitative composition
3. Pharmaceutical form
4. Clinical particulars
4.1 Therapeutic indications
4.2 Posology and method of administration
4.3 Contraindications
4.4 Special warnings and precautions for use
4.5 Interaction with other medicinal products and other forms of interaction
4.6 Fertility, pregnancy and lactation
4.7 Effects on ability to drive and use machines
4.8 Undesirable effects
4.9 Overdose
5. Pharmacological properties
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
5.3 Preclinical safety data
6. Pharmaceutical particulars
6.1 List of excipients
6.2 Incompatibilities
6.3 Shelf life
6.4 Special precautions for storage
6.5 Nature and contents of container
6.6 Special precautions for disposal and other handling
7. Marketing authorisation holder
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
10. Date of revision of the text
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Eliquis 2.5 mg film-coated tablets
1. Name of the medicinal product
Eliquis 2.5 mg film-coated tablets
2. Qualitative and quantitative composition
Each film-coated tablet contains 2.5 mg apixaban.
Excipients with known effect:
Each 2.5 mg film-coated tablet contains 51.43 mg lactose (see section 4.4).
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Film-coated tablet (tablet)
Yellow, round tablets debossed with 893 on one side and 2½ on the other side.
4. Clinical particulars
4.1 Therapeutic 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 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).
4.2 Posology and method of administration
Posology
Prevention of VTE (VTEp): elective hip or knee replacement surgery
The recommended dose of Eliquis 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 Eliquis is 5 mg taken orally twice daily.
Dose reduction
The recommended dose of Eliquis 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.
Missed Dose
If a dose is missed, the patient should take Eliquis immediately and then continue with twice daily intake as before.
Switching
Switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose (see section 4.5).
Switching from Vitamin K antagonist (VKA) therapy to Eliquis
When converting patients from Vitamin K antagonist (VKA) therapy to Eliquis, discontinue warfarin or other VKA therapy and start Eliquis when the international normalized ratio (INR) is < 2.0.
Switching from Eliquis to VKA therapy
When converting patients from Eliquis to VKA therapy, continue administration of Eliquis for at least 2 days after beginning VKA therapy. After 2 days of coadministration of Eliquis with VKA therapy, obtain an INR prior to the next scheduled dose of Eliquis. Continue coadministration of Eliquis and VKA therapy until the INR is ≥ 2.0.
Renal impairment
As there is no clinical experience in patients with creatinine clearance < 15 ml/min, or in patients undergoing dialysis, apixaban is not recommended in these patients (see sections 4.4 and 5.2).
Prevention of VTE (VTEp): elective hip or knee replacement surgery
No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2).
Limited clinical data in patients with severe renal impairment (creatinine clearance 15-29 ml/min) indicate that apixaban plasma concentrations are increased in this patient population, therefore, apixaban is to be used with caution in these patients (see sections 4.4 and 5.2).
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF)
No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2).
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.
Patients with exclusive criteria of severe renal impairment (creatinine clearance 15-29 ml/min) should also receive the lower dose of apixaban 2.5 mg twice daily.
Hepatic impairment
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 (ALT/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.
Body weight
VTEp - No dose adjustment required (see section 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).
Elderly
VTEp – 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).
Cardioversion (NVAF)
Patients can stay on apixaban while being cardioverted.
Paediatric population
The safety and efficacy of Eliquis in children and adolescents below age 18 have not been established. No data are available.
Method of administration
Oral use.
Eliquis should be swallowed with water, with or without food.
4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Active clinically significant bleeding.
• Hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 5.2).
• 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 the circumstances of switching therapy to or from apixaban (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5).
4.4 Special warnings and precautions for use
Haemorrhage risk
As with other anticoagulants, patients taking Eliquis are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Eliquis administration should be discontinued if severe haemorrhage occurs (see sections 4.8 and 4.9).
Although treatment with apixaban does not require routine monitoring of exposure, a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge of apixaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery (see section 5.1).
Interaction with other medicinal products affecting haemostasis
Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated (see section 4.3).
The concomitant use of Eliquis with antiplatelet agents increases the risk of bleeding (see section 4.5).
Care is to be taken if patients are treated concomitantly with non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid.
Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with Eliquis (see section 4.5).
In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with Eliquis.
In a clinical trial of patients with atrial fibrillation, concomitant use of ASA increased the major bleeding risk on apixaban from 1.8% per year to 3.4% per year and increased the bleeding risk on warfarin from 2.7% per year to 4.6% per year. In this clinical trial, there was limited (2.1%) use of concomitant dual antiplatelet therapy.
In a clinical trial of high-risk post acute coronary syndrome patients, characterized by multiple cardiac and non-cardiac comorbidities, who received ASA or the combination of ASA and clopidogrel, a significant increase in risk of ISTH (International Society on Thrombosis and Haemostasis) major bleeding was reported for apixaban (5.13% per year) compared to placebo (2.04% per year) .
Use of Thrombolytic agents for the treatment of acute ischemic stroke
There is very limited experience with the use of thrombolytic agents for the treatment of acute ischemic stroke in patients administered apixaban.
Patients with prosthetic heart valves
Safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation. Therefore, the use of Eliquis is not recommended in this setting.
Surgery and invasive procedures
Eliquis should be discontinued at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. This includes interventions for which the probability of clinically significant bleeding cannot be excluded or for which the risk of bleeding would be unacceptable.
Eliquis should be discontinued at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. This includes interventions for which any bleeding that occurs is expected to be minimal, non-critical in its location or easily controlled.
If surgery or invasive procedures 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.
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 cardioversion see section 4.2).
Temporary discontinuation
Discontinuing anticoagulants, including Eliquis, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with Eliquis must be temporarily discontinued for any reason, therapy should be restarted as soon as possible.
Spinal/epidural anaesthesia or puncture
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. The risk of these events may be increased by the post-operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Eliquis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis.
There is no clinical experience with the use of apixaban with indwelling intrathecal or epidural catheters. In case there is such need and based on the general PK characteristics of apixaban, a time interval of 20-30 hours (i.e., 2 x half-life) between the last dose of apixaban and catheter withdrawal should elapse, and at least one dose should be omitted before catheter withdrawal. The next dose of apixaban may be given at least 5 hours after catheter removal. As with all new anticoagulant drugs, experience with neuraxial blockade is limited and extreme caution is therefore recommended when using apixaban in the presence of neuraxial blockade.
Renal impairment
As there is no clinical experience in patients with creatinine clearance < 15 ml/min, or in patients undergoing dialysis, apixaban is not recommended in these patients (see sections 4.2 and 5.2).
Prevention of VTE (VTEp): elective hip or knee replacement surgery
No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 5.2).
Limited clinical data in patients with severe renal impairment (creatinine clearance 15-29 ml/min) indicate that apixaban plasma concentrations are increased in this patient population, therefore, apixaban alone or in combination with acetylsalicylic acid (ASA) is to be used with caution in these patients because of a potentially higher bleeding risk (see sections 4.2 and 5.2).
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF)
No dose adjustment is necessary in patients with mild or moderate renal impairment (see section 4.2 and 5.2).
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. Patients with exclusive criteria of severe renal impairment (creatinine clearance 15-29 ml/min) should also receive the lower dose of apixaban 2.5 mg twice daily (see section 4.2).
Elderly patients
The co-administration of Eliquis with ASA in elderly patients s