Apixaban Accord

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 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 51.97  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 shaped, approximate 6.00 mm in diameter, biconvex, film-coated tablet debossed with 
“IU1” on one side and plain 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). 
 
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). 
 
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. 
 



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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: 
 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). 
 
Missed dose 
If a dose is missed, the patient should take Apixaban Accordimmediately and then continue with twice 
daily intake as before. 
 
Switching 
Switching treatment from parenteral anticoagulants to Apixaban Accord(and vice versa) can be done 
at the next scheduled dose (see section 4.5). These medicinal products should not be administered 
simultaneously. 
 
Switching from vitamin K antagonist (VKA) therapy to Apixaban AccordWhen converting patients 
from vitamin K antagonist (VKA) therapy toApixaban Accord, warfarin or other VKA therapy 
should be discontinued and Apixaban Accord started when the international normalised ratio (INR) is 
< 2. 
 
Switching from Apixaban Accord to VKA therapy 
When converting patients from Apixaban Accord to VKA therapy, administration of Apixaban Accord 
should be continued for at least 2 days after beginning VKA therapy. After 2 days of coadministration 
of Apixaban Accord with VKA therapy, an INR should be obtained prior to the next scheduled dose of 
Apixaban Accord. Coadministration of Apixaban Accordand VKA therapy should be continued until 
the INR is ≥ 2. 
 



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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 Accordis 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 Apixaban 
Accordshould be used with caution in this population (see sections 4.4 and 5.2). Prior to 
initiatingApixaban Accord, 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). 
 
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). 
 
Patients undergoing catheter ablation (NVAF) 
Patients can continue apixaban use while undergoing catheter ablation (see sections 4.3, 4.4 and 4.5). 



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Patients undergoing cardioversion 
Apixaban can be initiated or continued in NVAF patients who may require cardioversion.  
 
For patients not previously treated with anticoagulants, exclusion of left atrial thrombus using an 
image guided approach (e.g. transesophageal  echocardiography (TEE) or computed tomographic scan 
(CT)) prior to cardioversion should be considered, in accordance with established medical guidelines. 

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 (see section 5.1). 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 (see above sections Dose reduction and Renal 
impairment). 
 
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). 
 
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. 
 
Patients with NVAF and acute coronary syndrome (ACS) and/or percutaneous coronary intervention 
(PCI) 
There is limited experience of treatment with apixaban at the recommended dose for NVAF 
patientswhen used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI 
afterhaemostasis is achieved (see sections 4.4, 5.1). 
 
Paediatric population 
The safety and efficacy of Apixaban Accordin children and adolescents below age 18 have not been 
established. No data are available. 
 
Method of administration 
 
Oral use 
Apixaban Accordshould be swallowed with water, with or without food. 
 
For patients who are unable to swallow whole tablets, Apixaban Accordtablets 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 Accordtablets 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 Accord tablets are stable in water, G5W, apple juice, and apple puree for up to 
4 hours. 
 
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 



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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 
specific circumstances of switching anticoagulant therapy (see section 4.2), or 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 (see sections 4.4 and 4.5). 

 
4.4 Special warnings and precautions for use 
 
Haemorrhage risk 
As with other anticoagulants, patients taking Apixaban Accordare to be carefully observed for signs of 
bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. 
Apixaban Accordadministration 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).  
 
An agent to reverse the anti-factor Xa activity of apixaban is available. 
 
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 Apixaban Accordwith antiplatelet agents increases the risk of bleeding (see 
section 4.5). 
 
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 
drugs (NSAIDs), including acetylsalicylic acid. 
 
Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with 
Apixaban Accord(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 withApixaban Accord. 
 
In a clinical trial of patients with atrial fibrillation, concomitant use of  acetylsalicylic acid (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(see section 5.1). 
 
A clinical trial enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and a 
plannedtreatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either 
apixabanor VKA) for 6 months. Concomitant use of ASA increased the risk of ISTH (International 
Society onThrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding in 
apixaban-treatedsubjects from 16.4% per year to 33.1% per year (see section 5.1). 
 
In a clinical trial of high-risk post acute coronary syndrome patientswithout atrial 
fibrillationcharacterised 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 



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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(see section 4.5). 
 
Patients with prosthetic heart valves 
Safety and efficacy of Apixaban Accordhave not been studied in patients with prosthetic heart valves, 
with or without atrial fibrillation. Therefore, the use of Apixaban Accordis not recommended in this 
setting. 
 
Patients with antiphospholipid syndrome 
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), treatment with DOACs could be associated with increased rates of recurrent thrombotic 
events compared with vitamin K antagonist therapy. 
 
Surgery and invasive procedures 
Apixaban Accordshould 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. 
 
Apixaban Accordshould 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 Accordshould 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). 
 
For patients undergoing catheter ablation for atrial fibrillation, Apixaban Accordtreatment does not 
need to be interrupted (see sections 4.2, 4.3 and 4.5). 
 
Temporary discontinuation 
Discontinuing anticoagulants, includingApixaban Accord, 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 Apixaban Accord 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 ofApixaban Accord. 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 



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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 medicinal 
products, experience with neuraxial blockade is limited and extreme caution is therefore recommended 
when using apixaban in the presence of neuraxial blockade. 
 
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary 
embolectomy 
Apixaban Accordis not recommended as an alternative to unfractionated heparin in patients with 
pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary 
embolectomy since the safety and efficacy of apixaban have not been established in these clinical 
situations. 
 
Patients with active cancer 
Efficacy and safety of apixaban in the treatment of DVT, treatment of PE and prevention of recurrent 
DVT and PE (VTEt) in patients with active cancer have not been established. 
 
Patients with renal impairment 
Limited clinical data indicate that apixaban plasma concentrations are increased in patients with severe 
renal impairment (creatinine clearance 15-29 mL/min) which may lead to an increased bleeding risk. 
For the prevention of VTE in elective hip or knee replacement surgery (VTEp), 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) (see sections 4.2 and 
5.2). 
 
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 (see section 4.2). 
 
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 4.2 and 5.2). 
 
Elderly patients 
Increasing age may increase haemorrhagic risk (see section 5.2). 
 
Also, the coadministration of Apixaban Accordwith  ASA in elderly patients should be used cautiously 
because of a potentially higher bleeding risk. 
 
Body weight 
Low body weight (< 60 kg) may increase haemorrhagic risk (see section 5.2). 
 
Patients with hepatic impairment 
Apixaban Accordis 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 section 5.2). 
 
It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or 
B) (see sections 4.2 and 5.2). 
 



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Patients with elevated liver enzymes ALT/AST > 2 x ULN or total bilirubin ≥ 1.5 x ULN were 
excluded in clinical trials. Therefore Apixaban Accordshould be used cautiously in this population 
(see section 5.2). Prior to initiating Apixaban Accord, liver function testing should be performed. 
 
Interaction with inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) 
The use of Apixaban Accordis 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). These 
medicinal products may increase apixaban exposure by 2-fold (see section 4.5), or greater in the 
presence of additional factors that increase apixaban exposure (e.g., severe renal impairment). 
 
Interaction with inducers of both CYP3A4 and P-gp 
The concomitant use of Apixaban Accordwith strong CYP3A4 and P-gp inducers (e.g., rifampicin, 
phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may lead to a ~50% reduction in 
apixaban exposure. In a clinical study in atrial fibrillation patients, diminished efficacy and a higher 
risk of bleeding were observed with coadministration of apixaban with strong inducers of both 
CYP3A4 and P-gp compared with using apixaban alone. 
 
In patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp 
the following recommendations apply (see section 4.5): 
 
A. - for the prevention of VTE in elective hip or knee replacement surgery, 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; 
 
B. - for the treatment of DVT and treatment of PE, apixaban should not be used since efficacy may be 
compromised. 
 
Hip fracture surgery 
Apixaban has not been studied in clinical trials in patients undergoing hip fracture surgery to evaluate 
efficacy and safety in these patients. Therefore, it is not recommended in these patients. 
 
Laboratory parameters 
Clotting tests [e.g., prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT)] 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 (see section 5.1). 
 
Information about excipients 
Apixaban Accordcontains lactose. Patients with rare hereditary problems of galactose intolerance, 
total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’ 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Inhibitors of CYP3A4 and P-gp 
Coadministration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both 
CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in mean 
apixaban Cmax. 
 
The use of Apixaban Accordis 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) (see 
section 4.4). 
 



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Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (eg., 
amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, verapamil) are expected to 
increase apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is required 
when coadministered with agents that are not strong inhibitors of both CYP3A4 and P-gp. For 
example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P-gp inhibitor, 
led to a 1.4-fold increase in mean apixaban AUC and a 1.3-fold increase in Cmax. Naproxen (500 mg, 
single dose) an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1.5-fold and 1.6-fold 
increase in mean apixaban AUC and Cmax, respectively. Clarithromycin (500 mg, twice a day), an 
inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1.6-fold and 1.3-fold increase in mean 
apixaban AUC and Cmax respectively. 
 
Inducers of CYP3A4 and P-gp 
Coadministration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an 
approximate 54% and 42% decrease in mean apixaban AUC and Cmax, respectively. The concomitant 
use of apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, 
phenobarbital or St. John’s Wort) may also lead to reduced apixaban plasma concentrations. No dose 
adjustment for apixaban is required during concomitant therapy with such medicinal products, 
however in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 
and P-gp apixaban should be used with caution for the prevention of VTE in elective hip or knee 
replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and 
for the prevention of recurrent DVT and PE. 
 
Apixaban is not recommended for the treatment of DVT and PE in patients receiving concomitant 
systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be 
compromised (see section 4.4). 
 
Anticoagulants, platelet aggregation inhibitors, SSRIs/SNRIs and NSAIDs 
Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is 
contraindicated 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 (see section 4.3). 
 
After combined administration of enoxaparin (40 mg single dose) with apixaban (5 mg single dose), 
an additive effect on anti-Factor Xa activity was observed. 
 
Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was 
coadministered with ASA 325 mg once a day. 
 
Apixaban coadministered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 
75 mg and ASA 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) in 
Phase I studies did not show a relevant increase in template bleeding time, or further inhibition of 
platelet aggregation, compared to administration of the antiplatelet agents without apixaban. Increases 
in clotting tests (PT, INR, and aPTT) were consistent with the effects of apixaban alone. 
 
Naproxen (500 mg), an inhibitor of P-gp, led to a 1.5-fold and 1.6-fold increase in mean apixaban 
AUC and Cmax, respectively. Corresponding increases in clotting tests were observed for apixaban. No 
changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and 
no clinically relevant prolongation of bleeding time was observed after concomitant administration of 
apixaban and naproxen. 
 
 
Despite these findings, there may be individuals with a more pronounced pharmacodynamic response 
when antiplatelet agents are coadministered with apixaban. Apixaban Accord should be used with 
caution when coadministered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because 
these medicinal products typically increase the bleeding risk (see section 4.4). 
 



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There is limited experience of co-administration  with other platelet aggregation inhibitors (such as 
GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As 
such agents increase the bleeding risk, co-administration of these medicinal products with Apixaban 
Accord is not recommended (see section 4.4). 
 
Other concomitant therapies 
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
apixaban was coadministered with atenolol or famotidine. Coadministration of apixaban 10 mg with 
atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of apixaban. 
Following administration of the two medicinal products together, mean apixaban AUC and Cmax were 
15% and 18% lower than when administered alone. The administration of apixaban 10 mg with 
famotidine 40 mg had no effect on apixaban AUC or Cmax. 
 
Effect of apixaban on other medicinal products 
In vitro apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, 
CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 > 45 µM) and weak inhibitory effect on the activity 
of CYP2C19 (IC50 > 20 µM) at concentrations that are significantly greater than peak plasma 
concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a 
concentration up to 20 µM. Therefore, apixaban is not expected to alter the metabolic clearance of 
coadministered medicinal products that are metabolised by these enzymes. Apixaban is not a 
significant inhibitor of P-gp. 
 
In studies conducted in healthy subjects, as described below, apixaban did not meaningfully alter the 
pharmacokinetics of digoxin, naproxen, or atenolol. 
 
Digoxin 
Coadministration of apixaban (20 mg once a day) and digoxin (0.25 mg once a day), a P-gp substrate, 
did not affect digoxin AUC or Cmax. Therefore, apixaban does not inhibit P-gp mediated substrate 
transport. 
 
Naproxen 
Coadministration of single doses of apixaban (10 mg) and naproxen (500 mg), a commonly used 
NSAID, did not have any effect on the naproxen AUC or Cmax. 
 
Atenolol 
Coadministration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, 
did not alter the pharmacokinetics of atenolol. 
 
Activated charcoal 
Administration of activated charcoal reduces apixaban exposure (see section 4.9). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no data from the use of apixaban in pregnant women. Animal studies do not indicate direct 
or indirect harmful effects with respect to reproductive toxicity. Apixaban is not recommended during 
pregnancy. 
 
Breast-feeding 
It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in 
animals have shown excretion of apixaban in milk. In rat milk, a high milk to maternal plasma ratio 
(Cmax about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to 
newborns and infants cannot be excluded. 
 
A decision must be made to either discontinue breast-feeding or to discontinue/abstain from apixaban 
therapy. 
 



12 

Fertility 
Studies in animals dosed with apixaban have shown no effect on fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Apixaban Accordhas no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety of apixaban has been investigated in 7 Phase III clinical studies including more than 
21,000 patients: more than 5,000 patients in VTEp studies, more than 11,000 patients in NVAF studies 
and more than 4,000 patients in the VTE treatment (VTEt) studies, for an average total exposure of 
20 days, 1.7 years and 221 days respectively (see section 5.1). 
 
Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 2 for 
adverse reaction profile and frequencies by indication). 
 
In the VTEp studies, in total, 11% of the patients treated with apixaban 2.5 mg twice daily experienced 
adverse reactions. The overall incidence of adverse reactions related to bleeding with apixaban was 
10% in the apixaban vs enoxaparin studies. 
 
In the NVAF studies, the overall incidence of adverse reactions related to bleeding with apixaban was 
24.3% in the apixaban vs warfarin study and 9.6% in the apixaban vs acetylsalicylic acid study. In the 
apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, 
lower GI, and rectal bleeding) with apixaban was 0.76%/year. The incidence of ISTH major 
intraocular bleeding with apixaban was 0.18%/year. 
 
In the VTEt studies, the overall incidence of adverse reactions related to bleeding with apixaban was 
15.6% in the apixaban vs enoxaparin/warfarin study and 13.3% in the apixaban vs placebo study (see 
section 5.1). 
 
Tabulated list of adverse reactions 
Table 2 shows the adverse reactions ranked under headings of system organ class and frequency using 
the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 
to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated 
from the available data) for VTEp, NVAF, and VTEt respectively. 
 
Table 2 
System organ class Prevention of 

VTE in adult 
patients who 

have undergone 
elective hip or 

knee replacement 
surgery (VTEp) 

Prevention of 
stroke and 
systemic 

embolism in 
adult patients 

with NVAF, with 
one or more risk 
factors (NVAF) 

Treatment of DVT 
and PE, and 
prevention of 

recurrent DVT and 
PE (VTEt) 

Blood and lymphatic system disorders 

Anaemia  Common Common Common 
Thrombocytopenia  Uncommon Uncommon Common 
Immune system disorders 

Hypersensitivity, allergic oedema and 
anaphylaxis  

Rare Uncommon Uncommon 

Pruritus Uncommon Uncommon Uncommon* 
Nervous system disorders 



13 

System organ class Prevention of 
VTE in adult 
patients who 

have undergone 
elective hip or 

knee replacement 
surgery (VTEp) 

Prevention of 
stroke and 
systemic 

embolism in 
adult patients 

with NVAF, with 
one or more risk 
factors (NVAF) 

Treatment of DVT 
and PE, and 
prevention of 

recurrent DVT and 
PE (VTEt) 

Brain haemorrhage† Not known Uncommon Rare 
Eye disorders 

Eye haemorrhage (including 
conjunctival haemorrhage) 

Rare Common Uncommon 

Vascular disorders 

Haemorrhage, haematoma Common Common Common 
Hypotension (including procedural 
hypotension) 

Uncommon Common Uncommon 

Intra-abdominal haemorrhage Not known Uncommon Not known 
Respiratory, thoracic and mediastinal disorders 

Epistaxis Uncommon Common Common 
Haemoptysis Rare Uncommon Uncommon 
Respiratory tract haemorrhage  Not known Rare Rare 
Gastrointestinal disorders 

Nausea Common Common Common 
Gastrointestinal haemorrhage Uncommon Common Common 
Haemorrhoidal haemorrhage Not known Uncommon Uncommon 
Mouth haemorrhage Not known Uncommon Common 
Haematochezia Uncommon Uncommon Uncommon 
Rectal haemorrhage, gingival 
bleeding 

Rare Common Common 

Retroperitoneal haemorrhage Not known Rare Not known 
Hepatobiliary disorders 

Liver function test abnormal, asparate 
aminotransferase increased, blood 
alkaline phosphatase increased, blood 
bilirubin increased 

Uncommon Uncommon Uncommon 

Gamma-glutamyltransferase 
increased 

Uncommon Common Common 

Alanine aminotransferase increased Uncommon Uncommon Common 
Skin and subcutaneous tissue disorders 

Skin rash Not known Uncommon Common 
Alopecia Rare Uncommon Uncommon 
Musculoskeletal and connective tissue disorders 

Muscle haemorrhage Rare Rare Uncommon 
Renal and urinary disorders 

Haematuria Uncommon Common Common 
Reproductive system and breast disorders 

Abnormal vaginal haemorrhage, 
urogenital haemorrhage 

Uncommon Uncommon Common 

General disorders and administration site conditions 

Application site bleeding Not known Uncommon Uncommon 
Investigations 



14 

System organ class Prevention of 
VTE in adult 
patients who 

have undergone 
elective hip or 

knee replacement 
surgery (VTEp) 

Prevention of 
stroke and 
systemic 

embolism in 
adult patients 

with NVAF, with 
one or more risk 
factors (NVAF) 

Treatment of DVT 
and PE, and 
prevention of 

recurrent DVT and 
PE (VTEt) 

Occult blood positive Not known Uncommon Uncommon 
Injury, poisoning and procedural complications 

Contusion Common Common Common 

Post procedural haemorrhage 
(including post procedural 
haematoma, wound haemorrhage, 
vessel puncture site haematoma and 
catheter site haemorrhage), wound 
secretion, incision site haemorrhage 
(including incision site haematoma), 
operative haemorrhage 

Uncommon Uncommon Uncommon 

Traumatic haemorrhage Not known Uncommon Uncommon 
* There were no occurrences of generalised pruritus in CV185057 (long term prevention of VTE)  
†

 The term “Brain haemorrhage” encompasses all intracranial or intraspinal haemorrhages (ie., haemorrhagic stroke or 
putamen, cerebellar, intraventricular, or subdural haemorrhages). 
 
The use of Apixaban Accordmay be associated with an increased risk of occult or overt bleeding from 
any tissue or organ, which may result in posthaemorrhagic anaemia. The signs, symptoms, and 
severity will vary according to the location and degree or extent of the bleeding (see sections 4.4 and 
5.1). 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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 or the 
administration of a reversal agent for factor Xa inhibitors 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 adverseevents. 
 
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. 
 
For situations when reversal of anticoagulation is needed due to life-threatening or uncontrolled 
bleeding, a reversal agent for factor Xa inhibitors is available (see section 4.4). Administration of 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


15 

prothrombin complex concentrates (PCCs) or recombinant factor VIIa may be considered. Reversal of 
Apixaban Accordpharmacodynamic 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 medicinal products to reverse bleeding in individuals who have received Apixaban 
Accord. 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF02 
 
Mechanism of action 
Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It 
does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound 
factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but 
indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban 
prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal 
models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis 
at doses that preserved haemostasis. 
 
Pharmacodynamic effects 
The pharmacodynamic effects of apixaban are reflective of the mechanism of action (FXa inhibition). 
As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR and 
activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected 
therapeutic dose are small and subject to a high degree of variability. They are not recommended to 
assess the pharmacodynamic effects of apixaban. In the thrombin generation assay, apixaban reduced 
endogenous thrombin potential, a measure of thrombin generation in human plasma. 
 
Apixaban also demonstrates anti-FXa activity as evident by reduction in Factor Xa enzyme activity in 
multiple commercial anti-FXa kits, however results differ across kits. Data from clinical trials are only 
available for the Rotachrom® Heparin chromogenic assay. Anti-FXa activity exhibits a close direct 
linear relationship with apixaban plasma concentration, reaching maximum values at the time of 
apixaban peak plasma concentrations. The relationship between apixaban plasma concentration and 
anti-FXa activity is approximately linear over a wide dose range of apixaban. 
 
Table 3 below shows the predicted steady state exposure and anti-Factor Xa activity for each 
indication. In patients taking apixaban for the prevention of VTE following hip or knee replacement 
surgery, the results demonstrate a less than 1.6-fold fluctuation in peak-to-trough levels. In 
non-valvular atrial fibrillation patients taking apixaban for the prevention of stroke and systemic 
embolism, the results demonstrate a less than 1.7-fold fluctuation in peak-to-trough levels. In patients 
taking apixaban for the treatment of DVT and PE or prevention of recurrent DVT and PE, the results 
demonstrate a less than 2.2-fold fluctuation in peak-to-trough levels. 



16 

Table 3: Predicted apixaban steady-state exposure and anti-Xa activity 

 Apix. 
Cmax (ng/mL) 

Apix. 
Cmin (ng/mL) 

Apix. anti-Xa 
activity max 

(IU/mL) 

Apix. anti-Xa 
activity min 

(IU/mL) 

 Median [5th, 95th Percentile] 

Prevention of VTE: elective hip or knee replacement surgery 

2.5 mg twice daily 77 [41, 146] 51 [23, 109] 1.3 [0.67, 2.4] 0.84 [0.37, 1.8] 

Prevention of stroke and systemic embolism: NVAF 

2.5 mg twice 
daily* 

123 [69, 221] 79 [34, 162] 1.8 [1.0, 3.3] 1.2 [0.51, 2.4] 

5 mg twice daily 171 [91, 321] 103 [41, 230] 2.6 [1.4, 4.8] 1.5 [0.61, 3.4] 

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) 

2.5 mg twice daily 67 [30, 153] 32 [11, 90] 1.0 [0.46, 2.5] 0.49 [0.17, 1.4] 

5 mg twice daily 132 [59, 302] 63 [22, 177] 2.1 [0.91, 5.2] 1.0 [0.33, 2.9] 

10 mg twice daily 251 [111, 572] 120 [41, 335] 4.2 [1.8, 10.8] 1.9 [0.64, 5.8] 
* Dose adjusted population based on 2 of 3 dose reduction criteria in the ARISTOTLE study. 
 
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. 
 
Clinical efficacy and safety 
 
Prevention of VTE (VTEp): elective hip or knee replacement surgery 
The apixaban clinical program was designed to demonstrate the efficacy and safety of apixaban for the 
prevention of VTE in a broad range of adult patients undergoing elective hip or knee replacement. A 
total of 8,464 patients were randomised in two pivotal, double-blind, multi-national studies, comparing 
apixaban 2.5 mg given orally twice daily (4,236 patients) or enoxaparin 40 mg once daily 
(4,228 patients). Included in this total were 1,262 patients (618 in the apixaban group) of age 75 or 
older, 1,004 patients (499 in the apixaban group) with low body weight (≤ 60 kg), 1,495 patients 
(743 in the apixaban group) with BMI ≥ 33 kg/m2, and 415 patients (203 in the apixaban group) with 
moderate renal impairment. 
 
The ADVANCE-3 study included 5,407 patients undergoing elective hip replacement, and the 
ADVANCE-2 study included 3,057 patients undergoing elective knee replacement. Subjects received 
either apixaban 2.5 mg given orally twice daily (po bid) or enoxaparin 40 mg administered 
subcutaneously once daily (sc od). The first dose of apixaban was given 12 to 24 hours post-surgery, 
whereas enoxaparin was started 9 to 15 hours prior to surgery. Both apixaban and enoxaparin were 
given for 32-38 days in the ADVANCE-3 study and for 10-14 days in the ADVANCE-2 study. 
 
Based on patient medical history in the studied population of ADVANCE-3 and ADVANCE-2 
(8,464 patients), 46% had hypertension, 10% had hyperlipidemia, 9% had diabetes, and 8% had 
coronary artery disease. 
 
Apixaban demonstrated a statistically superior reduction in the primary endpoint, a composite of all 
VTE/all cause death, and in the Major VTE endpoint, a composite of proximal DVT, non-fatal PE, and 
VTE-related death, compared to enoxaparin in both elective hip or knee replacement surgery (see 
Table 4). 
 



17 

Table 4: Efficacy results from pivotal phase III studies 
Study ADVANCE-3 (hip) ADVANCE-2 (knee) 
Study treatment 
Dose 
Duration of treatment  

Apixaban 
2.5 mg po 
twice daily 

35 ± 3 d 

Enoxaparin 
40 mg sc 

once daily 
35 ± 3 d 

p-value Apixaban 
2.5 mg po 
twice daily 

12 ± 2 d 

Enoxaparin 
40 mg sc 

once daily 
12 ± 2 d 

p-value 

Total VTE/all-cause death 
Number of 
events/subjects 
Event rate 

27/1,949 
1.39% 

74/1,917 
3.86% < 0.000

1 

147/976 
15.06% 

243/997 
24.37% 

<0.0001 
Relative risk 
95% CI 

0.36 
(0.22, 0.54) 

 0.62 
(0.51, 0.74) 

 

Major VTE 
Number of 
events/subjects 
Event rate 

10/2,199 
0.45% 

25/2,195 
1.14% 

0.0107 

13/1,195 
1.09% 

26/1,199 
2.17% 

0.0373 
Relative risk 
95% CI 

0.40 
(0.15, 0.80) 

 0.50 
(0.26, 0.97) 

 

 
The safety endpoints of major bleeding, the composite of major and clinically relevant non-major 
(CRNM) bleeding, and all bleeding showed similar rates for patients treated with apixaban 2.5 mg 
compared with enoxaparin 40 mg (see Table 5). All the bleeding criteria included surgical site 
bleeding. 
 
Table 5: Bleeding results frompivotal phase III studies* 
 ADVANCE-3 ADVANCE-2 
 Apixaban 

2.5 mg po twice 
daily 

35 ± 3 d 

Enoxaparin 
40 mg sc once 

daily 
35 ± 3 d 

Apixaban 
2.5 mg po twice 

daily 
12 ± 2 d 

Enoxaparin 
40 mg sc once daily 

12 ± 2 d 

All treated n = 2,673 n = 2,659 n = 1,501 n = 1,508 
Treatment Period 1 
Major 22 (0.8%) 18 (0.7%) 9 (0.6%) 14 (0.9%) 
 Fatal 0 0 0 0 
Major + CRNM 129 (4.8%) 134 (5.0%) 53 (3.5%) 72 (4.8%) 
All 313 (11.7%) 334 (12.6%) 104 (6.9%) 126 (8.4%) 
Post-surgery treatment period 2 
Major 9 (0.3%) 11 (0.4%) 4 (0.3%) 9 (0.6%) 
 Fatal 0 0 0 0 
Major + CRNM 96 (3.6%) 115 (4.3%) 41 (2.7%) 56 (3.7%) 
All 261 (9.8%) 293 (11.0%) 89 (5.9%) 103 (6.8%) 

* All the bleeding criteria included surgical site bleeding 
1 Includes events occurring after first dose of enoxaparin (pre-surgery) 
2 Includes events occurring after first dose of apixaban (post-surgery) 
 
The overall incidences of adverse reactions of bleeding, anaemia and abnormalities of transaminases 
(e.g., ALT levels) were numerically lower in patients on apixaban compared to enoxaparin in the 
phase II and phase III studies in elective hip and knee replacement surgery. 
 
In the knee replacement surgery study during the intended treatment period, in the apixaban arm 
4 cases of PE were diagnosed against no cases in the enoxaparin arm. No explanation can be given to 
this higher number of PE. 
 



18 

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) 
A total of 23,799 patients were randomised in the clinical program (ARISTOTLE: apixaban versus 
warfarin, AVERROES: apixaban versus ASA) including 11,927 randomised to apixaban. The program 
was designed to demonstrate the efficacy and safety of apixaban for the prevention of stroke and 
systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and one or more additional 
risk factors, such as:  
• prior stroke or transient ischaemic attack (TIA) 
• age ≥ 75 years 
• hypertension 
• diabetes mellitus 
• symptomatic heart failure (NYHA Class ≥ II) 

 
ARISTOTLE STUDY 
In the ARISTOTLE study a total of 18,201 patients were randomised to double-blind treatment with 
apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [4.7%], see section 4.2) or 
warfarin (target INR range 2.0-3.0), patients were exposed to study drug for a mean of 20 months. The 
mean age was 69.1 years, the mean CHADS2 score was 2.1 and 18.9% of patients had prior stroke or 
TIA. 
 
In the study, apixaban achieved statistically significant superiority in the primary endpoint of 
prevention of stroke (haemorrhagic or ischaemic) and systemic embolism (see Table 6) compared with 
warfarin. 
 
Table 6: Efficacy outcomes in patients with atrial fibrillation in the ARISTOTLE study 
 Apixaban  

N=9,120 
n (%/yr) 

Warfarin  
N=9,081 
n (%/yr) 

Hazard ratio 
(95% CI) 

 
p-value 

Stroke or systemic embolism 212 (1.27) 265 (1.60) 0.79 (0.66, 0.95) 0.0114 
Stroke     

Ischaemic or unspecified 162 (0.97) 175 (1.05) 0.92 (0.74, 1.13)  
Haemorrhagic 40 (0.24) 78 (0.47) 0.51 (0.35, 0.75)  

Systemic embolism 15 (0.09) 17 (0.10) 0.87 (0.44, 1.75)  
 
For patients randomised to warfarin, the median percentage of time in therapeutic range (TTR) 
(INR 2-3) was 66%. 
 
Apixaban showed a reduction of stroke and systemic embolism compared to warfarin across the 
different levels of center TTR; within the highest quartile of TTR according to center, the hazard ratio 
for apixaban vs warfarin was 0.73 (95% CI, 0.38, 1.40). 
 
Key secondary endpoints of major bleeding and all cause death were tested in a pre-specified 
hierarchical testing strategy to control the overall type 1 error in the trial. Statistically significant 
superiority was also achieved in the key secondary endpoints of both major bleeding and all-cause 
death (see Table 7). With improving monitoring of INR the observed benefits of apixaban compared to 
warfarin regarding all cause death diminish. 
 



19 

Table 7: Secondary endpoints in patients with atrial fibrillation in the ARISTOTLE study 
 Apixaban 

N = 9,088 
n (%/year) 

Warfarin 
N = 9,052 

n (%/year) 

Hazard ratio 
(95% CI) 

p-value 

Bleeding outcomes 
Major* 327 (2.13) 462 (3.09) 0.69 (0.60, 0.80) < 0.0001 

Fatal 10 (0.06) 37 (0.24)   
Intracranial 52 (0.33) 122 (0.80)   

Major + CRNM 613 (4.07) 877 (6.01) 0.68 (0.61, 0.75) < 0.0001 
All 2356 (18.1) 3060 (25.8) 0.71 (0.68, 0.75) < 0.0001 

Other endpoints 
All-cause death 603 (3.52) 669 (3.94) 0.89 (0.80, 1.00) 0.0465 
Myocardial 
infarction 

90 (0.53)  102 (0.61) 0.88 (0.66, 1.17)  

* Major bleeding defined per International Society on Thrombosis and Haemostasis (ISTH) criteria. 
 
The overall discontinuation rate due to adverse reactions was 1.8% for apixaban and 2.6% for warfarin 
in the ARISTOTLE study. 
 
The efficacy results for prespecified subgroups, including CHADS2 score, age, body weight, gender, 
status of renal function, prior stroke or TIA and diabetes were consistent with the primary efficacy 
results for the overall population studied in the trial. 
 
The incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal 
bleeding) was 0.76%/year with apixaban and 0.86%/year with warfarin. 
 
The major bleeding results for prespecified subgroups including CHADS2 score, age, body weight, 
gender, status of renal function, prior stroke or TIA and diabetes were consistent with the results for 
the overall population studied in the trial. 
 
AVERROES STUDY 
In the AVERROES study a total of 5,598 patients considered to be unsuitable for VKA by the 
investigators were randomised to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in 
selected patients [6.4%], see section 4.2) or ASA. ASA was given at a once daily dose of 81 mg 
(64%), 162 (26.9%), 243 (2.1%), or 324 mg (6.6%) at the discretion of the investigator. Patients were 
exposed to study drug for a mean of 14 months. The mean age was 69.9 years, the mean CHADS2 
score was 2.0 and 13.6% of patients had prior stroke or TIA. 
 
Common reasons for unsuitability for VKA therapy in the AVERROES study included 
unable/unlikely to obtain INRs at requested intervals (42.6%), patient refused treatment with VKA 
(37.4%), CHADS2 score = 1 and physician did not recommend VKA (21.3%), patient could not be 
relied on to adhere to VKA medicinal product instruction (15.0%), and difficulty/expected difficulty in 
contacting patient in case of urgent dose change (11.7%). 
 
AVERROES was stopped early based on a recommendation by the independent Data Monitoring 
Committee due to clear evidence of reduction of stroke and systemic embolism with an acceptable 
safety profile. 
 
The overall discontinuation rate due to adverse reactions was 1.5% for apixaban and 1.3% for ASA in 
the AVERROES study. 
 
In the study, apixaban achieved statistically significant superiority in the primary endpoint of 
prevention of stroke (haemorrhagic, ischaemic or unspecified) or systemic embolism (see Table 8) 
compared to ASA. 
 



20 

Table 8: Key efficacy outcomes in patients with atrial fibrillation in the AVERROES study 
 Apixaban 

N = 2,807  
n (%/year) 

ASA  
N = 2,791 

n (%/year) 

Hazard ratio 
(95% CI) 

 
p-value 

Stroke or systemic embolism* 51 (1.62) 113 (3.63) 0.45 (0.32, 0.62) < 0.0001 
Stroke     

Ischaemic or unspecified 43 (1.37) 97 (3.11) 0.44 (0.31, 0.63)  
Haemorrhagic 6 (0.19) 9 (0.28) 0.67 (0.24, 1.88)  

Systemic embolism 2 (0.06) 13 (0.41) 0.15 (0.03, 0.68)  
Stroke, systemic embolism, 
MI, or vascular death*† 

132 (4.21) 197 (6.35) 0.66 (0.53, 0.83) 0.003 

Myocardial infarction 24 (0.76) 28 (0.89) 0.86 (0.50, 1.48)  
Vascular death 84 (2.65) 96 (3.03) 0.87 (0.65, 1.17)  

All-cause death† 111 (3.51) 140 (4.42) 0.79 (0.62, 1.02) 0.068 
* Assessed by sequential testing strategy designed to control the overall type I error in the trial. 
† Secondary endpoint. 
 
There was no statistically significant difference in the incidence of major bleeding between apixaban 
and ASA (see Table 9). 
 
Table 9: Bleeding events in patients with atrial fibrillation in the AVERROES study 

 Apixaban 
N = 2,798 
n(%/year) 

ASA 
N = 2,780 

n (%/year) 

Hazard ratio 
(95%CI) 

p-value 

Major* 45 (1.41) 29 (0.92) 1.54 (0.96, 2.45)  0.0716 
Fatal, n 5 (0.16) 5 (0.16)   
Intracranial, n 11 (0.34) 11 (0.35)   

Major + CRNM† 140 (4.46) 101 (3.24) 1.38 (1.07, 1.78) 0.0144 
All 325 (10.85) 250 (8.32) 1.30 (1.10, 1.53) 0.0017 
*Major bleeding defined per International Society on Thrombosis ad Haemostasis (ISTH) criteria. 
† Clinically Relevant Non-Major 
 
NVAF patients with ACS and/or undergoing PCI 
AUGUSTUS, an open-label, randomised , controlled, 2 by 2 factorial design trial, enrolled 4,614 
patients with NVAF who had ACS (43%) and/or underwent PCI (56%). All patients 
receivedbackground therapy with a P2Y12 inhibitor (clopidogrel: 90.3%) prescribed per local standard 
of care. 
 
Patients were randomised, up to 14 days after the ACS and/or PCI to either apixaban 5 mg twice 
daily(2.5 mg twice daily if two or more of the dose-reduction criteria were met; 10% received lower 
dose)or VKA and to either ASA (81 mg once daily) or placebo. The mean age was 69.9 years, 94% 
ofpatients randomised, had a CHA2DS2-VASc score > 2, and 47% had a HAS-BLED score > 3. 
Forpatients randomised to VKA, the proportion of time in therapeutic range (TTR) (INR 2-3) was 
56%,with 32% of time below TTR and 12% above TTR. 
 
The primary objective of AUGUSTUS was to assess safety, with a primary endpoint of ISTH major 
orCRNM bleeding. In the apixaban versus VKA comparison, the primary safety endpoint of ISTH 
majoror CRNM bleeding at month 6 occurred in 241 (10.5%), and 332 (14.7%) patients in the 
apixaban armand in the VKA arm respectively (HR=0.69, 95% CI: 0.58, 0.82; 2-sided p<0.0001 for 
non-inferiorityand p<0.0001 for superiority). For VKA, additional analyses using subgroups by TTR 
showed that thehighest rate of bleeding was associated with the lowest quartile of TTR. The rate of 
bleeding wassimilar between apixaban and the highest quartile of TTR. 
 
In the ASA versus placebo comparison, the primary safety endpoint of ISTH major or CRNMbleeding 
at month 6 occurred in 367 (16.1%), and 204 (9.0%) patients in the ASA arm and in theplacebo arm 
respectively (HR=1.88, 95% CI: 1.58, 2.23; two-sided p<0.0001). 



21 

 
Specifically, in apixaban-treated patients, major or CRNM bleeding occurred in 157 (13.7%), and 84 
(7.4%) patients in the ASA arm and in the placebo arm respectively. In VKA-treated patients, major 
orCRNM bleeding occurred in 208 (18.5%), and 122 (10.8%) patients in the ASA arm and in 
theplacebo arm respectively. 
 
Other treatment effects were evaluated as a secondary objective of the study, with 
compositeendpoints. 
In the apixaban versus VKA comparison, the composite endpoint of death or re-hospitalization 
occurred in 541 (23.5%) and 632 (27.4%) patients in the apixaban and in the VKA arm, 
respectively.The composite endpoint of death or ischemic event (stroke, myocardial infarction, stent 
thrombosis or urgent revascularization) occurred in 170 (7.4%), and 182 (7.9%) patients in the 
apixaban and in the 
VKA arm, respectively. 
In the ASA versus placebo comparison, the composite endpoint of death or re-hospitalization 
occurredin 604 (26.2%) and 569 (24.7%) patients in the ASA and in the placebo arm, respectively. 
Thecomposite endpoint of death or ischemic event (stroke, myocardial infarction, stent thrombosis 
orurgent revascularization) occurred in 163 (7.1%), and 189 (8.2%) patients in the ASA and in 
theplacebo arm, respectively. 
 
Patients undergoing cardioversion 
EMANATE, an open-label, multi-center study, enrolled 1500 patients who were either oral 
anticoagulant naïve or pre-treated less than 48 hours, and scheduled for cardioversion for NVAF. 
Patients were randomised, 1:1 to apixaban or to heparin and/or VKA for the prevention of 
cardiovascular events. Electrical and/or pharmacologic cardioversion was conducted after at least 5 
doses of 5 mg twice daily apixaban (or 2.5 mg twice daily in selected patients (see section 4.2)) or at 
least 2 hours after a 10 mg loading dose (or a 5 mg loading dose in selected patients (see section 4.2)) 
if earlier cardioversion was required. In the apixaban group, 342 patients received a loading dose (331 
patients received the 10 mg dose and 11 patients received the 5 mg dose). 
 
There were no strokes (0%) in the apixaban group (n= 753) and 6 (0.80%) strokes in the heparin 
and/or VKA group (n = 747; RR 0.00, 95% CI 0.00, 0.64). All-cause death occurred in 2 patients 
(0.27%) in the apixaban group and 1 patient (0.13%) in the heparin and/or VKA group. No systemic 
embolism events were reported. 
 
Major bleeding and CRNM bleeding events occurred in 3 (0.41%) and 11 (1.50%) patients, 
respectively, in the apixaban group, compared to 6 (0.83%) and 13 (1.80%) patients in the heparin 
and/or VKA group. 
 
This exploratory study showed comparable efficacy and safety between apixaban and heparin and/or 
VKA treatment groups in the setting of cardioversion. 
 
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) 
The clinical program (AMPLIFY: apixaban versus enoxaparin/warfarin, AMPLIFY-EXT: apixaban 
versus placebo) was designed to demonstrate the efficacy and safety of apixaban for the treatment of 
DVT and/or PE (AMPLIFY), and extended therapy for the prevention of recurrent DVT and/or PE 
following 6 to 12 months of anticoagulant treatment for DVT and/or PE (AMPLIFY-EXT). Both 
studies were randomised, parallel-group, double-blind, multinational trials in patients with 
symptomatic proximal DVT or symptomatic PE. All the key safety and efficacy endpoints were 
adjudicated by an independent blinded committee. 
 
AMPLIFY STUDY  
In the AMPLIFY study a total of 5,395 patients were randomised to treatment with apixaban 10 mg 
twice daily orally for 7 days followed by apixaban 5 mg twice daily orally for 6 months, or enoxaparin 
1 mg/kg twice daily subcutaneously for at least 5 days (until INR≥ 2) and warfarin (target INR range 
2.0-3.0) orally for 6 months. 
 



22 

The mean age was 56.9 years and 89.8% of randomised patients had unprovoked VTE events. 
 
For patients randomised to warfarin, the mean percentage of time in therapeutic range (INR 2.0-3.0) 
was 60.9. Apixaban showed a reduction in recurrent symptomatic VTE or VTE- related death across 
the different levels of center TTR; within the highest quartile of TTR according to center, the relative 
risk for apixaban vs enoxaparin/warfarin was 0.79 (95% CI, 0.39, 1.61). 
 
In the study, apixaban was shown to be non-inferior to enoxaparin/warfarin in the combined primary 
endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related 
death (see Table 10). 
 
Table 10: Efficacy results in the AMPLIFY study 
 Apixaban 

N=2,609 
n (%) 

Enoxaparin/warfari
n 

N=2,635 
n (%) 

Relative risk 
(95% CI) 

VTE or VTE-related 
death 

59 (2.3) 71 (2.7) 0.84 (0.60, 1.18)* 

 DVT 20 (0.7) 33 (1.2)  

 PE 27 (1.0) 23 (0.9)  

 VTE-related 
 death 

12 (0.4) 15 (0.6)  

VTE or all-cause 
death 

84 (3.2) 104 (4.0) 0.82 (0.61, 1.08) 

VTE or CV-related 
death 

61 (2.3) 77 (2.9) 0.80 (0.57, 1.11) 

VTE, VTE-related 
death, or major 
bleeding 

73 (2.8) 118 (4.5) 0.62 (0.47, 0.83) 

* Noninferior compared to enoxaparin/warfarin (p-value <0.0001) 
 
Apixaban efficacy in initial treatment of VTE was consistent between patients who were treated for a 
PE [Relative Risk 0.9; 95% CI (0.5, 1.6)] or DVT [Relative Risk 0.8; 95% CI (0.5, 1.3)]. Efficacy 
across subgroups, including age, gender, body mass index (BMI), renal function, extent of index PE, 
location of DVT thrombus, and prior parenteral heparin use was generally consistent. 
 
The primary safety endpoint was major bleeding. In the study, apixaban was statistically superior to 
enoxaparin/warfarin in the primary safety endpoint [Relative Risk 0.31, 95% confidence interval 
(0.17, 0.55), P-value <0.0001] (see Table 11). 
 
Table 11: Bleeding results in the AMPLIFY study 
 Apixaban 

N=2,676 
n (%) 

Enoxaparin/ 
warfarin 
N=2,689 

n (%) 

Relative risk 
(95% CI) 

Major 15 (0.6) 49 (1.8) 0.31 (0.17, 0.55) 

Major + CRNM 115 (4.3) 261 (9.7) 0.44 (0.36, 0.55) 

Minor 313 (11.7) 505 (18.8) 0.62 (0.54, 0.70) 

All 402 (15.0) 676 (25.1) 0.59 (0.53, 0.66) 
 



23 

The adjudicated major bleeding and CRNM bleeding at any anatomical site were generally lower in 
the apixaban group as compared to the enoxaparin/warfarin group. Adjudicated ISTH major 
gastrointestinal bleeding occurred in 6 (0.2%) apixaban-treated patients and 17 (0.6%) 
enoxaparin/warfarin-treated patients. 
 
AMPLIFY-EXT STUDY 
In the AMPLIFY-EXT study a total of 2,482 patients were randomised to treatment with apixaban 
2.5 mg twice daily orally, apixaban 5 mg twice daily orally, or placebo for 12 months after completing 
6 to 12 months of initial anticoagulant treatment. Of these, 836 patients (33.7%) participated in the 
AMPLIFY study prior to enrollment in the AMPLIFY-EXT study. 
 
The mean age was 56.7 years and 91.7% of randomised patients had unprovoked VTE events. 
 
In the study, both doses of apixaban were statistically superior to placebo in the primary endpoint of 
symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death (see Table 12). 
 
Table 12: Efficacy results in the AMPLIFY-EXT study 
 Apixaban  Apixaban Placebo Relative risk (95% CI) 

 2.5 mg 
(N=840) 

5.0 mg 
(N=813) 

 
(N=829) 

Apix 2.5 mg 
vs. placebo 

Apix 5.0 mg 
vs. placebo 

 n (%)   

Recurrent 
VTE or all-
cause death 

19 (2.3) 14 (1.7) 77 (9.3) 0.24 
(0.15, 0.40)¥ 

0.19 
(0.11, 0.33)¥ 

DVT* 6 (0.7) 7 (0.9) 53 (6.4)   

PE* 7 (0.8) 4 (0.5) 13 (1.6)   

All-cause 
death 

6 (0.7) 3 (0.4) 11 (1.3)   

Recurrent 
VTE or VTE-
related death 

14 (1.7) 14 (1.7) 73 (8.8) 0.19 
(0.11, 0.33) 

0.20 
(0.11, 0.34) 

Recurrent 
VTE or CV-
related death 

14 (1.7) 14 (1.7) 76 (9.2) 0.18 
(0.10, 0.32) 

0.19 
(0.11, 0.33) 

Nonfatal 
DVT† 

6 (0.7) 8 (1.0) 53 (6.4) 0.11 
(0.05, 0.26) 

0.15 
(0.07, 0.32) 

Nonfatal PE† 8 (1.0) 4 (0.5) 15 (1.8) 0.51 
(0.22, 1.21) 

0.27 
(0.09, 0.80) 

VTE-related 
death 

2 (0.2) 3 (0.4) 7 (0.8) 0.28 
(0.06, 1.37) 

0.45 
(0.12, 1.71) 

¥ p-value < 0.0001 
* For patients with more than one event contributing to the composite endpoint, only the first event was reported (eg, if a 
subject experienced both a DVT and then a PE, only the DVT was reported) 
† Individual subjects could experience more than one event and be represented in both classifications 
 
Apixaban efficacy for prevention of a recurrence of a VTE was maintained across subgroups, 
including age, gender, BMI, and renal function. 
 
The primary safety endpoint was major bleeding during the treatment period. In the study, the 
incidence in major bleeding for both apixaban doses was not statistically different from placebo. There 



24 

was no statistically significant difference in the incidence of major + CRNM, minor, and all bleeding 
between the apixaban 2.5 mg twice daily and placebo treatment groups (see Table 13). 
 
Table 13: Bleeding results in the AMPLIFY-EXT study 
 Apixaban  Apixaban Placebo Relative risk (95% CI) 

 2.5 mg 
(N=840) 

5.0 mg 
(N=811) 

 
(N=826) 

Apix 2.5 mg 
vs. placebo 

Apix 5.0 mg 
vs. placebo 

  n (%)    

Major 2 (0.2) 1 (0.1) 4 (0.5) 0.49 
(0.09, 2.64) 

0.25 
(0.03, 2.24) 

Major + 
CRNM 

27 (3.2) 35 (4.3) 22 (2.7) 1.20 
(0.69, 2.10) 

1.62 
(0.96, 2.73) 

Minor 75 (8.9) 98 (12.1) 58 (7.0) 1.26 
(0.91, 1.75) 

1.70 
(1.25, 2.31)  

All 94 (11.2) 121 (14.9) 74 (9.0) 1.24 
(0.93, 1.65) 

1.65 
(1.26, 2.16)  

 
Adjudicated ISTH major gastrointestinal bleeding occurred in 1 (0.1%) apixaban-treated patient at the 
5 mg twice daily dose, no patients at the 2.5 mg twice daily dose, and 1 (0.1%) placebo-treated patient. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Apixabanin one or more subsets of the paediatric population in venous and arterial embolism and 
thrombosis (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is 
rapidly absorbed with maximum concentrations (Cmax) appearing 3 to 4 hours after tablet intake. Intake 
with food does not affect apixaban AUC or Cmax at the 10 mg dose. Apixaban can be taken with or 
without food. 
 
Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral 
doses up to 10 mg. At doses ≥ 25 mg apixaban displays dissolution limited absorption with decreased 
bioavailability. Apixaban exposure parameters exhibit low to moderate variability reflected by a 
within-subject and inter-subject variability of ~20% CV and ~30% CV, respectively. 
 
Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of 
water, exposure was comparable to exposure after oral administration of 2 whole 5 mg tablets. 
Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets with 30 g of apple 
puree, the Cmax and AUC were 21% and 16% lower, respectively, when compared to administration of 
2 whole 5 mg tablets. The reduction in exposure is not considered clinically relevant. 
 
Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of G5W and 
delivered via a nasogastric tube, exposure was similar to exposure seen in other clinical trials 
involving healthy subjects receiving a single oral 5 mg apixaban tablet dose. 
 
Given the predictable, dose-proportional pharmacokinetic profile of apixaban, the bioavailability 
results from the conducted studies are applicable to lower apixaban doses. 
 



25 

Distribution 
Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is 
approximately 21 litres. 
 
Biotransformation and elimination 
Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, 
approximately 25% was recovered as metabolites, with the majority recovered in faeces. Renal 
excretion of apixaban accounts for approximately 27% of total clearance. Additional contributions 
from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, 
respectively. 
 
Apixaban has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours. 
 
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. Unchanged apixaban is the major drug-related component in 
human plasma with no active circulating metabolites present. Apixaban is a substrate of transport 
proteins, P-gp and breast cancer resistance protein (BCRP). 
 
Renal impairment 
There was no impact of impaired renal function on peak concentration of apixaban. There was an 
increase in apixaban exposure correlated to decrease in renal function, as assessed via measured 
creatinine clearance. In individuals with mild (creatinine clearance 51-80 mL/min), moderate 
(creatinine clearance 30-50 mL/min) and severe (creatinine clearance 15-29 mL/min) renal 
impairment, apixaban plasma concentrations (AUC) were increased 16, 29, and 44% respectively, 
compared to individuals with normal creatinine clearance. Renal impairment had no evident effect on 
the relationship between apixaban plasma concentration and anti-FXa activity. 
 
In subjects with end-stage renal disease (ESRD), the AUC of apixaban was increased by 36% when a 
single dose of apixaban 5 mg was administered immediately after haemodialysis, compared to that 
seen in subjects with normal renal function. Haemodialysis, started two hours after administration of a 
single dose of apixaban 5 mg, decreased apixaban AUC by 14% in these ESRD subjects, 
corresponding to an apixaban dialysis clearance of 18 mL/min. Therefore, haemodialysis is unlikely to 
be an effective means of managing apixaban overdose. 
 
Hepatic impairment 
In a study comparing 8 subjects with mild hepatic impairment, Child-Pugh A score 5 (n = 6) and 
score 6 (n = 2), and 8 subjects with moderate hepatic impairment, Child-Pugh B score 7 (n = 6) and 
score 8 (n = 2), to 16 healthy control subjects, the single-dose pharmacokinetics and 
pharmacodynamics of apixaban 5 mg were not altered in subjects with hepatic impairment. Changes in 
anti-Factor Xa activity and INR were comparable between subjects with mild to moderate hepatic 
impairment and healthy subjects. 
 
Elderly 
Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with 
mean AUC values being approximately 32% higher and no difference in Cmax. 
 
Gender 
Exposure to apixaban was approximately 18% higher in females than in males. 
 
Ethnic origin and race 
The results across phase I studies showed no discernible difference in apixaban pharmacokinetics 
between White/Caucasian, Asian and Black/African American subjects. Findings from a population 
pharmacokinetic analysis in patients who received apixaban were generally consistent with the phase I 
results. 
 



26 

Body weight 
Compared to apixaban exposure in subjects with body weight of 65 to 85 kg, body weight > 120 kg 
was associated with approximately 30% lower exposure and body weight < 50 kg was associated with 
approximately 30% higher exposure.  
 
Pharmacokinetic/pharmacodynamics  relationship 
The pharmacokinetic /pharmacodynamic (PK/PD) relationship between apixaban plasma 
concentration and several PD endpoints (anti-FXa activity, INR, PT, aPTT) has been evaluated after 
administration of a wide range of doses (0.5 – 50 mg). The relationship between apixaban plasma 
concentration and anti-Factor Xa activity was best described by a linear model. The PK/PD 
relationship observed in patients was consistent with that established in healthy subjects. 
 
5.3 Preclinical safety data 
 
Preclinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, fertility and embryo-foetal 
development and juvenile toxicity. 
 
The major observed effects in the repeated dose toxicity studies were those related to the 
pharmacodynamic action of apixaban on blood coagulation parameters. In the toxicity studies little to 
no increase of bleeding tendency was found. However, since this may be due to a lower sensitivity of 
the non-clinical species compared to humans, this result should be interpreted with caution when 
extrapolating to humans. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
 
Lactose 
Cellulose, microcrystalline 
Croscarmellose sodium 
Sodium laurilsulfate  
Magnesium stearate  
 
Film coat: 
 
Hypromellose 
Lactose monohydrate  
Titanium dioxide (E171) 
Triacetin 
Iron oxide yellow (E172) 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage condition. 
 



27 

6.5 Nature and contents of container 
 
PVC/PVdC-Aluminium blisters are available in 10, 14, 20, 28, 56, 60, 100, 112, 168, and 
200 film-coated tablets. 
 
PVC/PVdC-Aluminium blisters are available in perforated unit dose blisters of 10 x 1, 20 x 1, 28 x 1, 
56 x 1, 60 x 1, 100 x 1 and 168 x 1 film-coated tablet. 
 
HDPE bottle with polypropylene child resistant/continues threaded closure containing 60, 100, 168, 
180, 200 and 1,000 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal  
 
No special requirements. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona s/n, 
Edifici Est, 6a Planta, 
Barcelona, 08039 
Spain 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1458/001  
EU/1/20/1458/003  
EU/1/20/1458/004  
EU/1/20/1458/006  
EU/1/20/1458/008  
EU/1/20/1458/010  
EU/1/20/1458/012  
EU/1/20/1458/014   
EU/1/20/1458/041  
EU/1/20/1458/043  
 
EU/1/20/1458/002  
EU/1/20/1458/005  
EU/1/20/1458/007  
EU/1/20/1458/009   
EU/1/20/1458/011  
EU/1/20/1458/013  
EU/1/20/1458/042  
 
EU/1/20/1458/015 
EU/1/20/1458/016 
EU/1/20/1458/017 
EU/1/20/1458/018 
EU/1/20/1458/019 



28 

EU/1/20/1458/020 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 
  

http://www.ema.europa.eu/


29 

1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 5 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 5 mg apixaban. 
 
Excipients with known effect 
Each 5 mg film-coated tablet contains 103.95 mg lactose (see section 4.4). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet) 
 
Pink, oval shaped, approximate 9.8 mm in length, 5.2 mm in width, biconvex, film-coated tablet 
debossed with “IU2” on one side and plain on other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic 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 (see section 4.4 for haemodynamically unstable PE patients). 
 
4.2 Posology and method of administration 
 
Posology 
 
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 



30 

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). 
 
Missed dose 
If a dose is missed, the patient should take Apixaban Accordimmediately and then continue with twice 
daily intake as before. 
 
Switching 
Switching treatment from parenteral anticoagulants to Apixaban Accord(and vice versa) can be done 
at the next scheduled dose (see section 4.5). These medicinal products should not be administered 
simultaneously. 
 
Switching from vitamin K antagonist (VKA) therapy to  Apixaban AccordWhen converting patients 
from vitamin K antagonist (VKA) therapy toApixaban Accord, warfarin or other VKA therapy 
should be discontinued and Apixaban Accord started when the international normalised ratio (INR) 
is < 2. 
 
Switching from Apixaban Accord to VKA therapy 
When converting patients from Apixaban Accordto VKA therapy, administration of Apixaban Accord 
should be continued for at least 2 days after beginning VKA therapy. After 2 days of coadministration 
of Apixaban Accordwith VKA therapy, an INR should be obtained prior to the next scheduled dose of 
Apixaban Accord. Coadministration of Apixaban Accord and VKA therapy should be continued until 
the INR is ≥ 2. 
 
Renal impairment 
In patients with mild or moderate renal impairment, the following recommendations apply: 
 
- 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 treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) 

apixaban is to be used with caution; 
 



31 

-  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 Accordis 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 Apixaban 
Accordshould be used with caution in this population (see sections 4.4 and 5.2). Prior to initiating 
Apixaban Accord, liver function testing should be performed. 
 
Body weight 
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). 
 
Elderly 
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). 
 
Patients undergoing catheter ablation (NVAF) 
Patients can continue apixaban use while undergoing catheter ablation (see sections 4.3, 4.4 and 4.5). 
 
Patients undergoing cardioversion 
Apixaban can be initiated or continued in NVAF patients who may require cardioversion.  
 
For patients not previously treated with anticoagulants, exclusion of left atrial thrombus using an 
image guided approach (e.g. transesophageal echocardiography (TEE) or computed tomographic scan 
(CT)) prior to cardioversion should be considered, in accordance with established medical guidelines. 

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 (see section 5.1). 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 (see above sections Dose reduction and Renal 
impairment). 
 
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). 
 



32 

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. 
 
Patients with NVAF and acute coronary syndrome (ACS) and/or percutaneous coronary intervention 
(PCI) 
There is limited experience of treatment with apixaban at the recommended dose for NVAF patients 
when used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI after 
haemostasis is achieved (see sections 4.4, 5.1). 
 
Paediatric population 
The safety and efficacy of Apixaban Accord in children and adolescents below age 18 have not been 
established. No data are available. 
 
Method of administration 
 
Oral use 
Apixaban Accord should be swallowed with water, with or without food. 
 
For patients who are unable to swallow whole tablets, Apixaban Accord 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 Accordtablets 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 Accord tablets are stable in water,G5W,apple juice,and apple puree for up to 
4 hours. 
 
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 
specific circumstances of switching anticoagulant therapy (see section 4.2) or 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 (see sections 4.4 and 4.5). 

 
4.4 Special warnings and precautions for use 
 
Haemorrhage risk 
As with other anticoagulants, patients taking Apixaban Accordare to be carefully observed for signs of 
bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. 
Apixaban Accordadministration should be discontinued if severe haemorrhage occurs (see sections 4.8 
and 4.9). 
 



33 

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). 
 
An agent to reverse the anti-factor Xa activity of apixaban is available. 
 
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 Apixaban Accord with antiplatelet agents increases the risk of bleeding (see 
section 4.5). 
 
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 
drugs (NSAIDs), including acetylsalicylic acid. 
 
Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with 
Apixaban Accord (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 Apixaban Accord. 
In a clinical trial of patients with atrial fibrillation, concomitant use of   acetylsalicylic acid (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(see section 5.1). 
A clinical trial enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and a planned 
treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either apixaban 
or VKA) for 6 months. Concomitant use of ASA increased the risk of ISTH (International Society on 
Thrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding in 
apixaban-treated subjects from 16.4% per year to 33.1% per year (see section 5.1). 
 
In a clinical trial of high-risk post acute coronary syndrome patientswithout atrial fibrillation, 
characterised 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(see section 4.5). 
 



34 

Patients with prosthetic heart valves 
Safety and efficacy of Apixaban Accordhave not been studied in patients with prosthetic heart valves, 
with or without atrial fibrillation. Therefore, the use of Apixaban Accord is not recommended in this 
setting. 
 
Patients with antiphospholipid syndrome 
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), treatment with DOACs could be associated with increased rates of recurrent thrombotic 
events compared with vitamin K antagonist therapy. 
 
Surgery and invasive procedures 
Apixaban Accordshould 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. 
 
Apixaban Accordshould 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 Accord 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). 
 
For patients undergoing catheter ablation for atrial fibrillation, Apixaban Accord treatment does not 
need to be interrupted (see sections 4.2, 4.3 and 4.5). 
 
Temporary discontinuation 
Discontinuing anticoagulants, including Apixaban Accord, 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 Apixaban Accord must be temporarily discontinued for any 
reason, therapy should be restarted as soon as possible. 
 
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary 
embolectomy 
Apixaban Accord is not recommended as an alternative to unfractionated heparin in patients with 
pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary 
embolectomy since the safety and efficacy of apixaban have not been established in these clinical 
situations.  
 
Patients with active cancer 
Efficacy and safety of apixaban in the treatment of DVT, treatment of PE and prevention of recurrent 
DVT and PE (VTEt) in patients with active cancer have not been established. 
 
Patients with renal impairment 
Limited clinical data indicate that apixaban plasma concentrations are increased in patients with severe 
renal impairment (creatinine clearance 15-29 mL/min) which may lead to an increased bleeding risk. 
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) (see sections 4.2 and 5.2). 
 



35 

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 (see section 4.2); 
 
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 4.2 and 5.2). 
 
Elderly patients 
Increasing age may increase haemorrhagic risk (see section 5.2). 
Also, the co-administration of Apixaban Accord with ASA in elderly patients should be used 
cautiously because of a potentially higher bleeding risk. 
 
Body weight 
Low body weight (< 60 kg) may increase haemorrhagic risk (see section 5.2). 
 
Patients with hepatic impairment 
Apixaban Accordis 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 section 5.2). 
 
It should be used with caution in patients with mild or moderate hepatic impairment (Child Pugh A or 
B) (see sections 4.2 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 Apixaban Accord should be used cautiously in this population 
(see section 5.2). Prior to initiating Apixaban Accord, liver function testing should be performed. 
 
Interaction with inhibitors of both cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) 
The use of Apixaban Accordis 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). These 
medicinal products may increase apixaban exposure by 2-fold (see section 4.5) or greater in the 
presence of additional factors that increase apixaban exposure (e.g., severe renal impairment). 
 
Interaction with inducers of both CYP3A4 and P-gp 
The concomitant use of Apixaban Accord with strong CYP3A4 and P-gp inducers (e.g., rifampicin, 
phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may lead to a ~50% reduction in 
apixaban exposure. In a clinical study in atrial fibrillation patients, diminished efficacy and a higher 
risk of bleeding were observed with coadministration of apixaban with strong inducers of both 
CYP3A4 and P-gp compared with using apixaban alone. 
 
In patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp 
the following recommendations apply (see section 4.5): 
 
-C.  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; 
 
-D.  for the treatment of DVT and treatment of PE, apixaban should not be used since efficacy may be 
compromised. 
 
Laboratory parameters 
Clotting tests [e.g., prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT)] 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 (see section 5.1). 
 



36 

Information about excipients 
Apixaban Accordcontains lactose. Patients with rare hereditary problems of galactose intolerance,  
total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 
This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 
‘sodium-free’ 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Inhibitors of CYP3A4 and P-gp 
Coadministration of apixaban with ketoconazole (400 mg once a day), a strong inhibitor of both 
CYP3A4 and P-gp, led to a 2-fold increase in mean apixaban AUC and a 1.6-fold increase in mean 
apixaban Cmax. 
 
The use of Apixaban Accord 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) (see section 4.4). 
 
Active substances which are not considered strong inhibitors of both CYP3A4 and P-gp, (e.g., 
amiodarone, clarithromycin, diltiazem, fluconazole, naproxen, quinidine, verapamil) are expected to 
increase apixaban plasma concentration to a lesser extent. No dose adjustment for apixaban is required 
when coadministered with agents that are not strong inhibitors of both CYP3A4 and P-gp. For 
example, diltiazem (360 mg once a day), considered a moderate CYP3A4 and a weak P-gp inhibitor, 
led to a 1.4-fold increase in mean apixaban AUC and a 1.3-fold increase in Cmax. Naproxen (500 mg, 
single dose) an inhibitor of P-gp but not an inhibitor of CYP3A4, led to a 1.5-fold and 1.6-fold 
increase in mean apixaban AUC and Cmax, respectively. Clarithromycin (500 mg, twice a day), an 
inhibitor of P-gp and a strong inhibitor of CYP3A4, led to a 1.6-fold and 1.3-fold increase in mean 
apixaban AUC and Cmax respectively. 
 
Inducers of CYP3A4 and P-gp  
Coadministration of apixaban with rifampicin, a strong inducer of both CYP3A4 and P-gp, led to an 
approximate 54% and 42% decrease in mean apixaban AUC and Cmax, respectively. The concomitant 
use of apixaban with other strong CYP3A4 and P-gp inducers (e.g., phenytoin, carbamazepine, 
phenobarbital or St. John’s Wort) may also lead to reduced apixaban plasma concentrations. No dose 
adjustment for apixaban is required during concomitant therapy with such medicinal products, 
however in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 
and P-gp apixaban should be used with caution for the prevention of stroke and systemic embolism in 
patients with NVAF and for the prevention of recurrent DVT and PE. Apixaban is not recommended 
for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong 
inducers of both CYP3A4 and P-gp since efficacy may be compromised (see section 4.4). 
 
Anticoagulants, platelet aggregation inhibitors, SSRIs/SNRIs and NSAIDs 
Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is 
contraindicated 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 (see section 4.3). 
 
After combined administration of enoxaparin (40 mg single dose) with apixaban (5 mg single dose), 
an additive effect on anti-Factor Xa activity was observed. 
 
Pharmacokinetic or pharmacodynamic interactions were not evident when apixaban was 
coadministered with ASA 325 mg once a day. 
 
Apixaban coadministered with clopidogrel (75 mg once a day) or with the combination of clopidogrel 
75 mg and ASA 162 mg once daily, or with prasugrel (60 mg followed by 10 mg once daily) in 
Phase I studies did not show a relevant increase in template bleeding time, or further inhibition of 



37 

platelet aggregation, compared to administration of the antiplatelet agents without apixaban. Increases 
in clotting tests (PT, INR, and aPTT) were consistent with the effects of apixaban alone. 
 
Naproxen (500 mg), an inhibitor of P-gp, led to a 1.5-fold and 1.6-fold increase in mean apixaban 
AUC and Cmax, respectively. Corresponding increases in clotting tests were observed for apixaban. No 
changes were observed in the effect of naproxen on arachidonic acid-induced platelet aggregation and 
no clinically relevant prolongation of bleeding time was observed after concomitant administration of 
apixaban and naproxen. 
 
Despite these findings, there may be individuals with a more pronounced pharmacodynamic response 
when antiplatelet agents are coadministered with apixaban. Apixaban Accord should be used with 
caution when coadministered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 because these 
medicinal products typically increase the bleeding risk (see section 4.4). 
 
There is limited experience of co-administration with other platelet aggregation inhibitors (such as 
GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As 
such agents increase the bleeding risk, co-administration of these medicinal products with Apixaban 
Accord is not recommended (see section 4.4). 
 
Other concomitant therapies 
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
apixaban was coadministered with atenolol or famotidine. Coadministration of apixaban 10 mg with 
atenolol 100 mg did not have a clinically relevant effect on the pharmacokinetics of apixaban. 
Following administration of the two medicinal products together, mean apixaban AUC and Cmax were 
15% and 18% lower than when administered alone. The administration of apixaban 10 mg with 
famotidine 40 mg had no effect on apixaban AUC or Cmax. 
 
Effect of apixaban on other medicinal products 
In vitro apixaban studies showed no inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, 
CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 > 45 µM) and weak inhibitory effect on the activity 
of CYP2C19 (IC50 > 20 µM) at concentrations that are significantly greater than peak plasma 
concentrations observed in patients. Apixaban did not induce CYP1A2, CYP2B6, CYP3A4/5 at a 
concentration up to 20 µM. Therefore, apixaban is not expected to alter the metabolic clearance of 
coadministered drugs that are metabolised by these enzymes. Apixaban is not a significant inhibitor of 
P-gp. 
 
In studies conducted in healthy subjects, as described below, apixaban did not meaningfully alter the 
pharmacokinetics of digoxin, naproxen, or atenolol. 
 
Digoxin 
Coadministration of apixaban (20 mg once a day) and digoxin (0.25 mg once a day), a P-gp substrate, 
did not affect digoxin AUC or Cmax. Therefore, apixaban does not inhibit P-gp mediated substrate 
transport. 
 
Naproxen 
Coadministration of single doses of apixaban (10 mg) and naproxen (500 mg), a commonly used 
NSAID, did not have any effect on the naproxen AUC or Cmax. 
 
Atenolol 
Coadministration of a single dose of apixaban (10 mg) and atenolol (100 mg), a common beta-blocker, 
did not alter the pharmacokinetics of atenolol. 
 
Activated charcoal 
Administration of activated charcoal reduces apixaban exposure (see section 4.9). 
 



38 

4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are no data from the use of apixaban in pregnant women. Animal studies do not indicate direct 
or indirect harmful effects with respect to reproductive toxicity. Apixaban is not recommended during 
pregnancy. 
 
Breast-feeding 
It is unknown whether apixaban or its metabolites are excreted in human milk. Available data in 
animals have shown excretion of apixaban in milk. In rat milk, a high milk to maternal plasma ratio 
(Cmax about 8, AUC about 30) was found, possibly due to active transport into the milk. A risk to 
newborns and infants cannot be excluded. 
 
A decision must be made to either discontinue breast-feeding or to discontinue/abstain from apixaban 
therapy. 
 
Fertility 
Studies in animals dosed with apixaban have shown no effect on fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Apixaban Accordhas no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety of apixaban has been investigated in 4 Phase III clinical studies including more than 
15,000 patients: more than 11,000 patients in NVAF studies and more than 4,000 patients in the VTE 
treatment (VTEt) studies, for an average total exposure of 1.7 years and 221 days respectively 
(see section 5.1). 
 
Common adverse reactions were haemorrhage, contusion, epistaxis, and haematoma (see Table 2 for 
adverse reaction profile and frequencies by indication). 
 
In the NVAF studies, the overall incidence of adverse reactions related to bleeding with apixaban was 
24.3% in the apixaban vs warfarin study and 9.6% in the apixaban vs acetylsalicylic acid study. In the 
apixaban vs warfarin study the incidence of ISTH major gastrointestinal bleeds (including upper GI, 
lower GI, and rectal bleeding) with apixaban was 0.76%/year. The incidence of ISTH major 
intraocular bleeding with apixaban was 0.18%/year. 
 
In the VTEt studies, the overall incidence of adverse reactions related to bleeding with apixaban was 
15.6% in the apixaban vs enoxaparin/warfarin study and 13.3% in the apixaban vs placebo study 
(see section 5.1). 
 
Tabulated list of adverse reactions 
Table 2 shows the adverse reactions ranked under headings of system organ class and frequency using 
the following convention: very common (≥ 1/10) common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 
to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated 
from the available data) for NVAF and VTEt respectively. 
 
 
 
 
 
 
 
 



39 

 
Table 2 
System organ class Prevention of stroke and systemic 

embolism in adult patients with 
NVAF, with one or more risk 

factors (NVAF) 

Treatment of DVT 
and PE, and 
prevention of 

recurrent DVT and 
PE (VTEt) 

Blood and lymphatic system disorders 
Anaemia Common Common 
Thrombocytopenia Uncommon Common 
Immune system disorders 

Hypersensitivity, allergic oedema and 
anaphylaxis  

Uncommon Uncommon 

Pruritus Uncommon Uncommon* 
Nervous system disorders 

Brain haemorrhage† Uncommon Rare 
Eye disorders 

Eye haemorrhage (including 
conjunctival haemorrhage) 

Common Uncommon 

Vascular disorders 

Haemorrhage, haematoma Common Common 
Hypotension (including procedural 
hypotension) 

Common Uncommon 

Intra-abdominal haemorrhage Uncommon Not known 
Respiratory, thoracic and mediastinal disorders 

Epistaxis Common Common 
Haemoptysis Uncommon Uncommon 
Respiratory tract haemorrhage  Rare Rare 
Gastrointestinal disorders 

Nausea Common Common 
Gastrointestinal haemorrhage  Common Common 
Haemorrhoidal haemorrhage Uncommon Uncommon 
Mouth haemorrhage Uncommon Common 
Haematochezia Uncommon Uncommon 
Rectal haemorrhage, gingival bleeding Common Common 
Retroperitoneal haemorrhage Rare Not known 
Hepatobiliary disorders  
Liver function test abnormal, aspartate 
aminotransferase increased, blood 
alkaline phosphatase increased, blood 
bilirubin increased 

Uncommon Uncommon 

Gamma-glutamyltransferase increased Common Common 
Alanine aminotransferase increased Uncommon Common 
Skin and subcutaneous tissue disorders 

Skin rash Uncommon Common 
Alopecia Uncommon Uncommon 
Musculoskeletal and connective tissue disorders 
Muscle haemorrhage Rare Uncommon 
Renal and urinary disorders 

Haematuria Common Common 
Reproductive system and breast disorders 



40 

System organ class Prevention of stroke and systemic 
embolism in adult patients with 
NVAF, with one or more risk 

factors (NVAF) 

Treatment of DVT 
and PE, and 
prevention of 

recurrent DVT and 
PE (VTEt) 

Abnormal vaginal haemorrhage, 
urogenital haemorrhage 

Uncommon Common 

General disorders and administration site conditions 

Application site bleeding Uncommon Uncommon 
Investigations 

Occult blood positive Uncommon Uncommon 
Injury, poisoning and procedural complications 

Contusion Common Common 

Post procedural haemorrhage 
(including post procedural 
haematoma, wound haemorrhage, 
vessel puncture site haematoma and 
catheter site haemorrhage), wound 
secretion, incision site haemorrhage 
(including incision site haematoma), 
operative haemorrhage 

Uncommon Uncommon 

Traumatic haemorrhage Uncommon Uncommon 
* There were no occurrences of generalised  pruritus in CV185057 (long term prevention of VTE)  
†

 The term “Brain haemorrhage” encompasses all intracranial or intraspinal haemorrhages (ie., haemorrhagic stroke or 
putamen, cerebellar, intraventricular, or subdural haemorrhages). 
 
The use of Apixaban Accordmay be associated with an increased risk of occult or overt bleeding from 
any tissue or organ, which may result in posthaemorrhagic anaemia. The signs, symptoms, and 
severity will vary according to the location and degree or extent of the bleeding (see sections 4.4 and 
5.1). 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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 haemostasisor the transfusion of fresh frozen plasma or the 
administration of a reversal agent for factor Xa inhibitors 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 adverseevents. 
 
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. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


41 

 
For situations when reversal of anticoagulation is needed due to life-threatening or uncontrolled 
bleeding, a reversal agent for factor Xa inhibitors is available (see section 4.4). Administration of 
prothrombin complex concentrates (PCCs) or recombinant factor VIIa may be considered. Reversal of 
Apixaban Accordpharmacodynamic 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  medicinal products to reverse bleeding in individuals who have received 
Apixaban Accord. 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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF02 
 
Mechanism of action 
Apixaban is a potent, oral, reversible, direct and highly selective active site inhibitor of factor Xa. It 
does not require antithrombin III for antithrombotic activity. Apixaban inhibits free and clot-bound 
factor Xa, and prothrombinase activity. Apixaban has no direct effects on platelet aggregation, but 
indirectly inhibits platelet aggregation induced by thrombin. By inhibiting factor Xa, apixaban 
prevents thrombin generation and thrombus development. Preclinical studies of apixaban in animal 
models have demonstrated antithrombotic efficacy in the prevention of arterial and venous thrombosis 
at doses that preserved haemostasis. 
 
Pharmacodynamic effects 
The pharmacodynamic effects of apixaban are reflective of the mechanism of action (FXa inhibition). 
As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), INR and 
activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the expected 
therapeutic dose are small and subject to a high degree of variability. They are not recommended to 
assess the pharmacodynamic effects of apixaban. In the thrombin generation assay, apixaban reduced 
endogenous thrombin potential, a measure of thrombin generation in human plasma. 
 
Apixaban also demonstrates anti-FXa activity as evident by reduction in Factor Xa enzyme activity in 
multiple commercial anti-FXa kits, however results differ across kits. Data from clinical trials are only 
available for the Rotachrom® Heparin chromogenic assay. Anti-FXa activity exhibits a close direct 
linear relationship with apixaban plasma concentration, reaching maximum values at the time of 
apixaban peak plasma concentrations. The relationship between apixaban plasma concentration and 
anti-FXa activity is approximately linear over a wide dose range of apixaban. 
 
Table 3 below shows the predicted steady state exposure and anti-Factor Xa activity. In non-valvular 
atrial fibrillation patients taking apixaban for the prevention of stroke and systemic embolism, the 
results demonstrate a less than 1.7-fold fluctuation in peak-to-trough levels. In patients taking 
apixaban for the treatment of DVT and PE or prevention of recurrent DVT and PE, the results 
demonstrate a less than 2.2-fold fluctuation in peak-to-trough levels. 
 



42 

Table 3:Predicted apixaban steady-state exposure and anti-Xa activity 

 Apix. 
Cmax (ng/mL) 

Apix. 
Cmin (ng/mL) 

Apix. anti-Xa 
activity max 

(IU/mL) 

Apix. anti-Xa 
activity min 

(IU/mL) 

 Median [5th, 95th Percentile] 

Prevention of stroke and systemic embolism: NVAF 

2.5 mg twice 
daily* 

123 [69, 221] 79 [34, 162] 1.8 [1.0, 3.3] 1.2 [0.51, 2.4] 

5 mg twice daily 171 [91, 321] 103 [41, 230] 2.6 [1.4, 4.8] 1.5 [0.61, 3.4] 

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) 

2.5 mg twice daily 67 [30, 153] 32 [11, 90] 1.0 [0.46, 2.5] 0.49 [0.17, 1.4] 

5 mg twice daily 132 [59, 302] 63 [22, 177] 2.1 [0.91, 5.2] 1.0 [0.33, 2.9] 

10 mg twice daily 251 [111, 572] 120 [41, 335] 4.2 [1.8, 10.8] 1.9 [0.64, 5.8] 
* Dose adjusted population based on 2 of 3 dose reduction criteria in the ARISTOTLE study. 
 
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. 
 
Clinical efficacy and safety 
 
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) 
A total of 23,799 patients were randomised in the clinical program (ARISTOTLE: apixaban versus 
warfarin, AVERROES: apixaban versus ASA) including 11,927 randomised to apixaban. The program 
was designed to demonstrate the efficacy and safety of apixaban for the prevention of stroke and 
systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and one or more additional 
risk factors, such as: 
• prior stroke or transient ischaemic attack (TIA) 
• age ≥ 75 years 
• hypertension 
• diabetes mellitus 
• symptomatic heart failure (NYHA Class ≥ II) 
 
ARISTOTLE STUDY  
In the ARISTOTLE study a total of 18,201 patients were randomised to double-blind treatment with 
apixaban 5 mg twice daily (or 2.5 mg twice daily in selected patients [4.7%], see section 4.2) or 
warfarin (target INR range 2.0-3.0), patients were exposed to study drug for a mean of 20 months. The 
mean age was 69.1 years, the mean CHADS2 score was 2.1, 18.9 % of patients had prior stroke or 
TIA. 
 
In the study, apixaban achieved statistically significant superiority in the primary endpoint of 
prevention of stroke (haemorrhagic or ischaemic) and systemic embolism (see Table 4) compared with 
warfarin. 
 



43 

Table 4: Efficacy outcomes in patients with atrial fibrillation in the ARISTOTLE study 
 Apixaban  

N=9,120 
n (%/yr) 

Warfarin  
N=9,081 
n (%/yr) 

Hazard ratio 
(95% CI) 

 
p-value 

Stroke or systemic embolism 212 (1.27) 265 (1.60) 0.79 (0.66, 0.95) 0.0114 
Stroke     

Ischaemic or unspecified 162 (0.97) 175 (1.05) 0.92 (0.74, 1.13)  
Haemorrhagic 40 (0.24) 78 (0.47) 0.51 (0.35, 0.75)  

Systemic embolism 15 (0.09) 17 (0.10) 0.87 (0.44, 1.75)  
 
For patients randomised to warfarin, the median percentage of time in therapeutic range (TTR) 
(INR 2-3) was 66%. 
 
Apixaban showed a reduction of stroke and systemic embolism compared to warfarin across the 
different levels of center TTR; within the highest quartile of TTR according to center, the hazard ratio 
for apixaban vs warfarin was 0.73 (95% CI, 0.38, 1.40). 
 
Key secondary endpoints of major bleeding and all cause death were tested in a pre-specified 
hierarchical testing strategy to control the overall type 1 error in the trial. Statistically significant 
superiority was also achieved in the key secondary endpoints of both major bleeding and all-cause 
death (see Table 5). With improving monitoring of INR the observed benefits of apixaban compared to 
warfarin regarding all cause death diminish. 
 
Table 5: Secondary endpoints in patients with atrial fibrillation in the ARISTOTLE study 

 Apixaban 
N = 9,088 

n (%/year) 

Warfarin 
N = 9,052 

n (%/year) 

Hazard ratio 
(95% CI) 

p-value 

Bleeding outcomes 
Major* 327 (2.13) 462 (3.09) 0.69 (0.60, 0.80) < 0.0001 

Fatal 10 (0.06) 37 (0.24)   
Intracranial 52 (0.33) 122 (0.80)   

Major + CRNM† 613 (4.07) 877 (6.01) 0.68 (0.61, 0.75) < 0.0001 
All 2,356 (18.1) 3,060 (25.8) 0.71 (0.68, 0.75) < 0.0001 

Other endpoints 
All-cause death 603 (3.52) 669 (3.94) 0.89 (0.80, 1.00) 0.0465 
Myocardial 
infarction 

90 (0.53)  102 (0.61) 0.88 (0.66, 1.17)  

* Major bleeding defined per International Society on Thrombosis and Haemostasis (ISTH) criteria. 
† Clinically Relevant Non-Major  
 
The overall discontinuation rate due to adverse reactions was 1.8% for apixaban and 2.6% for warfarin 
in the ARISTOTLE study. 
 
The efficacy results for prespecified subgroups, including CHADS2 score, age, body weight, gender, 
status of renal function, prior stroke or TIA and diabetes were consistent with the primary efficacy 
results for the overall population studied in the trial. 
 
The incidence of ISTH major gastrointestinal bleeds (including upper GI, lower GI, and rectal 
bleeding) was 0.76%/year with apixaban and 0.86%/year with warfarin. 
 
The major bleeding results for prespecified subgroups including CHADS2 score, age, body weight, 
gender, status of renal function, prior stroke or TIA and diabetes were consistent with the results for 
the overall population studied in the trial. 
 



44 

AVERROES STUDY 
In the AVERROES study a total of 5,598 patients considered to be unsuitable for VKA by the 
investigators were randomised to treatment with apixaban 5 mg twice daily (or 2.5 mg twice daily in 
selected patients [6.4%], see section 4.2) or ASA. ASA was given at a once daily dose of 81 mg 
(64%), 162 (26.9%), 243 (2.1%), or 324 mg (6.6%) at the discretion of the investigator. Patients were 
exposed to study drug for a mean of 14 months. The mean age was 69.9 years, the mean CHADS2 
score was 2.0 and 13.6% of patients had prior stroke or TIA. 
 
Common reasons for unsuitability for VKA therapy in the AVERROES study included 
unable/unlikely to obtain INRs at requested intervals (42.6%), patient refused treatment with VKA 
(37.4%), CHADS2 score = 1 and physician did not recommend VKA (21.3%), patient could not be 
relied on to adhere to VKA medicinal product instruction (15.0%), and difficulty/expected difficulty in 
contacting patient in case of urgent dose change (11.7%). 
 
AVERROES was stopped early based on a recommendation by the independent Data Monitoring 
Committee due to clear evidence of reduction of stroke and systemic embolism with an acceptable 
safety profile. 
 
The overall discontinuation rate due to adverse reactions was 1.5% for apixaban and 1.3% for ASA in 
the AVERROES study. 
 
In the study, apixaban achieved statistically significant superiority in the primary endpoint of 
prevention of stroke (haemorrhagic, ischaemic or unspecified) or systemic embolism (see Table 6) 
compared to ASA. 
 
Table 6: Key efficacy outcomes in patients with atrial fibrillation in the AVERROES study 
 Apixaban 

N = 2,807  
n (%/year) 

ASA  
N = 2,791 

n (%/year) 

Hazard ratio 
(95% CI) 

 
p-value 

Stroke or systemic embolism* 51 (1.62) 113 (3.63) 0.45 (0.32, 0.62) < 0.0001 
Stroke     

Ischaemic or unspecified 43 (1.37) 97 (3.11) 0.44 (0.31, 0.63)  
Haemorrhagic 6 (0.19) 9 (0.28) 0.67 (0.24, 1.88)  

Systemic embolism 2 (0.06) 13 (0.41) 0.15 (0.03, 0.68)  
Stroke, systemic embolism, 
MI, or vascular death*† 

132 (4.21) 197 (6.35) 0.66 (0.53, 0.83) 0.003 

Myocardial infarction 24 (0.76) 28 (0.89) 0.86 (0.50, 1.48)  
Vascular death 84 (2.65) 96 (3.03) 0.87 (0.65, 1.17)  

All-cause death† 111 (3.51) 140 (4.42) 0.79 (0.62, 1.02) 0.068 
* Assessed by sequential testing strategy designed to control the overall type I error in the trial 
† Secondary endpoint. 
 
There was no statistically significant difference in the incidence of major bleeding between apixaban 
and ASA (see Table 7). 
 
Table 7: Bleeding events in patients with atrial fibrillation in the AVERROES study 

 Apixaban 
N = 2,798 
n(%/year) 

ASA 
N = 2,780 

n (%/year) 

Hazard ratio 
(95%CI) 

p-value 

Major* 45 (1.41) 29 (0.92) 1.54 (0.96, 2.45)  0.0716 
Fatal, n 5 (0.16) 5 (0.16)   
Intracranial, n 11 (0.34) 11 (0.35)   

Major + CRNM† 140 (4.46) 101 (3.24) 1.38 (1.07, 1.78) 0.0144 
All 325 (10.85) 250 (8.32) 1.30 (1.10, 1.53) 0.0017 
*Major bleeding defined per International Society on Thrombosis ad Haemostasis (ISTH) criteria. 
† Clinically Relevant Non-Major  



45 

 
NVAF patients with ACS and/or undergoing PCI 
AUGUSTUS, an open-label, randomised,, controlled, 2 by 2 factorial design trial, enrolled4614 
patients with NVAF who had ACS (43%) and/or underwent PCI (56%). All patients 
receivedbackground therapy with a P2Y12 inhibitor (clopidogrel: 90.3%) prescribed per local standard 
of care. 
 
Patients were randomised, up to 14 days after the ACS and/or PCI to either apixaban 5 mg twice 
daily(2.5 mg twice daily if two or more of the dose-reduction criteria were met; 10% received lower 
dose)or VKA and to either ASA (81 mg once daily) or placebo. The mean age was 69.9 years, 94% 
ofpatients randomised, had a CHA2DS2-VASc score > 2, and 47% had a HAS-BLED score > 3. 
Forpatients randomised to VKA, the proportion of time in therapeutic range (TTR) (INR 2-3) was 
56%,with 32% of time below TTR and 12% above TTR. 
 
The primary objective of AUGUSTUS was to assess safety, with a primary endpoint of ISTH major 
orCRNM bleeding. In the apixaban versus VKA comparison, the primary safety endpoint of ISTH 
majoror CRNM bleeding at month 6 occurred in 241 (10.5%), and 332 (14.7%) patients in the 
apixaban armand in the VKA arm respectively (HR=0.69, 95% CI: 0.58, 0.82; 2-sided p<0.0001 for 
non inferiorityand p<0.0001 for superiority). For VKA, additional analyses using subgroups by TTR 
showed that thehighest rate of bleeding was associated with the lowest quartile of TTR. The rate of 
bleeding wassimilar between apixaban and the highest quartile of TTR. 
In the ASA versus placebo comparison, the primary safety endpoint of ISTH major or CRNMbleeding 
at month 6 occurred in 367 (16.1%), and 204 (9.0%) patients in the ASA arm and in theplacebo arm 
respectively (HR=1.88, 95% CI: 1.58, 2.23; two-sided p<0.0001). 
 
Specifically, in apixaban-treated patients, major or CRNM bleeding occurred in 157 (13.7%), and 
84(7.4%) patients in the ASA arm and in the placebo arm respectively. In VKA-treated patients, major 
orCRNM bleeding occurred in 208 (18.5%), and 122 (10.8%) patients in the ASA arm and in 
theplacebo arm respectively. 
 
Other treatment effects were evaluated as a secondary objective of the study, with composite end 
points. 
In the apixaban versus VKA comparison, the composite endpoint of death or re-hospitalization 
occurred in 541 (23.5%) and 632 (27.4%) patients in the apixaban and in the VKA arm, respectively. 
The composite endpoint of death or ischemic event (stroke, myocardial infarction, stent thrombosis 
orurgent revascularization) occurred in 170 (7.4%), and 182 (7.9%) patients in the apixaban and in 
theVKA arm, respectively. 
 
In the ASA versus placebo comparison, the composite endpoint of death or re-hospitalization occurred 
in 604 (26.2%) and 569 (24.7%) patients in the ASA and in the placebo arm, respectively. The 
composite endpoint of death or ischemic event (stroke, myocardial infarction, stent thrombosis or 
urgent revascularization) occurred in 163 (7.1%), and 189 (8.2%) patients in the ASA and in 
theplacebo arm, respectively. 
 
Patients undergoing cardioversion 
EMANATE, an open-label, multi-center study, enrolled 1500 patients who were either oral 
anticoagulant naïve or pre-treated less than 48 hours, and scheduled for cardioversion for NVAF. 
Patients were randomized 1:1 to apixaban or to heparin and/or VKA for the prevention of 
cardiovascular events. Electrical and/or pharmacologic cardioversion was conducted after at least 5 
doses of 5 mg twice daily apixaban (or 2.5 mg twice daily in selected patients (see section 4.2)) or at 
least 2 hours after a 10 mg loading dose (or a 5 mg loading dose in selected patients (see section 4.2)) 
if earlier cardioversion was required. In the apixaban group, 342 patients received a loading dose (331 
patients received the 10 mg dose and 11 patients received the 5 mg dose). 
 
There were no strokes (0%) in the apixaban group (n= 753) and 6 (0.80%) strokes in the heparin 
and/or VKA group (n = 747; RR 0.00, 95% CI 0.00, 0.64). All-cause death occurred in 2 patients 



46 

(0.27%) in the apixaban group and 1 patient (0.13%) in the heparin and/or VKA group. No systemic 
embolism events were reported. 
 
Major bleeding and CRNM bleeding events occurred in 3 (0.41%) and 11 (1.50%) patients, 
respectively, in the apixaban group, compared to 6 (0.83%) and 13 (1.80%) patients in the heparin 
and/or VKA group. 
 
This exploratory study showed comparable efficacy and safety between apixaban and heparin and/or 
VKA treatment groups in the setting of cardioversion. 
 
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) 
The clinical program (AMPLIFY: apixaban versus enoxaparin/warfarin, AMPLIFY-EXT: apixaban 
versus placebo) was designed to demonstrate the efficacy and safety of apixaban for the treatment of 
DVT and/or PE (AMPLIFY), and extended therapy for the prevention of recurrent DVT and/or PE 
following 6 to 12 months of anticoagulant treatment for DVT and/or PE (AMPLIFY-EXT). Both 
studies were randomised, parallel-group, double-blind, multinational trials in patients with 
symptomatic proximal DVT or symptomatic PE. All the key safety and efficacy endpoints were 
adjudicated by an independent blinded committee. 
 
AMPLIFY STUDY 
In the AMPLIFY study a total of 5,395 patients were randomised to treatment with apixaban 10 mg 
twice daily orally for 7 days followed by apixaban 5 mg twice daily orally for 6 months, or enoxaparin 
1 mg/kg twice daily subcutaneously for at least 5 days (until INR≥ 2) and warfarin (target INR range 
2.0-3.0) orally for 6 months. 
 
The mean age was 56.9 years and 89.8% of randomised patients had unprovoked VTE events. 
For patients randomised to warfarin, the mean percentage of time in therapeutic range (INR 2.0-3.0) 
was 60.9. Apixaban showed a reduction in recurrent symptomatic VTE or VTE- related death across 
the different levels of center TTR; within the highest quartile of TTR according to center, the relative 
risk for apixaban vs enoxaparin/warfarin was 0.79 (95% CI, 0.39, 1.61). 
 
In the study, apixaban was shown to be non-inferior to enoxaparin/warfarin in the combined primary 
endpoint of adjudicated recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related 
death (see Table 8). 
 



47 

Table 8: Efficacy results in the AMPLIFY study 
 Apixaban 

N=2,609 
n (%) 

Enoxaparin/ 
warfarin 
N=2,635 

n (%) 

Relative risk 
(95% CI) 

VTE or VTE-related 
death 

59 (2.3) 71 (2.7) 0.84 (0.60, 1.18)* 

 DVT 20 (0.7) 33 (1.2)  

 PE 27 (1.0) 23 (0.9)  

 VTE-related 
 death 

12 (0.4) 15 (0.6)  

VTE or all-cause 
death 

84 (3.2) 104 (4.0) 0.82 (0.61, 1.08) 

VTE or CV-related 
death 

61 (2.3) 77 (2.9) 0.80 (0.57, 1.11) 

VTE, VTE-related 
death, or major 
bleeding 

73 (2.8) 118 (4.5) 0.62 (0.47, 0.83) 

* Noninferior compared to enoxaparin/warfarin (p-value < 0.0001) 
 
Apixaban efficacy in initial treatment of VTE was consistent between patients who were treated for a 
PE [Relative Risk 0.9; 95% CI (0.5, 1.6)] or DVT [Relative Risk 0.8; 95% CI (0.5, 1.3)]. Efficacy 
across subgroups, including age, gender, body mass index (BMI), renal function, extent of index PE, 
location of DVT thrombus, and prior parenteral heparin use was generally consistent. 
 
The primary safety endpoint was major bleeding. In the study, apixaban was statistically superior to 
enoxaparin/warfarin in the primary safety endpoint [Relative Risk 0.31, 95% confidence interval 
(0.17, 0.55), P-value < 0.0001] (see Table 9). 
 
Table 9: Bleeding results in the AMPLIFY study 
 Apixaban 

N=2,676 
n (%) 

Enoxaparin/ 
warfarin 
N=2,689 

n (%) 

Relative risk 
(95% CI) 

Major 15 (0.6) 49 (1.8) 0.31 (0.17, 0.55) 

Major + CRNM 115 (4.3) 261 (9.7) 0.44 (0.36, 0.55) 

Minor 313 (11.7) 505 (18.8) 0.62 (0.54, 0.70) 

All 402 (15.0) 676 (25.1) 0.59 (0.53, 0.66) 
 
The adjudicated major bleeding and CRNM bleeding at any anatomical site were generally lower in 
the apixaban group as compared to the enoxaparin/warfarin group. Adjudicated ISTH major 
gastrointestinal bleeding occurred in 6 (0.2%) apixaban-treated patients and 17 (0.6%) 
enoxaparin/warfarin-treated patients. 
 



48 

AMPLIFY-EXT STUDY 
In the AMPLIFY-EXT study a total of 2,482 patients were randomised to treatment with apixaban 
2.5 mg twice daily orally, apixaban 5 mg twice daily orally, or placebo for 12 months after completing 
6 to 12 months of initial anticoagulant treatment. Of these, 836 patients (33.7%) participated in the 
AMPLIFY study prior to enrollment in the AMPLIFY-EXT study. The mean age was 56.7 years and 
91.7% of randomised patients had unprovoked VTE events. 
 
In the study, both doses of apixaban were statistically superior to placebo in the primary endpoint of 
symptomatic, recurrent VTE (nonfatal DVT or nonfatal PE) or all-cause death (see Table 10). 
 
Table 10: Efficacy results in the AMPLIFY-EXT rtudy 
 Apixaban  Apixaban Placebo Relative Risk (95% CI) 

 2.5 mg 
(N=840) 

5.0 mg 
(N=813) 

 
(N=829) 

Apix 2.5 mg 
vs. placebo 

Apix 5.0 mg 
vs. placebo 

 n (%)   

Recurrent 
VTE or all-
cause death 

19 (2.3) 14 (1.7) 77 (9.3) 0.24 
(0.15, 0.40)¥ 

0.19 
(0.11, 0.33)¥ 

DVT* 6 (0.7) 7 (0.9) 53 (6.4)   

PE* 7 (0.8) 4 (0.5) 13 (1.6)   

All-cause 
death 

6 (0.7) 3 (0.4) 11 (1.3)   

Recurrent 
VTE or VTE-
related death 

14 (1.7) 14 (1.7) 73 (8.8) 0.19 
(0.11, 0.33) 

0.20 
(0.11, 0.34) 

Recurrent 
VTE or CV-
related death 

14 (1.7) 14 (1.7) 76 (9.2) 0.18 
(0.10, 0.32) 

0.19 
(0.11, 0.33) 

Nonfatal 
DVT† 

6 (0.7) 8 (1.0) 53 (6.4) 0.11 
(0.05, 0.26) 

0.15 
(0.07, 0.32) 

Nonfatal PE† 8 (1.0) 4 (0.5) 15 (1.8) 0.51 
(0.22, 1.21) 

0.27 
(0.09, 0.80) 

VTE-related 
death 

2 (0.2) 3 (0.4) 7 (0.8) 0.28 
(0.06, 1.37) 

0.45 
(0.12, 1.71) 

¥ p-value < 0.0001 
* For patients with more than one event contributing to the composite endpoint, only the first event was reported (e.g., if a 
subject experienced both a DVT and then a PE, only the DVT was reported) 
† Individual subjects could experience more than one event and be represented in both classifications 
 
Apixaban efficacy for prevention of a recurrence of a VTE was maintained across subgroups, 
including age, gender, BMI, and renal function. 
 
The primary safety endpoint was major bleeding during the treatment period. In the study, the 
incidence in major bleeding for both apixaban doses was not statistically different from placebo. There 
was no statistically significant difference in the incidence of major + CRNM, minor, and all bleeding 
between the apixaban 2.5 mg twice daily and placebo treatment groups (see Table 11). 
 



49 

Table 11: Bleeding results in the AMPLIFY-EXT rtudy 

 Apixaban  Apixaban Placebo Relative risk (95% CI) 

 2.5 mg 
(N=840) 

5.0 mg 
(N=811) 

 
(N=826) 

Apix 2.5 mg 
vs. placebo 

Apix 5.0 mg 
vs. pacebo 

  n (%)    

Major 2 (0.2) 1 (0.1) 4 (0.5) 0.49 
(0.09, 2.64) 

0.25 
(0.03, 2.24) 

Major + 
CRNM 

27 (3.2) 35 (4.3) 22 (2.7) 1.20 
(0.69, 2.10) 

1.62 
(0.96, 2.73) 

Minor 75 (8.9) 98 (12.1) 58 (7.0) 1.26 
(0.91, 1.75) 

1.70 
(1.25, 2.31)  

All 94 (11.2) 121 (14.9) 74 (9.0) 1.24 
(0.93, 1.65) 

1.65 
(1.26, 2.16)  

 
Adjudicated ISTH major gastrointestinal bleeding occurred in 1 (0.1%) apixaban-treated patient at the 
5 mg twice daily dose, no patients at the 2.5 mg twice daily dose, and 1 (0.1%) placebo-treated patient. 
 
Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Apixabanin one or more subsets of the paediatric population in venous and arterial embolism and 
thrombosis (see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg. Apixaban is 
rapidly absorbed with maximum concentrations (Cmax) appearing 3 to 4 hours after tablet intake. Intake 
with food does not affect apixaban AUC or Cmax at the 10 mg dose. Apixaban can be taken with or 
without food. 
 
Apixaban demonstrates linear pharmacokinetics with dose proportional increases in exposure for oral 
doses up to 10 mg. At doses ≥ 25 mg apixaban displays dissolution limited absorption with decreased 
bioavailability. Apixaban exposure parameters exhibit low to moderate variability reflected by a 
within-subject and inter-subject variability of ~20% CV and ~30% CV, respectively. 
 
Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets suspended in 30 mL of 
water, exposure was comparable to exposure after oral administration of 2 whole 5 mg tablets. 
Following oral administration of 10 mg of apixaban as 2 crushed 5 mg tablets with 30 g of apple 
puree, the Cmax and AUC were 21% and 16% lower, respectively, when compared to administration of 
2 whole 5 mg tablets. The reduction in exposure is not considered clinically relevant. 
 
Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of G5W and 
delivered via a nasogastric tube, exposure was similar to exposure seen in other clinical trials 
involving healthy subjects receiving a single oral 5 mg apixaban tablet dose. 
 
Given the predictable, dose-proportional pharmacokinetic profile of apixaban, the bioavailability 
results from the conducted studies are applicable to lower apixaban doses. 
 



50 

Distribution 
Plasma protein binding in humans is approximately 87%. The volume of distribution (Vss) is 
approximately 21 litres. 
 
Biotransformation and elimination 
Apixaban has multiple routes of elimination. Of the administered apixaban dose in humans, 
approximately 25% was recovered as metabolites, with the majority recovered in faeces. Renal 
excretion of apixaban accounts for approximately 27% of total clearance. Additional contributions 
from biliary and direct intestinal excretion were observed in clinical and nonclinical studies, 
respectively. 
 
Apixaban has a total clearance of about 3.3 L/h and a half-life of approximately 12 hours. 
 
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. Unchanged apixaban is the major drug-related component in 
human plasma with no active circulating metabolites present. Apixaban is a substrate of transport 
proteins, P-gp and breast cancer resistance protein (BCRP). 
 
Renal impairment 
There was no impact of impaired renal function on peak concentration of apixaban. There was an 
increase in apixaban exposure correlated to decrease in renal function, as assessed via measured 
creatinine clearance. In individuals with mild (creatinine clearance 51-80 mL/min), moderate 
(creatinine clearance 30-50 mL/min) and severe (creatinine clearance 15-29 mL/min) renal 
impairment, apixaban plasma concentrations (AUC) were increased 16, 29, and 44% respectively, 
compared to individuals with normal creatinine clearance. Renal impairment had no evident effect on 
the relationship between apixaban plasma concentration and anti-FXa activity. 
 
In subjects with end-stage renal disease (ESRD), the AUC of apixaban was increased by 36% when a 
single dose of apixaban 5 mg was administered immediately after haemodialysis, compared to that 
seen in subjects with normal renal function. Haemodialysis, started two hours after administration of a 
single dose of apixaban 5 mg, decreased apixaban AUC by 14% in these ESRD subjects, 
corresponding to an apixaban dialysis clearance of 18 mL/min. Therefore, haemodialysis is unlikely to 
be an effective means of managing apixaban overdose. 
 
Hepatic impairment 
In a study comparing 8 subjects with mild hepatic impairment, Child-Pugh A score 5 (n = 6) and 
score 6 (n = 2), and 8 subjects with moderate hepatic impairment, Child-Pugh B score 7 (n = 6) and 
score 8 (n = 2), to 16 healthy control subjects, the single-dose pharmacokinetics and 
pharmacodynamics of apixaban 5 mg were not altered in subjects with hepatic impairment. Changes in 
anti-Factor Xa activity and INR were comparable between subjects with mild to moderate hepatic 
impairment and healthy subjects. 
 
Elderly 
Elderly patients (above 65 years) exhibited higher plasma concentrations than younger patients, with 
mean AUC values being approximately 32% higher and no difference in Cmax. 
 
Gender 
Exposure to apixaban was approximately 18% higher in females than in males. 
 
Ethnic origin and race 
The results across phase I studies showed no discernible difference in apixaban pharmacokinetics 
between White/Caucasian, Asian and Black/African American subjects. Findings from a population 
pharmacokinetic analysis in patients who received apixaban were generally consistent with the phase I 
results. 
 



51 

Body weight 
Compared to apixaban exposure in subjects with body weight of 65 to 85 kg, body weight > 120 kg 
was associated with approximately 30% lower exposure and body weight < 50 kg was associated with 
approximately 30% higher exposure. 
 
Pharmacokinetic/pharmacodynamic relationship 
The pharmacokinetic /pharmacodynamic (PK/PD) relationship between apixaban plasma 
concentration and several PD endpoints (anti-FXa activity, INR, PT, aPTT) has been evaluated after 
administration of a wide range of doses (0.5 – 50 mg). The relationship between apixaban plasma 
concentration and anti-Factor Xa activity was best described by a linear model. The PK/PD 
relationship observed in patients was consistent with that established in healthy subjects. 
 
5.3 Preclinical safety data 
 
Preclinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, fertility and embryo-foetal 
development and juvenile toxicity. 
 
The major observed effects in the repeated dose toxicity studies were those related to the 
pharmacodynamic action of apixaban on blood coagulation parameters. In the toxicity studies little to 
no increase of bleeding tendency was found. However, since this may be due to a lower sensitivity of 
the non-clinical species compared to humans, this result should be interpreted with caution when 
extrapolating to humans. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Lactose 
Cellulose, microcrystalline 
Croscarmellose sodium 
Sodium laurilsulfate  
Magnesium stearate 
 
Film coat: 
Hypromellose 
Lactose monohydrate  
Titanium dioxide (E171) 
Triacetin 
Iron oxide red (E172) 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage condition. 
 



52 

6.5 Nature and contents of container 
 
PVC/PVdC-Aluminium blisters are available in 10, 14, 20, 28, 56, 60, 100, 112, 168, and 
200 film-coated tablets. 
 
PVC/PVdC-Aluminium blisters are available in perforated unit dose blisters of 10 x 1, 20 x 1, 28 x 1, 
56 x 1, 60 x 1, 100 x 1 and 168 x 1 film-coated tablet. 
 
HDPE bottle with polypropylene child resistant/continues threaded closure containing 60, 100, 168, 
180, 200 and 1,000 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
No special requirements. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona s/n, 
Edifici Est, 6a Planta, 
Barcelona, 08039 
Spain 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1458/021   
EU/1/20/1458/023  
EU/1/20/1458/024  
EU/1/20/1458/026  
EU/1/20/1458/028  
EU/1/20/1458/030   
EU/1/20/1458/032  
EU/1/20/1458/034  
EU/1/20/1458/044  
EU/1/20/1458/046  
 
EU/1/20/1458/022   
EU/1/20/1458/025  
EU/1/20/1458/027  
EU/1/20/1458/029  
EU/1/20/1458/031  
EU/1/20/1458/033  
EU/1/20/1458/045  
 
EU/1/20/1458/035  
EU/1/20/1458/036  
EU/1/20/1458/037  
EU/1/20/1458/038  
EU/1/20/1458/039  
EU/1/20/1458/040 



53 

 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation:  
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

  

http://www.ema.europa.eu/


54 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



55 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
LABORATORI FUNDACIÓ DAU 
C/ C, 12-14 Pol. Ind. Zona Franca, Barcelona, 
08040 Barcelona, Spain 
 
Accord Healthcare Polska Sp. z.o.o. 
ul.Lutomierska 50, 
95-200, Pabianice, 
Poland 
 
Pharmadox Healthcare Limited 
KW20A Kordin Industrial Park, 
Paola PLA 3000, Malta 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
 AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information being 

received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Additional risk minimisation measures 
 
The Marketing Authorisation Holder shall ensure that all physicians who are expected to prescribe 
apixaban are provided with the following educational material: 
 



56 

• Summary of Product Characteristics 
• Prescriber Guide 
• Patient Alert Cards 
 
Key Elements of the Prescriber Guide: 
• Details of populations potentially at higher risk of bleeding 
• Recommended doses and guidance on the posology for different indications 
• Recommendations for dose adjustment in at risk populations, including renal or hepatic 

impairment patients 
• Guidance regarding switching from or to Apixaban Accordtreatment 
• Guidance regarding surgery or invasive procedure, and temporary discontinuation 
• Management of overdose situations and haemorrhage 
• The use of coagulation tests and their interpretation 
• That all patients should be provided with a Patient alert card and be counselled about: 

- Signs or symptoms of bleeding and when to seek attention from a health care provider 
- Importance of treatment compliance 
- Necessity to carry the Patient alert card with them at all times 
- The need to inform Health Care Professionals that they are taking Apixaban Accordif 

they need to have any surgery or invasive procedure. 
 
Key Elements of the Patient Alert Card: 
• Signs or symptoms of bleeding and when to seek attention from a health care provider. 
• Importance of treatment compliance 
• Necessity to carry the Patient alert card with them at all times 
• The need to inform Health Care Professionals that they are taking Apixaban Accord if they 

need to have any surgery or invasive procedure. 
  



57 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
ANNEX III 

 
LABELLING AND PACKAGE LEAFLET 

  



58 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
A. LABELLING 



59 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON OF UNIT PACK  2.5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 2.5 mg film-coated tablets 
apixaban  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 2.5 mg apixaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contain lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
10 film-coated tablets 
14 film-coated tablets 
20 film-coated tablets 
28 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
100 film-coated tablets 
112 film-coated tablets 
168 film-coated tablets 
200 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 



60 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona s/n, 
Edifici Est, 6a Planta, 
Barcelona, 08039 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1458/001  
EU/1/20/1458/003  
EU/1/20/1458/004  
EU/1/20/1458/006  
EU/1/20/1458/008  
EU/1/20/1458/010 
EU/1/20/1458/012  
EU/1/20/1458/014   
EU/1/20/1458/041  
EU/1/20/1458/043  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Apixaban Accord 2.5 mg 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
 



61 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
  



62 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOR UNIT PACK  2.5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 2.5 mg tablets 
 
apixaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Accord 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
  



63 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON FOR UNIT PACK 5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 5 mg film-coated tablets 
apixaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 5 mg apixaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Containlactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
10 film-coated tablets 
14 film-coated tablets 
20 film-coated tablets 
28 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
100 film-coated tablets 
112 film-coated tablets 
168 film-coated tablets 
200 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 



64 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona s/n, 
Edifici Est, 6a Planta, 
Barcelona, 08039 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/20/1458/021   
EU/1/20/1458/023  
EU/1/20/1458/024  
EU/1/20/1458/026  
EU/1/20/1458/028  
EU/1/20/1458/030   
EU/1/20/1458/032  
EU/1/20/1458/034  
EU/1/20/1458/044 
EU/1/20/1458/046 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Apixaban Accord 5 mg 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



65 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
  



66 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER FOR UNT PACKS 5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 5 mg  tablets 
 
apixaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Accord 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  



67 

 
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON OF UNIT PACK CONTAINING SINGLE-UNIT-DOSE BLISTERS 2.5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 2.5 mg film-coated tablets 
apixaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 2.5 mg apixaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contain lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
10 x 1 film-coated tablet 
20 x 1 film-coated tablet 
28 x 1 film-coated tablet 
56 x 1 film-coated tablet 
60 x 1 film-coated tablet 
100 x 1 film-coated tablet 
168 x 1 film-coated tablet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



68 

9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona s/n, 
Edifici Est, 6a Planta, 
Barcelona, 08039 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1458/002 
EU/1/20/1458/005  
EU/1/20/1458/007  
EU/1/20/1458/009  
EU/1/20/1458/011  
EU/1/20/1458/013  
EU/1/20/1458/042 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Apixaban Accord 2.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 



69 

 
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
SINGLE-UNIT-DOSE BLISTERS 2.5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 2.5 mg tablets  
 
apixaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Accord 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  



70 

 
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON OF UNIT PACK CONTAINING SINGLE-UNIT-DOSE BLISTERS 5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 5 mg film-coated tablets 
apixaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 5 mg apixaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contain lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
10 x 1 film-coated tablet 
20 x 1 film-coated tablet 
28 x 1 film-coated tablet 
56 x 1 film-coated tablet 
60 x 1 film-coated tablet 
100 x 1 film-coated tablet 
168 x 1 film-coated tablet 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



71 

9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona s/n, 
Edifici Est, 6a Planta, 
Barcelona, 08039 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1458/022  
EU/1/20/1458/025  
EU/1/20/1458/027  
EU/1/20/1458/029  
EU/1/20/1458/031  
EU/1/20/1458/033  
EU/1/20/1458/045  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Apixaban Accord 5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



72 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
SINGLE-UNIT-DOSE BLISTERS 5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 5 mg  tablets 
 
apixaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Accord 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



73 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON OF BOTTLE PACK 2.5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 2.5 mg film-coated tablets 
apixaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 2.5 mg apixaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contain lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
60 film-coated tablets 
100 film-coated tablets 
168 film-coated tablets 
180 film-coated tablets 
200 film-coated tablets 
1,000 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 



74 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona s/n, 
Edifici Est, 6a Planta, 
Barcelona, 08039 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1458/015  
EU/1/20/1458/016  
EU/1/20/1458/017  
EU/1/20/1458/018  
EU/1/20/1458/019  
EU/1/20/1458/020  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Apixaban Accord 2.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
LABEL FOR BOTTLE PACK 2.5 mg 



75 

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 2.5 mg  tablets 
apixaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 2.5 mg apixaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contain lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
60 film-coated tablets 
100 film-coated tablets 
168 film-coated tablets 
180 film-coated tablets 
200 film-coated tablets 
1,000 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 



76 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona s/n, 
Edifici Est, 6a Planta, 
Barcelona, 08039 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1458/015  
EU/1/20/1458/016  
EU/1/20/1458/017  
EU/1/20/1458/018  
EU/1/20/1458/019  
EU/1/20/1458/020  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 



77 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
CARTON OF BOTTLE PACK 5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 5 mg film-coated tablets 
apixaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 5 mg apixaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contain lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
60 film-coated tablets 
100 film-coated tablets 
168 film-coated tablets 
180 film-coated tablets 
200 film-coated tablets 
1,000 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



78 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona s/n, 
Edifici Est, 6a Planta, 
Barcelona, 08039 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1458/035  
EU/1/20/1458/036  
EU/1/20/1458/037  
EU/1/20/1458/038  
EU/1/20/1458/039  
EU/1/20/1458/040  
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Apixaban Accord 5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



79 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
LABEL FOR BOTTLE PACK 5 mg 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Apixaban Accord 5 mg  tablets 
apixaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 5 mg apixaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contain lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
60 film-coated tablets 
100 film-coated tablets 
168 film-coated tablets 
180 film-coated tablets 
200 film-coated tablets 
1,000 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 



80 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona s/n, 
Edifici Est, 6a Planta, 
Barcelona, 08039 
Spain 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/20/1458/035  
EU/1/20/1458/036  
EU/1/20/1458/037  
EU/1/20/1458/038  
EU/1/20/1458/039  
EU/1/20/1458/040  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



81 

 
 
PATIENT ALERT CARD 
 
Apixaban Accord (apixaban) 
Patient Alert Card 

Carry this card with you at all times 
 
Show this card to your pharmacist, dentist and any other healthcare professionals that treat you. 
 
I am under anticoagulation treatment with Apixaban Accord (apixaban) to prevent blood clots 
 
Please complete this section or ask your doctor to do it 
Name: 
Birth Date: 
Indication: 
Dose:      mg twice daily 
Doctor's Name: 
Doctor's telephone: 
 
Information for patients 
 
 Take Apixaban Accordregularly as instructed. If you miss a dose, take it as soon as you remember 

and continue to follow your dosing schedule. 
 Do not stop taking Apixaban Accordwithout talking to your doctor, as you are at risk of suffering 

from a stroke or other complications. 
 Apixaban Accordhelps to thin your blood. However, this may increase your risk of bleeding. 
 Signs and symptoms of bleeding include bruising or bleeding under the skin, tar-coloured stools, 

blood in urine, nose-bleed, dizziness, tiredness, paleness or weakness, sudden severe headache, 
coughing up blood or vomiting blood. 

 If the bleeding does not stop on its own, seek medical attention immediately. 
 If you need surgery, inform your doctor that you are takingApixaban Accord. 

 
Information for healthcare professionals 
 Apixaban Accord (apixaban) is an oral anticoagulant acting by direct selective inhibition of factor 

Xa. 
 Apixaban Accordmay increase the risk of bleeding. In case of major bleeding events, it should be 

stopped immediately. 
 Treatment with Apixaban Accorddoes not require routine monitoring of exposure. A calibrated 

quantitative anti-Factor Xa assay may be useful in exceptional situations, e.g., overdose and 
emergency surgery (prothrombin time (PT), international normalised  ratio (INR) and activated 
partial thromboplastin time (aPTT) clotting tests are not recommended) – see SmPC.  

 An agent to reverse the anti-factor Xa activity of apixaban is available. 
 

  



82 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



83 

Package leaflet: Information for the user 
 

Apixaban Accord 2.5 mg film-coated tablets 
apixaban 

 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Apixaban Accord is and what it is used for 
2. What you need to know before you take Apixaban Accord 
3. How to take Apixaban Accord 
4. Possible side effects 
5. How to store Apixaban Accord 
6. Contents of the pack and other information 
 
 
1. What Apixaban Accord is and what it is used for 
 
Apixaban Accordcontains the active substance apixaban and belongs to a group of medicines called 
anticoagulants. This medicine helps to prevent blood clots from forming by blocking Factor Xa, which 
is an important component of blood clotting. 
 
Apixaban Accord is used in adults: 
- to prevent blood clots (deep vein thrombosis [DVT]) from forming after hip or knee replacement 

operations. After an operation to the hip or knee you may be at a higher risk of developing blood 
clots in your leg veins. This can cause the legs to swell, with or without pain. If a blood clot travels 
from your leg to your lungs, it can block blood flow causing breathlessness, with or without chest 
pain. This condition (pulmonary embolism) can be life-threatening and requires immediate medical 
attention. 

 
- to prevent a blood clot from forming in the heart in patients with an irregular heart beat (atrial 

fibrillation) and at least one additional risk factor. Blood clots may break off and travel to the brain 
and lead to a stroke or travelto other organs and prevent normal blood flow to that organ (also 
known as a systemic embolism). A stroke can be life-threatening and requires immediate medical 
attention. 

 
- to treat blood clots in the veins of your legs (deep vein thrombosis) and in the blood vessels of your 

lungs (pulmonary embolism), and to prevent blood clots from re-occurring in the blood vessels of 
your legs and/or lungs. 

 
 
2. What you need to know before you take Apixaban Accord 
 
Do not take Apixaban Accordif: 

- you are allergic to apixaban or any of the other ingredients of this medicine (listed in section 6) 
- you are bleeding excessively 
- you have a disease in an organ of the body that increases the risk of serious bleeding (such as an 

active or a recent ulcer of your stomach or bowel, recent bleeding in your brain) 



84 

- you have a liver disease which leads to increased risk of bleeding (hepatic coagulopathy) 
- you are taking medicines to prevent blood clotting (e.g., warfarin, rivaroxaban, dabigatran or 

heparin), except when changing anticoagulant treatment, while having a venous or arterial line and 
you get heparin through this line to keep it open, or if a tube is inserted into your blood vessel 
(catheter ablation) to treat an irregular heartbeat (arrhythmia). 

 
Warnings and precautions 
 
Talk to your doctor, pharmacist or nurse before you take this medicine if you have any of the 
following: 

- an increased risk of bleeding, such as: 
 bleeding disorders, including conditions resulting in reduced platelet activity 
 very high blood pressure, not controlled by medical treatment 
 you are older than 75 years 
 you weigh 60 kg or less 
 

- a severe kidney disease or if you are on dialysis 
- a liver problem or a history of liver problems  
Apixaban Accord will be used with caution in patients with signs of altered liver function. 
- had a tube (catheter) or an injection into your spinal column (for anaesthesia or pain 

reduction), your doctor will tell you to take Apixaban Accord 5 hours or more after catheter 
removal 

- if you have a prosthetic heart valve 
- if your doctor determines that your blood pressure is unstable  

- if another treatment or surgicalprocedure to remove ablood clot from your lungs is planned 
 

Take special care with Apixaban Accord 
 

- if you know that you have a disease called antiphospholipid syndrome (a disorder of the immune 
system that causes an increased risk of blood clots),.In that casetell your doctor who will decide if 
the treatment may need to be changed. 

 
If you need to have surgery or a procedure which may cause bleeding, your doctor might ask you to 
temporarily stop taking this medicine for a short while. If you are not sure whether a procedure may 
cause bleeding ask your doctor. 
 
Children and adolescents 
 
Apixaban Accordis not recommended in children and adolescents under 18 years of age. 
 
Other medicines and Apixaban Accord 
 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 
 
Some medicines may increase the effects of Apixaban Accord and some may decrease its effects. 
Your doctor will decide, if you should be treated with Apixaban Accord when taking these medicines 
and how closely you should be monitored. 
 
The following medicines may increase the effects of Apixaban Accordand increase the chance for 
unwanted bleeding: 

- some medicines for fungal infections (e.g., ketoconazole,.) 
- some antiviral medicines for HIV / AIDS (e.g., ritonavir) 
- other medicines that are used to reduce blood clotting (e.g., enoxaparin,) 



85 

- anti-inflammatory or pain medicines (e.g., acetylsalicylic acid or naproxen). Especially, if you 
are older than 75 years and are taking acetylsalicylic acid, you may have an increased chance of 
bleeding. 

- medicines for high blood pressure or heart problems (e.g., diltiazem) 
- antidepressant medicines called selective serotonin re-uptake inhibitors or serotonin 

norepinephrine re-uptake inhibitors 
 
The following medicines may reduce the ability of Apixaban Accord  to help prevent blood clots from 
forming: 

- medicines to prevent epilepsy or seizures (e.g., phenytoin,) 
- St John’s Wort (a herbal supplement used for depression) 
- medicines to treat tuberculosis or other infections (e.g., rifampicin) 

 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor, pharmacist or nurse for advice before taking this medicine. 
 
The effects of Apixaban Accord on pregnancy and the unborn child are not known. You should not 
take Apixaban Accord if you are pregnant. Contact your doctor immediately if you become 
pregnant while taking  Apixaban Accord. 
 
It is not known if Apixaban Accord passes into human breast milk. Ask your doctor, pharmacist or 
nurse for advice before taking this medicine while breast-feeding. They will advise you to either stop 
breast-feeding or to stop/not start taking Apixaban Accord. 
 
Driving and using machines 
 
Apixaban Accord has not been shown to impair your ability to drive or use machine. 
 
Apixaban Accordcontains lactose (a type of sugar) and sodium 
 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product.  
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially "sodium-
free". 
 
 
3. How to take Apixaban Accord 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor, 
pharmacist or nurse if you are not sure. 
 
Dose 
 
Swallow the tablet with a drink of water. Apixaban Accordcan be taken with or without food. 
Try to take the tablets at the same times every day to have the best treatment effect. 
 
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to 
takeApixaban Accord. The tablet may be crushed and mixed with water, or 5% glucose in water, or 
apple juice or apple puree, immediately before you take it. 
 
Instructions for crushing: 

• Crush the tablets with a pestle and mortaror with the convex side of a spoon on a plate. 
• Transfer all the powder carefully into a suitable container then mix the powder with a little 

e.g., 30 mL (2 tablespoons), water or one of the other liquids mentioned above to make a 
mixture. 



86 

• Swallow the mixture. 
• Rinse the pestle andmortar or the spoon and plate)you used for crushing the tablet and the 

container, with a little water or one of the other liquids (e.g., 30 mL), and swallow the rinse. 
 
If necessary, your doctor may also give you the crushed Apixaban Accordtablet mixed in 60 mL of 
water or 5%  glucose in water, through a nasogastric tube. 
 
Take Apixaban Accord as recommended for the following: 
 
To prevent blood clots from forming after hip or knee replacement operations. 
The recommended dose is one tablet of Apixaban Accord  2.5 mg twice a day. 
For example, one in the morning and one in the evening.  
You should take the first tablet 12 to 24 hours after your operation. 
 
If you have had a major hip operation you will usually take the tablets for 32 to38 days 
If you have had a major knee operation you will usually take the tablets for 10 to 14 days 
 
To prevent a blood clot from forming in the heart in patients with an irregular heart beat and at least 
one additional risk factor. 
 
The recommended dose is one tablet of Apixaban Accord 5 mg twice a day. 
 
The recommended dose is one tablet of Apixaban Accord2.5 mg twice a day if: 

-  you have severely reduced kidney function 
- two or more of the following apply to you: 

- your blood test results suggest poor kidney function (value of serum creatinine is 
1.5 mg/dL (133 micromole/L) or greater) 

- you are 80 years old or older 
- your weight is 60 kg or lower. 

 
The recommended dose is one tablet twice a day, for example, one in the morning and one in the 
evening. Your doctor will decide how long you must continue treatment for. 
 
To treat blood clots in the veins of your legs and blood clots in the blood vessels of your lungs 
 
The recommended dose is two tablets of Apixaban Accord 5 mg twice a day for the first 7 days, for 
example, two in the morning and two in the evening. 
After 7 days the recommended dose is one tablet of Apixaban Accord 5 mg twice a day, for example, 
one in the morning and one in the evening.  
 
For preventing blood clots from re-occurring following completion of 6 months of treatment 
 
The recommended dose is one tablet of Apixaban Accord 2.5 mg twice a day for example, one in the 
morning and one in the evening.  
Your doctor will decide how long you must continue treatment for. 
 
Your doctor might change your anticoagulant treatment as follows: 
 
- Changing from Apixaban Accord to anticoagulant medicines 
Stop taking Apixaban Accord. Start treatment with the anticoagulant medicines (for example heparin) 
at the time you would have taken the next tablet.  
 
- Changing from anticoagulant medicines to Apixaban Accord 
Stop taking the anticoagulant medicines. Start treatment with Apixaban Accord  at the time you would 
have had the next dose of anticoagulant medicine, then continue as normal. 
 



87 

- Changing from treatment with anticoagulant containing vitamin K antagonist (e.g., warfarin) to 
Apixaban AccordStop taking the medicine containing a vitamin K antagonist. Your doctor needs to 
do blood-measurements and instruct you when to start taking Apixaban Accord . 

 
- Changing from Apixaban Accordto anticoagulant treatment containing vitamin K antagonist (e.g., 

warfarin). 
If your doctor tells you that you have to start taking the medicine containing a vitamin K antagonist, 
continue to take Apixaban Accordfor at least 2 days after your first dose of the medicine containing a 
vitamin K antagonist. Your doctor needs to do blood-measurements and instruct you when to stop 
taking Apixaban Accord . 
 
Patients undergoing cardioversion 
 
If your abnormal heartbeat needs to be restored to normal by a procedure called cardioversion, take 
Apixaban Accordat the times your doctor tells you, to prevent blood clots in blood vessels in your 
brain and other blood vessels in your body. 
 
If you take more Apixaban Accord than you should 
 
Tell your doctor immediately if you have taken more than the prescribed dose of Apixaban Accord . 
Take the medicine pack with you, even if there are no tablets left. 
 
If you take more Apixaban Accord  than recommended, you may have an increased risk of bleeding. If 
bleeding occurs, surgeryor blood transfusions or other treatments that may reverse anti-factor Xa 
activity may be required. 
 
If you forget to take Apixaban Accord 
 
 
- Take the dose as soon as you remember and: 

- take the next dose of Apixaban Accordat the usual time 
- then continue as normal. 

 
If you are not sure what to do or have missed more than one dose, ask your doctor, pharmacist or 
nurse. 
 
If you stop taking  
Apixaban Accord 
 
Do not stop taking Apixaban Accord without talking to your doctor first, because the risk of 
developing a blood clot could be higher if you stop treatment too early. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. Apixaban 
Accord can be given for three different medical conditions. The known side effects and how 
frequently they occur for each of these medical conditions may differ and are listed separately 
below.For these conditions, the most common general side effect of Apixaban Accord is bleeding 
which may be potentially life threatening and require immediate medical attention. 
 
The following side effects are known if you take Apixaban Accord to prevent blood clots from 
forming after hip or knee replacement operations. 
 
Common side effects (may affect up to 1 in 10 people) 



88 

 
- Anaemia which may cause tiredness or paleness 
- Bleeding including: 

- bruising and swelling 
- Nausea (feeling sick) 
 
Uncommon side effects (may affect up to 1 in 100 people) 
 
- Reduced number of platelets in your blood (which can affect clotting) 
- Bleeding: 

- occurring after your operation including bruising and swelling, blood or liquid leaking from 
the surgical wound/incision (wound secretion) or injection site 

- in your stomach, bowel or bright/red blood in the stools 
- blood in the urine 
- from your nose 
- from the vagina 

- Low blood pressure which may make you feel faint or have a quickened heartbeat 
- Blood tests may show: 

- abnormal liver function 
- an increase in some liver enzymes 
- an increase in bilirubin, a breakdown product of red blood cells, which can cause yellowing 

of the skin and eyes. 
- Itching 
 
Rare side effects (may affect up to 1 in 1,000 people) 
 
- Allergic reactions (hypersensitivity) which may cause: swelling of the face, lips, mouth, tongue 

and/or throat and difficulty breathing. Contact your doctor immediately if you experience any of 
these symptoms. 

- Bleeding: 
- into a muscle 
- in your eyes 
- from your gums and blood in your spit when coughing 
- from your rectum 

- Hair loss 
 
Not known (frequency cannot be estimated from the available data) 
 
- Bleeding: 

- in your brain or in your spinal column,  
- in your lungs or your throat 
- in your mouth 
- into your abdomen or space behind your abdominal cavity 
- from a haemorrhoid 
- tests showing blood in the stools or in the urine 

- Skin rash 
 
The following side effects are known if you take Apixaban Accord to prevent a blood clot from 
forming in the heart in patients with an irregular heart beat and at least one additional risk factor. 
 
Common side effects (may affect up to 1 in 10 people) 
 
- Bleeding including: 

- in your eyes 
- in your stomach or bowel 
- from your rectum 
- blood in the urine 



89 

- from your nose 
- from your gums 
- bruising and swelling 

- Anaemia which may cause tiredness or paleness 
- Low blood pressure which may make you feel faint or have a quickened heartbeat 
- Nausea (feeling sick) 
- Blood tests may show: 

- an increase in gamma-glutamyltransferase (GGT) 
 
Uncommon side effects (may affect up to 1 in 100 people) 
 
- Bleeding: 

- in your brain or in your spinal column 
- in your mouth or blood in your spit when coughing 
- into your abdomen, or from the vagina 
- bright/red blood in the stools 
- bleeding occurring after your operation including bruising and swelling, blood or liquid 

leaking from the surgical wound/incision (wound secretion) or injection site 
- from a haemorrhoid 
- tests showing blood in the stools or in the urine 

- Reduced number of platelets in your blood (which can affect clotting) 
- Blood tests may show: 

- abnormal liver function 
- an increase in some liver enzymes 
- an increase in bilirubin, a breakdown product of red blood cells, which can cause yellowing 

of the skin and eyes 
- Skin rash 
- Itching 
- Hair loss 
- Allergic reactions (hypersensitivity) which may cause: swelling of the face, lips, mouth, tongue 

and/or throat and difficulty breathing. Contact your doctor immediately if you experience any of 
these symptoms. 

 
Rare side effects (may affect up to 1 in 1,000 people) 
 
- Bleeding: 

- in your lungs or your throat 
- into the space behind your abdominal cavity 
- into a muscle 

 
The following side effects are known if you take Apixaban Accord to treat or prevent re-occurrence of 
blood clots in the veins of your legs and blood clots in the blood vessels of your lungs. 
 
Common side effects (may affect up to 1 in 10 people) 
 
- Bleeding including: 

- from your nose 
- from your gums 
- blood in the urine  
- bruising and swelling 



90 

- in your stomach, your bowel, from your rectum 
- in your mouth 
- from the vagina 

- Anaemia which may cause tiredness or paleness 
- Reduced number of platelets in your blood (which can affect clotting) 
- Nausea (feeling sick) 
- Skin rash 
- Blood tests may show: 

- an increase in gamma-glutamyltransferase (GGT) or alanine aminotransferase (ALT) 
 
Uncommon side effects (may affect up to 1 in 100 people) 
 
- Low blood pressure which may make you feel faint or have a quickened heartbeat 
- Bleeding: 

- in your eyes 
- in your mouth or blood in your spit when coughing 
- bright/red blood in the stools 
- tests showing blood in the stools or in the urine 
- bleeding occurring after your operation including bruising and swelling, blood or liquid 

leaking from the surgical wound/incision (wound secretion) or injection site 
- from a haemorrhoid 
- into a muscle 

- Itching 
- Hair loss 
- Allergic reactions (hypersensitivity) which may cause: swelling of the face, lips, mouth, tongue 
and/or throat and difficulty breathing. Contact your doctor immediately if you experience any of 
these symptoms. 
- Blood tests may show: 

- abnormal liver function 
- an increase in some liver enzymes 
- an increase in bilirubin, a breakdown product of red blood cells, which can cause yellowing 

of the skin and eyes. 
 
Rare side effects (may affect up to 1 in 1,000 people) 
 
Bleeding: 

- in your brain or in your spinal column 
- in your lungs 

 
Not known (frequency cannot be estimated from the available data) 
 
Bleeding: 

- into your abdomen or the space behind your abdominal cavity 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Apixaban Accord 
 
Keep this medicine out of the sight and reach of children. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


91 

Do not use this medicine after the expiry date which is stated on the carton and on blister after EXP. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Apixaban Accord contains 
 
• The active substance is apixaban. Each tablet contains 2.5 mg of apixaban. 
• The other ingredients are: 

- Tablet core: Lactose (see section 2), cellulose microcrystalline, croscarmellose sodium, 
sodium laurilsulfate, magnesium stearate  

- Film coat: Lactose monohydrate (see section 2), hypromellose, titanium dioxide 
(E171), triacetin, iron oxide yellow (E172) 

 
What Apixaban Accord looks like and contents of the pack 
 
The film-coated tablets are yellow, round shaped, biconvex, film coated tablet debossed with “IU1” on 
one side and plain on the other side. 
 
PVC/PVdC-Aluminium blisters are available in 10, 14, 20, 28, 56, 60, 100, 112, 168, and 
200 film-coated tablets. 
 
PVC/PVdC-Aluminium blisters are available in perforated unit dose blisters of 10 x 1, 20 x 1, 28 x 1, 
56 x 1, 60 x 1, 100 x 1 and 168 x 1 film-coated tablet. 
 
HDPE bottle with polypropylene child resistant/continues threaded closure containing 60, 100, 168, 
180, 200 and 1,000 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
Patient Alert Card: handling information 
 
Inside the Apixaban Accordpack together with the package leaflet you will find a Patient Alert Card or 
your doctor might give you a similar card. 
 
This Patient Alert Card includes information that will be helpful to you and alert other doctors that you 
are taking Apixaban Accord. You should keep this card with you at all times. 
 
1. Take the card 

2. Separate your language as needed (this is facilitated by the perforated edges) 

3. Complete the following sections or ask your doctor to do it: 

- Name: 
- Birth Date: 
- Indication: 
- Dose :  ........mg twice daily 
- Doctor's Name: 
- Doctor's telephone: 

 



92 

4. Fold the card and keep it with you at all times 

Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 
 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona, s/n, 
Edifici Est, 6a Planta, 
08039 Barcelona, 
Spain 
 
Manufacturer 
LABORATORI FUNDACIÓ DAU 
C/ C, 12-14 Pol. Ind. Zona Franca, Barcelona, 
08040 Barcelona, Spain 
 
Accord Healthcare Polska Sp. z.o.o. 
ul.Lutomierska 50, 
95-200, Pabianice, 
Poland 
 
Pharmadox Healthcare Limited 
KW20A Kordin Industrial Park, 
Paola PLA 3000, Malta 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 

  

http://www.ema.europa.eu/


93 

Package leaflet: Information for the user 
 

Apixaban Accord  5 mg film-coated tablets 
apixaban 

 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What Apixaban Accord is and what it is used for 
2. What you need to know before you take Apixaban Accord 
3. How to take Apixaban Accord 
4. Possible side effects 
5. How to store Apixaban Accord 
6. Contents of the pack and other information 
 
 
1. What Apixaban Accord is and what it is used for 
 
Apixaban Accord contains the active substance apixaban and belongs to a group of medicines called 
anticoagulants. This medicine helps to prevent blood clots from forming by blocking Factor Xa, which 
is an important component of blood clotting. 
 
Apixaban Accord is used in adults: 
- to prevent a blood clot from forming in the heart in patients with an irregular heart beat (atrial 

fibrillation) and at least one additional risk factor. Blood clots may break off and travel to the brain 
and lead to a stroke or travel  other organs and prevent normal blood flow to that organ (also known 
as a systemic embolism). A stroke can be life-threatening and requires immediate medical attention. 

- to treat blood clots in the veins of your legs (deep vein thrombosis) and in the blood vessels of your 
lungs (pulmonary embolism), and to prevent blood clots from re-occurring in the blood vessels of 
your legs and/or lungs. 

 
 
2. What you need to know before you take Apixaban Accord 
Do not take Apixaban Accord if: 
- you are allergic to apixaban or any of the other ingredients of this medicine (listed in section 6) 
- you are bleeding excessively 
- you have a disease in an organ of the body that increases the risk of serious bleeding (such as an 

active or a recent ulcer of your stomach or bowel, recent bleeding in your brain) 
- you have a liver disease which leads to increased risk of bleeding (hepatic coagulopathy) 
- you are taking medicines to prevent blood clotting (e.g., warfarin, rivaroxaban, dabigatran or 

heparin), except when changing anticoagulant treatmentor while having a venous or arterial line and 
you get heparin through this line to keep it open, or if a tube is inserted into your blood vessel 
(catheter ablation) to treat an irregular heartbeat (arrhythmia). 

 



94 

Warnings and precautions 
 
Talk to your doctor, pharmacist or nurse before you take this medicine if you have any of the 
following: 
- an increased risk of bleeding, such as: 

 bleeding disorders, including conditions resulting in reduced platelet activity 
 very high blood pressure, not controlled by medical treatment 
 you are older than 75 years 
 you weigh 60 kg or less 

 
- a severe kidney disease or if you are on dialysis 
- a liver problem or a history of liver problems 

Apixaban Accord will be used with caution in patients with signs of altered liver function. 
- if you have a prosthetic heart valve 
- if your doctor determines that your blood pressure is unstable  
- if another treatment or surgical procedure to remove ablood clot from your lungs is planned 
 
If you need to have surgery or a procedure which may cause bleeding, your doctor might ask you to 
temporarily stop taking this medicine for a short while. If you are not sure whether a procedure may 
cause bleeding ask your doctor. 
 
Take special care with Apixaban Accord 
- if you know that you have a disease called antiphospholipid syndrome (a disorder of the 

immunesystem that causes an increased risk of blood clots). In that case tell your doctor who 
will decide if the treatmentmay need to be changed. 

 
Children and adolescents 
 
Apixaban Accord  is not recommended in children and adolescents under 18 years of age. 
 
Other medicines and  Apixaban Accord  
 
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 
medicines. 
 
Some medicines may increase the effects of Apixaban Accordand some may decrease its effects. Your 
doctor will decide, if you should be treated with Apixaban Accordwhen taking these medicines and 
how closely you should be monitored. 
 
The following medicines may increase the effects of Apixaban Accordand increase the chance for 
unwanted bleeding: 
- some medicines for fungal infections (e.g., ketoconazole,) 
- some antiviral medicines for HIV / AIDS (e.g., ritonavir) 
- other medicines that are used to reduce blood clotting (e.g., enoxaparin.) 
- anti-inflammatory or pain medicines (e.g., acetylsalicylic acid or naproxen). Especially, if you are 

older than 75 years and are taking acetylsalicylic acid, you may have an increased chance of 
bleeding. 

- medicines for high blood pressure or heart problems (e.g., diltiazem) 
- antidepressant medicines called selective serotonin re-uptake inhibitors or serotonin 

norepinephrine re-uptake inhibitors 
 
The following medicines may reduce the ability of Apixaban Accordto help prevent blood clots from 
forming: 
- medicines to prevent epilepsy or seizures (e.g., phenytoin) 
- St John’s Wort (a herbal supplement used for depression) 



95 

- medicines to treat tuberculosis or other infections (e.g., rifampicin) 
 
Pregnancy and breast-feeding 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor, pharmacist or nurse for advice before taking this medicine. 
 
The effects of Apixaban Accordon pregnancy and the unborn child are not known. You should not 
take Apixaban Accord  if you are pregnant. Contact your doctor immediately if you become 
pregnant while taking Apixaban Accord. 
 
It is not known if Apixaban Accordpasses into human breast milk. Ask your doctor, pharmacist or 
nurse for advice before taking this medicine while breast-feeding. They will advise you to either stop 
breast-feeding or to stop/not start taking Apixaban Accord. 
Driving and using machines 
 
Apixaban Accord  has not been shown to impair your ability to drive or use machines. 
 
Apixaban Accordcontains lactose (a type of sugar) and sodium 
 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicinal product.  
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially "sodium-
free". 
 
 
3. How to take Apixaban Accord 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor, 
pharmacist or nurse if you are not sure. 
 
Dose 
 
Swallow the tablet with a drink of water. Apixaban Accord  can be taken with or without food. 
Try to take the tablets at the same times every day to have the best treatment effect. 
 
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take 
Apixaban Accord. The tablet may be crushed and mixed with water, or 5%  glucose in water, or apple 
juice or apple puree, immediately before you take it. 
 
Instructions for crushing: 

• Crush the tablets with a pestle and mortaror with the convex side of a spoon on a plate. 
• Transfer all the powder carefully into a suitable container then mix the powder with a little 

e.g., 30 mL (2 tablespoons), water or one of the other liquids mentioned above to make a 
mixture. 

• Swallow the mixture. 
• Rinse the pestle and mortar (or the spoon and plate)  you used for crushing the tablet and the 

container, with a little water or one of the other liquids (e.g., 30 mL), and swallow the rinse. 
 
If necessary, your doctor may also give you the crushed Apixaban Accordtablet mixed in 60 mL of 
water or 5%  glucose in water, through a nasogastric tube. 
 
Take Apixaban Accordas recommended for the following: 
 
To prevent a blood clot from forming in the heart in patients with an irregular heart beat and at least 
one additional risk factor. 
 



96 

The recommended dose is one tablet of Apixaban Accord 5 mg twice a day. 
 
The recommended dose is one tablet of Apixaban Accord 2.5 mg twice a day if: 
 

-  you have severely reduced kidney function 
- two or more of the following apply to you: 

- your blood test results suggest poor kidney function (value of serum creatinine is 
1.5 mg/dL (133 micromole/L) or greater) 

- you are 80 years old or older 
- your weight is 60 kg or lower. 

 
The recommended dose is one tablet twice a day, for example, one in the morning and one in the 
evening.  
Your doctor will decide how long you must continue treatment for. 
 
To treat blood clots in the veins of your legs and blood clots in the blood vessels of your lungs 
 
The recommended dose is two tablets of Apixaban Accord 5 mg twice a day for the first 7 days, for 
example, two in the morning and two in the evening. 
After 7 days the recommended dose is one tablet of Apixaban Accord 5 mg twice a day, for example, 
one in the morning and one in the evening.  
 
For preventing blood clots from re-occurring following completion of 6 months of treatment 
 
The recommended dose is one tablet of Apixaban Accord2.5 mg twice a day for example, one in the 
morning and one in the evening.  
Your doctor will decide how long you must continue treatment for. 
 
Your doctor might change your anticoagulant treatment as follows: 
 
- Changing from Apixaban Accord to anticoagulant medicines 
Stop taking Apixaban Accord. Start treatment with the anticoagulant medicines (for example heparin) 
at the time you would have taken the next tablet. 
 
- Changing from anticoagulant medicines to Apixaban Accord 
Stop taking the anticoagulant medicines. Start treatment with Apixaban Accordat the time you would 
have had the next dose of anticoagulant medicine, then continue as normal. 
 
- Changing from treatment with anticoagulant containing vitamin K antagonist (e.g., warfarin) to 

Apixaban AccordStop taking the medicine containing a vitamin K antagonist. Your doctor needs to 
do blood-measurements and instruct you when to start taking Apixaban Accord. 

- Changing from Apixaban Accord to anticoagulant treatment containing vitamin K antagonist (e.g., 
warfarin). 

If your doctor tells you that you have to start taking the medicine containing a vitamin K antagonist, 
continue to take Apixaban Accord for at least 2 days after your first dose of the medicine containing a 
vitamin K antagonist. Your doctor needs to do blood-measurements and instruct you when to stop 
taking Apixaban Accord. 
 
Patients undergoing cardioversion 
 
If your abnormal heartbeat needs to be restored to normal by a procedure called cardioversion, take 
Apixaban Accord at the times your doctor tells you, to prevent blood clots in blood vessels in your 
brain and other blood vessels in your body. 
 



97 

If you take more Apixaban Accordthan you should 
 
Tell your doctor immediately if you have taken more than the prescribed dose of Apixaban Accord. 
Take the medicine pack with you, even if there are no tablets left. 
 
If you take more Apixaban Accord than recommended, you may have an increased risk of bleeding. If 
bleeding occurs, surgery or blood transfusions, or other treatments that may reverse anti-factor Xa 
activity may be required. 
 
If you forget to take Apixaban Accord 
 
- Take the dose as soon as you remember and: 

-  take the next dose of Apixaban Accord at the usual time 
-  then continue as normal. 

 
If you are not sure what to do or have missed more than one dose, ask your doctor, pharmacist or 
nurse. 
 
If you stop taking Apixaban Accord 
 
Do not stop taking Apixaban Accordwithout talking to your doctor first, because the risk of 
developing a blood clot could be higher if you stop treatment too early. 
 
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. The most 
common general side effect of Apixaban Accord is bleeding which may be potentially life threatening 
and require immediate medical attention. 
 
The following side effects are known if you take Apixaban Accordto prevent a blood clot from 
forming in the heart in patients with an irregular heart beat and at least one additional risk factor. 
 
Common side effects (may affect up to 1 in 10 people) 
 
- Bleeding including: 

- in your eyes 
- in your stomach or bowel 
- from your rectum 
- blood in the urine  
- from your nose 
- from your gums 
- bruising and swelling 

- Anaemia which may cause tiredness or paleness 
- Low blood pressure which may make you feel faint or have a quickened heartbeat 
- Nausea (feeling sick)  
- Blood tests may show: 

- an increase in gamma-glutamyltransferase (GGT) 
 
Uncommon side effects (may affect up to 1 in 100 people) 
 
- Bleeding: 



98 

- in your brain or in your spinal column 
- in your mouth or blood in your spit when coughing 
- into your abdomen, or from the vagina 
- bright/red blood in the stools 
- bleeding occurring after your operation including bruising and swelling, blood or liquid 

leaking from the surgical wound/incision (wound secretion) or injection site 
- from a haemorrhoid 
- tests showing blood in the stools or in the urine 

- Reduced number of platelets in your blood (which can affect clotting) 
- Blood tests may show: 

- abnormal liver function 
- an increase in some liver enzymes 
- an increase in bilirubin, a breakdown product of red blood cells, which can cause yellowing 

of the skin and eyes. 
- Skin rash 
- Itching 
- Hair loss 
- Allergic reactions (hypersensitivity) which may cause: swelling of the face, lips, mouth, tongue 

and/or throat and difficulty breathing. Contact your doctor immediately if you experience any of 
these symptoms. 

 
Rare side effects (may affect up to 1 in 1,000 people) 
 
- Bleeding: 

- in your lungs or your throat 
- into the space behind your abdominal cavity 
- into a muscle 

 
The following side effects are known if you take Apixaban Accord  to treat or prevent re-occurrence 
of blood clots in the veins of your legs and blood clots in the blood vessels of your lungs. 
 
Common side effects (may affect up to 1 in 10 people) 
 
- Bleeding including: 

- from your nose 
- from your gums 
- blood in the urine  
- bruising and swelling 
- in your stomach, your bowel, from your rectum 
- in your mouth 
- from the vagina 

- Anaemia which may cause tiredness or paleness 
- Reduced number of platelets in your blood (which can affect clotting) 
- Nausea (feeling sick) 
- Skin rash 
- Blood tests may show: 

- an increase in gamma-glutamyltransferase (GGT) or alanine aminotransferase (ALT) 
 
Uncommon side effects (may affect up to 1 in 100 people) 
 



99 

- Low blood pressure which may make you feel faint or have a quickened heartbeat 
- Bleeding: 

- in your eyes  
- in your mouth or blood in your spit when coughing 
- bright/red blood in the stools 
- tests showing blood in the stools or in the urine 
- bleeding occurring after  your operation including bruising and swelling, blood or liquid 

leaking from the surgical wound/incision (wound secretion) or injection site 
- from a haemorrhoid 
- into a muscle 

- Itching 
- Hair loss 
- Allergic reactions (hypersensitivity) which may cause: swelling of the face, lips, mouth, tongue 

and/or throat and difficulty breathing. Contact your doctor immediately if you experience any of 
these symptoms.  

- Blood tests may show: 
- abnormal liver function 
- an increase in some liver enzymes 
- an increase in bilirubin, a breakdown product of red blood cells, which can cause yellowing 

of the skin and eyes. 
 
Rare side effects (may affect up to 1 in 1,000 people) 
 
Bleeding: 

- in your brain or in your spinal column 
- in your lungs 

 
Not known (frequency cannot be estimated from the available data) 
 
Bleeding: 

- into your abdomen or the space behind your abdominal cavity 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Apixaban Accord 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and on blister after EXP. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Apixaban Accord contains 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


100 

• The active substance is apixaban. Each tablet contains 5 mg of apixaban. 
• The other ingredients are: 

- Tablet core: Lactose (see section 2), cellulose microcrystalline, croscarmellose sodium, 
sodium laurilsulfate, magnesium stearate  

- Film coat: Lactose monohydrate (see section 2), hypromellose, titanium dioxide 
(E171), triacetin, iron oxide red (E172) 

 
What Apixaban Accord looks like and contents of the pack 
 
The film-coated tablets are pink, oval shaped, biconvex, film coated tablet debossed with “IU2” on 
one side and plain on other side. 
 
PVC/PVdC-Aluminium blisters are available in 10, 14, 20, 28, 56, 60, 100, 112, 168, and 
200 film-coated tablets. 
PVC/PVdC-Aluminium blisters are available in perforated unit dose blisters of 10 x 1, 20 x 1, 28 x 1, 
56 x 1, 60 x 1, 100 x 1 and 168 x 1 film-coated tablet. 
 
HDPE bottle with polypropylene child resistant/continues threaded closure containing 60, 100, 168, 
180, 200 and 1,000 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
Patient Alert Card: handling information 
 
Inside the Apixaban Accordpack together with the package leaflet you will find a Patient Alert Card or 
your doctor might give you a similar card. 
This Patient Alert Card includes information that will be helpful to you and alert other doctors that you 
are takingApixaban Accord. You should keep this card with you at all times. 
 
1. Take the card 

2. Separate your language as needed (this is facilitated by the perforated edges) 

3. Complete the following sections or ask your doctor to do it: 

- Name: 
- Birth Date: 
- Indication: 
- Dose :  ........mg twice daily 
- Doctor's Name: 
- Doctor's telephone: 

 
4. Fold the card and keep it with you at all times 

Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder 
Accord Healthcare S.L.U. 
World Trade Center, Moll de Barcelona, s/n, 
Edifici Est, 6a Planta, 
08039 Barcelona, 
Spain 
 
Manufacturer 
LABORATORI FUNDACIÓ DAU 
C/ C, 12-14 Pol. Ind. Zona Franca, Barcelona, 
08040 Barcelona, Spain 



101 

 
Accord Healthcare Polska Sp. z.o.o. 
ul.Lutomierska 50, 
95-200, Pabianice, 
Poland 
 
Pharmadox Healthcare Limited 
KW20A Kordin Industrial Park, 
Paola PLA 3000, Malta 
 
This leaflet was last revised in 
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency website: 

http://www.ema.europa.eu 

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET