Roteas

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



2 

This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions.  
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 15 mg film-coated tablets 
Roteas 30 mg film-coated tablets 
Roteas 60 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Roteas 15 mg film-coated tablets 
Each 15 mg film-coated tablet contains 15 mg edoxaban (as tosilate). 
 
Roteas 30 mg film-coated tablets 
Each 30 mg film-coated tablet contains 30 mg edoxaban (as tosilate). 
 
Roteas 60 mg film-coated tablets 
Each 60 mg film-coated tablet contains 60 mg edoxaban (as tosilate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
 
Roteas 15 mg film-coated tablets 
Orange, round-shaped film-coated tablets (6.7 mm diameter) debossed with “DSC L15”. 
 
Roteas 30 mg film-coated tablets 
Pink, round-shaped film-coated tablets (8.5 mm diameter) debossed with “DSC L30”. 
 
Roteas 60 mg film-coated tablets 
Yellow, round-shaped film-coated tablets (10.5 mm diameter) debossed with “DSC L60”. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Roteas is indicated in prevention of stroke and systemic embolism in adult patients with nonvalvular 
atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, 
age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA). 
 
Roteas is indicated in treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and 
for the prevention of recurrent DVT and PE in adults (see section 4.4 for haemodynamically unstable 
PE patients). 
 



3 

4.2 Posology and method of administration 
 
Posology 
 
Prevention of stroke and systemic embolism 
The recommended dose is 60 mg edoxaban once daily.  
Therapy with edoxaban in NVAF patients should be continued long term. 
 
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTE) 
The recommended dose is 60 mg edoxaban once daily following initial use of parenteral anticoagulant 
for at least 5 days (see section 5.1). Edoxaban and initial parenteral anticoagulant should not be 
administered simultaneously. 
The duration of therapy for treatment of DVT and PE (venous thromboembolism (VTE)), and 
prevention of recurrent VTE should be individualised after careful assessment of the treatment benefit 
against the risk for bleeding (see section 4.4). Short duration of therapy (at least 3 months) should be 
based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations 
should be based on permanent risk factors or idiopathic DVT or PE. 
 
For NVAF and VTE the recommended dose is 30 mg edoxaban once daily in patients with one or 
more of the following clinical factors: 
• Moderate or severe renal impairment (creatinine clearance (CrCl) 15 - 50 mL/min) 
• Low body weight ≤ 60 kg 
• Concomitant use of the following P-glycoprotein (P-gp) inhibitors: ciclosporin, dronedarone, 

erythromycin, or ketoconazole. 
 
Table 1: Summary of posology in NVAF and VTE (DVT and PE) 

Summary guide for dosing 

Recommended dose  
60 mg edoxaban  

once daily 
Dose recommendation for patients with one or more of the following clinical factors: 

Renal impairment Moderate or severe (CrCl 15 – 50 mL/min) 

30 mg edoxaban  
once daily Low body weight ≤ 60 kg  

P-gp inhibitors Ciclosporin, dronedarone, erythromycin, 
ketoconazole 

 
Missed dose 
If a dose of edoxaban is missed, the dose should be taken immediately and then be continued the 
following day with the once-daily intake as recommended. The patient should not take double the 
prescribed dose on the same day to make up for a missed dose. 
 
 
Switching to and from edoxaban 
Continued anticoagulant therapy is important in patients with NVAF and VTE. There may be 
situations that warrant a change in anticoagulation therapy (Table 2). 
 



4 

Table 2: Switching of anticoagulant treatment in NVAF and VTE (DVT and PE) 

  

Switching to edoxaban 

From To Recommendation 
Vitamin K antagonist 

(VKA) Edoxaban Discontinue the VKA and start edoxaban when the 
international normalised ratio (INR) is ≤ 2.5. 

Oral anticoagulants 
other than VKA 
• dabigatran 
• rivaroxaban 
• apixaban 

Edoxaban 
Discontinue dabigatran, rivaroxaban or apixaban and 
start edoxaban at the time of the next dose of the oral 
anticoagulant (see section 5.1). 

Parenteral 
anticoagulants Edoxaban 

These medicinal products should not be administered 
simultaneously. 
Subcutaneous anticoagulant (i.e. low molecular weight 
heparin (LMWH), fondaparinux):  
Discontinue subcutaneous anticoagulant and start 
edoxaban at the time of the next scheduled subcutaneous 
anticoagulant dose. 
Intravenous unfractionated heparin (UFH): 
Discontinue the infusion and start edoxaban 4 hours 
later. 



5 

 
 

Switching from edoxaban 

From To Recommendation 

Edoxaban VKA 

There is a potential for inadequate anticoagulation 
during the transition from edoxaban to VKA. 
Continuous adequate anticoagulation should be 
ensured during any transition to an alternate 
anticoagulant.  
 
Oral option: For patients currently on a 60 mg dose, 
administer an edoxaban dose of 30 mg once daily 
together with an appropriate VKA dose.  
 
For patients currently on a 30 mg dose (for one or 
more of the following clinical factors: moderate to 
severe renal impairment (CrCl 15 – 50 mL/min), 
low body weight, or use with certain P-gp 
inhibitors), administer an edoxaban dose of 15 mg 
once daily together with an appropriate VKA dose. 
 
Patients should not take a loading dose of VKA in 
order to promptly achieve a stable INR between 2 
and 3. It is recommended to take into account the 
maintenance dose of VKA and if the patient was 
previously taking a VKA or to use valid INR driven 
VKA treatment algorithm, in accordance with local 
practice.  
 
Once an INR ≥ 2.0 is achieved, edoxaban should be 
discontinued. Most patients (85%) should be able to 
achieve an INR ≥ 2.0 within 14 days of concomitant 
administration of edoxaban and VKA. After 14 days 
it is recommended that edoxaban is discontinued 
and the VKA continued to be titrated to achieve an 
INR between 2 and 3. 
 
It is recommended that during the first 14 days of 
concomitant therapy the INR is measured at least 
3 times just prior to taking the daily dose of 
edoxaban to minimise the influence of edoxaban on 
INR measurements. Concomitant edoxaban and 
VKA can increase the INR post edoxaban dose by 
up to 46%. 
 
Parenteral option: Discontinue edoxaban and 
administer a parenteral anticoagulant and VKA at 
the time of the next scheduled edoxaban dose. Once 
a stable INR of ≥ 2.0 is achieved, the parenteral 
anticoagulant should be discontinued and the VKA 
continued. 

Edoxaban Oral anticoagulants 
other than VKA 

Discontinue edoxaban and start the non-VKA 
anticoagulant at the time of the next scheduled dose 
of edoxaban. 



6 

Switching from edoxaban 

From To Recommendation 

Edoxaban Parenteral 
anticoagulants 

These medicinal products should not be 
administered simultaneously. Discontinue edoxaban 
and start the parenteral anticoagulant at the time of 
the next scheduled dose of edoxaban. 

 
Special populations 
Elderly population 
No dose reduction is required (see section 5.2). 
 
Renal impairment 
Renal function should be assessed in all patients by calculating the CrCl prior to initiation of treatment 
with edoxaban to exclude patients with end stage renal disease (i.e. CrCl < 15 mL/min), to use the 
correct edoxaban dose in patients with CrCl 15 – 50 mL/min (30 mg once daily), in patients with CrCl 
> 50 mL/min (60 mg once daily) and when deciding on the use of edoxaban in patients with increased 
CrCl (see section 4.4). 

 
Renal function should also be assessed when a change in renal function is suspected during treatment 
(e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products). 
 
The method used to estimate renal function (CrCl in mL/min) during the clinical development of 
edoxaban was the Cockcroft-Gault method. The formula is as follows: 
 
• For creatinine in µmol/L: 

1.23 × (140-age [years]) × weight [kg] (× 0.85 if female) 
serum creatinine [µmol/L] 

 
• For creatinine in mg/dL: 

(140-age [years]) × weight [kg] (× 0.85 if female) 
72 × serum creatinine [mg/dL] 

 
This method is recommended when assessing patients’ CrCl prior to and during edoxaban treatment. 
 
In patients with mild renal impairment (CrCl > 50 – 80 mL/min), the recommended dose is 60 mg 
edoxaban once daily. 
 
In patients with moderate or severe renal impairment (CrCl 15 – 50 mL/min), the recommended dose 
is 30 mg edoxaban once daily (see section 5.2). 
 
In patients with end stage renal disease (ESRD) (CrCl < 15 mL/min) or on dialysis, the use of 
edoxaban is not recommended (see sections 4.4 and 5.2). 
 
Hepatic impairment 
Edoxaban is contraindicated in patients with hepatic disease associated with coagulopathy and 
clinically relevant bleeding risk (see section 4.3). 
 
In patients with severe hepatic impairment edoxaban is not recommended (see sections 4.4 and 5.2). 
 
In patients with mild to moderate hepatic impairment the recommended dose is 60 mg edoxaban once 
daily (see section 5.2). Edoxaban should be used with caution in patients with mild to moderate 
hepatic impairment (see section 4.4). 
 



7 

Patients with elevated liver enzymes (alanine aminotransferase (ALT) or aspartate transaminase (AST) 
> 2 x upper limit of normal (ULN)) or total bilirubin ≥ 1.5 x ULN, were excluded in clinical studies. 
Therefore edoxaban should be used with caution in this population (see sections 4.4 and 5.2). Prior to 
initiating edoxaban, liver function testing should be performed. 
 
Body weight 
For patients with body weight ≤ 60 kg, the recommended dose is 30 mg edoxaban once daily (see 
section 5.2). 
 
Gender 
No dose reduction is required (see section 5.2). 
 
Concomitant use of Roteas with P-glycoprotein (P-gp) inhibitors 
In patients concomitantly taking Roteas and the following P-gp inhibitors: ciclosporin, dronedarone, 
erythromycin, or ketoconazole, the recommended dose is 30 mg Roteas once daily (see section 4.5). 
No dose reduction is required for concomitant use of amiodarone, quinidine or verapamil (see section 
4.5). 
The use of Roteas with other P-gp inhibitors including HIV protease inhibitors has not been studied. 
 
Paediatric population 
The safety and efficacy of edoxaban in children and adolescents less than 18 years of age have not 
been established. No data are available. 
 
Patients undergoing cardioversion 
Roteas can be initiated or continued in patients who may require cardioversion. For transoesophageal 
echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, 
Roteas treatment should be started at least 2 hours before cardioversion to ensure adequate 
anticoagulation (see sections 5.1 and 5.2). Cardioversion should be performed no later than 12 hours 
after the dose of Roteas on the day of the procedure.  
For all patients undergoing cardioversion: Confirmation should be sought prior to cardioversion 
that the patient has taken Roteas as prescribed. Decisions on initiation and duration of treatment 
should follow established guidelines for anticoagulant treatment in patients undergoing cardioversion. 
 
Method of administration  
 
For oral use.  
Edoxaban can be taken with or without food (see section 5.2). 
 
For patients who are unable to swallow whole tablets, Roteas tablets may be crushed and mixed with 
water or apple puree and immediately administered orally (see section 5.2).  
 
Alternatively, Roteas tablets may be crushed and suspended in a small amount of water and 
immediately delivered through a gastric tube after which it should be flushed with water (see section 
5.2). Crushed Roteas tablets are stable in water 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. 

Clinically significant active bleeding. 

Hepatic disease associated with coagulopathy and clinically relevant bleeding risk. 

Lesion or condition, if considered to be a significant risk 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. 



8 

Uncontrolled severe hypertension. 

Concomitant treatment with any other anticoagulants e.g. UFH, LMWH (enoxaparin, dalteparin, etc.), 
heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, 
rivaroxaban, apixaban etc.) except under specific circumstances of switching oral anticoagulant 
therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous 
or arterial catheter (see section 4.5). 

Pregnancy and breast-feeding (see section 4.6). 

 
4.4 Special warnings and precautions for use 
 
Edoxaban 15 mg is not indicated as monotherapy, as it may result in decreased efficacy. It is only 
indicated in the process of switching from edoxaban 30 mg (patients with one or more clinical factors 
for increased exposure; see table 1) to VKA, together with an appropriate VKA dose (see table 2, 
section 4.2). 
 
Haemorrhagic risk 
 
Edoxaban increases the risk of bleeding and can cause serious, potentially fatal bleeding. Edoxaban, 
like other anticoagulants, is recommended to be used with caution in patients with increased risk of 
bleeding. Edoxaban administration should be discontinued if severe haemorrhage occurs (see sections 
4.8 and 4.9). 
 
In the clinical studies mucosal bleedings (e.g. epistaxis, gastrointestinal, genitourinary) and anaemia 
were seen more frequently during long term edoxaban treatment compared with VKA treatment. Thus, 
in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be 
of value to detect occult bleeding, as judged to be appropriate. 
 
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are 
to be carefully monitored for signs and symptoms of bleeding complications and anaemia after 
initiation of treatment (see section 4.8). Any unexplained fall in haemoglobin or blood pressure should 
lead to a search for a bleeding site. 
 
The anticoagulant effect of edoxaban cannot be reliably monitored with standard laboratory testing.  
A specific anticoagulant reversal agent for edoxaban is not available (see section 4.9). 
 
Haemodialysis does not significantly contribute to edoxaban clearance (see section 5.2). 
 
Elderly  
The co-administration of edoxaban with acetylsalicylic acid (ASA) in elderly patients should be used 
cautiously because of a potentially higher bleeding risk (see section 4.5). 
 
Renal impairment 
The plasma area under the curve (AUC) for subjects with mild (CrCl > 50 - 80 mL/min), moderate 
(CrCl 30 - 50 mL/min) and severe (CrCl < 30 mL/min but not undergoing dialysis) renal impairment 
was increased by 32%, 74%, and 72%, respectively, relative to subjects with normal renal function 
(see section 4.2 for dose reduction). 
 
In patients with end stage renal disease or on dialysis, Roteas is not recommended (see sections 4.2 
and 5.2). 
 



9 

Renal function in NVAF 
A trend towards decreasing efficacy with increasing CrCl was observed for edoxaban compared to 
well-managed warfarin (see section 5.1 for ENGAGE AF-TIMI 48 and additional data from E314 and 
ETNA-AF). 
Edoxaban should be used in patients with NVAF and high CrCl only after a careful evaluation of the 
individual thromboembolic and bleeding risk. 
 
Assessment of renal function: CrCl should be monitored at the beginning of the treatment in all 
patients and afterwards when clinically indicated (see section 4.2). 
 
Hepatic impairment 
 
Edoxaban is not recommended in patients with severe hepatic impairment (see sections 4.2 and 5.2). 
 
Edoxaban should be used with caution in patients with mild or moderate hepatic impairment (see 
section 4.2). 
 
Patients with elevated liver enzymes (ALT/AST > 2 x ULN) or total bilirubin ≥ 1.5 x ULN were 
excluded in clinical studies. Therefore edoxaban should be used with caution in this population (see 
sections 4.2 and 5.2). Prior to initiating edoxaban, liver function testing should be performed. 
Periodic hepatic monitoring is recommended for patients on edoxaban treatment beyond 1 year. 
 
Discontinuation for surgery and other interventions 
 
If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other 
procedures, edoxaban should be stopped as soon as possible and preferably at least 24 hours before the 
procedure. 
 
In deciding whether a procedure should be delayed until 24 hours after the last dose of edoxaban, the 
increased risk of bleeding should be weighed against the urgency of the intervention. Edoxaban should 
be restarted after the surgical or other procedures as soon as adequate haemostasis has been 
established, noting that the time to onset of the edoxaban anticoagulant therapeutic effect is 
1 – 2 hours. If oral medicinal products cannot be taken during or after surgical intervention, consider 
administering a parenteral anticoagulant and then switch to oral once daily edoxaban (see section 4.2). 
 
Interaction with other medicinal products affecting haemostasis 
 
Concomitant use of medicines affecting haemostasis may increase the risk of bleeding. These include 
ASA, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, selective serotonin 
reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), and chronic 
nonsteroidal anti-inflammatory drugs (NSAIDs) (see section 4.5). 
 
Prosthetic heart valves and moderate to severe mitral stenosis 
 
Edoxaban has not been studied in patients with mechanical heart valves, in patients during the first 
3 months after implantation of a bioprosthetic heart valve, with or without atrial fibrillation, or in 
patients with moderate to severe mitral stenosis. Therefore, use of edoxaban is not recommended in 
these patients. 
 
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary 
embolectomy  
 
Edoxaban is not recommended as an alternative to UFH in patients with pulmonary embolism who are 
haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety 
and efficacy of edoxaban have not been established in these clinical situations. 
 



10 

Patients with active cancer 
 
Efficacy and safety of edoxaban in the treatment and/or prevention of VTE in patients with active 
cancer have not been established. 
 
Patients with antiphospholipid syndrome 
 
Direct acting oral anticoagulants (DOACs) including edoxaban 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. 
 
Laboratory coagulation parameters 
 
Although treatment with edoxaban does not require routine monitoring, the effect on anticoagulation 
can be estimated by a calibrated quantitative anti-Factor Xa (anti-FXa) assay which may help to 
inform clinical decisions in particular situations as, e.g. overdose and emergency surgery (see also 
section 5.2).  
 
Edoxaban prolongs standard clotting tests such as prothrombin time (PT), INR, and activated partial 
thromboplastin time (aPTT) as a result of Factor Xa (FXa) inhibition. Changes observed in these 
clotting tests at the expected therapeutic dose are, however, small, subject to a high degree of 
variability, and not useful in monitoring the anticoagulation effect of edoxaban. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Edoxaban is predominantly absorbed in the upper gastrointestinal (GI) tract. Thus, medicines or 
disease conditions that increase gastric emptying and gut motility have the possibility of reducing 
edoxaban dissolution and absorption. 
 
P-gp inhibitors 
 
Edoxaban is a substrate for the efflux transporter P-gp. In pharmacokinetic (PK) studies, concomitant 
administration of edoxaban with the P-gp inhibitors ciclosporin, dronedarone, erythromycin, 
ketoconazole, quinidine, or verapamil resulted in increased plasma concentrations of edoxaban. 
Concomitant use of edoxaban with ciclosporin, dronedarone, erythromycin, or ketoconazole requires 
dose reduction to 30 mg once daily. Concomitant use of edoxaban with quinidine, verapamil, or 
amiodarone does not require dose reduction based on clinical data (see section 4.2). 
The use of edoxaban with other P-gp inhibitors including human immunodeficiency virus (HIV) 
protease inhibitors has not been studied. 
 
Edoxaban 30 mg once daily must be administered during concomitant use with the following P-gp 
inhibitors: 

• Ciclosporin: Concurrent administration of a single dose of ciclosporin 500 mg with a single dose 
of edoxaban 60 mg increased edoxaban AUC and maximum serum concentration (Cmax) by 73% 
and 74%, respectively. 

• Dronedarone: Dronedarone 400 mg twice daily for 7 days with a single concomitant dose of 
edoxaban 60 mg on day 5 increased edoxaban AUC and Cmax by 85% and 46%, respectively. 

• Erythromycin: Erythromycin 500 mg four times daily for 8 days with a single concomitant dose of 
edoxaban 60 mg on day 7 increased the edoxaban AUC and Cmax by 85% and 68%, respectively. 

• Ketoconazole: Ketoconazole 400 mg once daily for 7 days with a single concomitant dose of 
edoxaban 60 mg on day 4, increased edoxaban AUC and Cmax by 87% and 89%, respectively. 

 



11 

Edoxaban 60 mg once daily is recommended during concomitant use with the following P-gp 

inhibitors: 

• Quinidine: Quinidine 300 mg once daily on days 1 and 4 and three times daily on days 2 and 3, 
with a single concomitant dose of edoxaban 60 mg on day 3, increased edoxaban AUC over 
24 hours by 77% and Cmax by 85%, respectively. 

• Verapamil: Verapamil 240 mg once daily for 11 days with a single concomitant dose of edoxaban 
60 mg on day 10 increased the edoxaban AUC and Cmax by approximately 53%. 

• Amiodarone: Co-administration of amiodarone 400 mg once daily with edoxaban 60 mg once 
daily increased AUC by 40% and Cmax by 66%. This was not considered clinically significant. In 
ENGAGE AF-TIMI 48 study in NVAF, efficacy and safety results were similar for subjects with 
and without concomitant amiodarone use. 

 
P-gp inducers 
 
Co-administration of edoxaban with the P-gp inducer rifampicin led to a decrease in mean edoxaban 
AUC and a shortened half-life, with possible decreases in its pharmacodynamic effects. The 
concomitant use of edoxaban with other P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbital 
or St. John's Wort) may lead to reduced edoxaban plasma concentrations. Edoxaban should be used 
with caution when co-administered with P-gp inducers. 
 
P-gp substrates 
 
Digoxin: Edoxaban 60 mg once daily on days 1 to 14 with coadministration of multiple daily doses of 
digoxin 0.25 mg twice daily (days 8 and 9) and 0.25 mg once daily (days 10 to 14) increased the Cmax 
of edoxaban by 17%, with no significant effect on AUC or renal clearance at steady state. When the 
effects of edoxaban on digoxin PK were also examined, the Cmax of digoxin increased by 
approximately 28% and AUC by 7%. This was not considered clinically relevant. No dose 
modification is necessary when edoxaban is administered with digoxin. 
 
Anticoagulants, antiplatelets, NSAIDs and SSRIs/SNRIs 
 
Anticoagulants: Co-administration of edoxaban with other anticoagulants is contraindicated due to 
increased risk of bleeding (see section 4.3). 
 
ASA: Co-administration of ASA (100 mg or 325 mg) and edoxaban increased bleeding time relative to 
either medicine alone. Co-administration of high dose ASA (325 mg) increased the steady state Cmax 
and AUC of edoxaban by 35% and 32%, respectively. The concomitant chronic use of high dose ASA 
(325 mg) with edoxaban is not recommended. Concomitant administration of higher doses than 
100 mg ASA should only be performed under medical supervision. 
 
In clinical studies concomitant use of ASA (low dose ≤ 100 mg/day), other antiplatelet agents, and 
thienopyridines was permitted and resulted in approximately a 2-fold increase in major bleeding in 
comparison with no concomitant use, although to a similar extent in the edoxaban and warfarin groups 
(see section 4.4). Co-administration of low dose ASA (≤ 100 mg) did not affect the peak or total 
exposure of edoxaban either after single dose or at steady-state. 
Edoxaban can be co-administered with low dose ASA (≤ 100 mg/day). 
 
Platelet inhibitors: In ENGAGE AF-TIMI 48 concomitant use of thienopyridines (e.g. clopidogrel) 
monotherapy was permitted and resulted in increased clinically relevant bleeding although with a 
lower risk of bleeding on edoxaban compared to warfarin (see section 4.4). 
 
There is very limited experience on the use of edoxaban with dual antiplatelet therapy or fibrinolytic 
agents. 
 



12 

NSAIDs: Co-administration of naproxen and edoxaban increased bleeding time relative to either 
medicine alone. Naproxen had no effect on the Cmax and AUC of edoxaban. In clinical studies, 
co-administration of NSAIDs resulted in increased clinically relevant bleeding. Chronic use of 
NSAIDs with edoxaban is not recommended. 
 
SSRIs/SNRIs: As with other anticoagulants the possibility may exist that patients are at increased risk 
of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets 
(see section 4.4). 
 
Effect of edoxaban on other medicinal products 
 
Edoxaban increased the Cmax of concomitantly administered digoxin by 28%; however, the AUC was 
not affected. Edoxaban had no effect on the Cmax and AUC of quinidine.  
 
Edoxaban decreased the Cmax and AUC of concomitantly administered verapamil by 14% and 16%, 
respectively. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential 
 
Women of childbearing potential should avoid becoming pregnant during treatment with edoxaban. 
 
Pregnancy 
 
Safety and efficacy of edoxaban have not been established in pregnant women. Studies in animals 
have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the 
intrinsic risk of bleeding and the evidence that edoxaban passes the placenta, Roteas is contraindicated 
during pregnancy (see section 4.3). 
 
Breast-feeding 
 
Safety and efficacy of edoxaban have not been established in breast-feeding women. Data from 
animals indicate that edoxaban is secreted into breast milk. Therefore Roteas is contraindicated during 
breast-feeding (see section 4.3). A decision must be made whether to discontinue breast-feeding or to 
discontinue/abstain from therapy. 
 
Fertility 
 
No specific studies with edoxaban in human beings have been conducted to evaluate effects on 
fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Roteas has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
The safety profile of edoxaban is based on two Phase 3 studies (21,105 patients with NVAF and 8,292 
patients with VTE (DVT and PE)), and from post-authorisation experience. 
The most commonly reported adverse reactions associated with edoxaban treatment are epistaxis 
(7.7%), haematuria (6.9%) and anaemia (5.3%). 
 
Bleeding can occur at any site and may be severe and even fatal (see section 4.4). 
 
 



13 

Tabulated list of adverse reactions 
 
Table 3 provides the list of adverse reactions from the two pivotal Phase 3 studies in patients with 
VTE and NVAF combined for both indications and adverse drug reactions identified in the post-
marketing setting. The adverse reactions are classified according to the MedDRA system organ class 
(SOC) 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). 
 
Table 3: List of adverse reactions for NVAF and VTE 

System organ class Frequency 
Blood and lymphatic system disorders  
Anaemia Common 
Thrombocytopenia Uncommon 
Immune system disorders  
Hypersensitivity Uncommon 
Anaphylactic reaction Rare 
Allergic oedema Rare 
Nervous system disorders  
Dizziness Common 
Headache Common 
Intracranial haemorrhage (ICH) Uncommon 
Subarachnoid haemorrhage Rare 
Eye disorders  
Conjunctival/scleral haemorrhage Uncommon 
Intraocular haemorrhage Uncommon 
Cardiac disorders  
Pericardial haemorrhage Rare 
Vascular disorders  
Other haemorrhage Uncommon 
Respiratory, thoracic and mediastinal disorders  
Epistaxis Common 
Haemoptysis Uncommon 
Gastrointestinal disorders  
Abdominal pain Common 
Lower GI haemorrhage Common 
Upper GI haemorrhage Common 
Oral/pharyngeal haemorrhage Common 
Nausea Common 
Retroperitoneal haemorrhage Rare 
Hepatobiliary disorders  
Blood bilirubin increased Common 
Gammaglutamyltransferase increased Common 
Blood alkaline phosphatase increased Uncommon 
Transaminases increased Uncommon 
Skin and subcutaneous tissue disorders  
Cutaneous soft tissue haemorrhage Common 
Rash Common 



14 

System organ class Frequency 
Pruritus Common 
Urticaria Uncommon 
Musculoskeletal and connective tissue disorders  
Intramuscular haemorrhage (no compartment syndrome) Rare 
Intra-articular haemorrhage Rare 
Renal and urinary disorders  
Macroscopic haematuria/urethral haemorrhage Common 
Reproductive system and breast disorders  
Vaginal haemorrhage1 Common 
General disorders and administration site conditions  
Puncture site haemorrhage Common 
Investigations  
Liver function test abnormal Common 
Injury, poisoning and procedural complications  
Surgical site haemorrhage Uncommon 
Subdural haemorrhage Rare 

Procedural haemorrhage Rare 
 

1 Reporting rates are based on the female population in clinical studies. Vaginal bleeds were reported 
commonly in women under the age of 50 years, while it was uncommon in women over the age of 
50 years. 

 
Description of selected adverse reactions 
 
Haemorrhagic anaemia 
Due to the pharmacological mode of action, the use of edoxaban may be associated with an increased 
risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic 
anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the 
location and degree or extent of the bleeding and/or anaemia (see section 4.9). In the clinical studies 
mucosal bleedings (e.g. epistaxis, gastrointestinal, genitourinary) and anaemia were seen more 
frequently during long term edoxaban treatment compared with VKA treatment. Thus, in addition to 
adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to 
detect occult bleeding, as judged to be appropriate. The risk of bleedings may be increased in certain 
patient groups e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant 
treatment affecting haemostasis (see section 4.4). Menstrual bleeding may be intensified and/or 
prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or 
unexplained swelling, dyspnoea, and unexplained shock. 
Known complications secondary to severe bleeding such as compartment syndrome and renal failure 
due to hypoperfusion have been reported for edoxaban. Therefore, the possibility of haemorrhage is to 
be considered in evaluating the condition in any anticoagulated patient. 
 
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. 
 

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


15 

4.9 Overdose 
 
Overdose with edoxaban may lead to haemorrhage. Experience with overdose cases is very limited. 
 
A specific antidote antagonising the pharmacodynamic effect of edoxaban is not available. 
 
Early administration of activated charcoal may be considered in case of edoxaban overdose to reduce 
absorption. This recommendation is based on standard treatment of medicinal product overdose and 
data available with similar compounds, as the use of activated charcoal to reduce absorption of 
edoxaban has not been specifically studied in the edoxaban clinical programme. 
 
Management of bleeding 
 
Should a bleeding complication arise in a patient receiving edoxaban, the next edoxaban 
administration should be delayed or treatment should be discontinued as appropriate. Edoxaban has a 
half-life of approximately 10 to 14 hours (see section 5.2). Management should be individualised 
according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could 
be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis 
with bleeding control procedures, fluid replacement and haemodynamic support, blood products 
(packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or 
platelets. 
 
For life-threatening bleeding that cannot be controlled with the measures such as transfusion or 
haemostasis, the administration of a 4-factor prothrombin complex concentrate (PCC) at 50 IU/kg has 
been shown to reverse the effects of edoxaban 30 minutes after completing the infusion. 
 
Recombinant factor VIIa (r-FVIIa) can also be considered. However, there is limited clinical 
experience with the use of this product in individuals receiving edoxaban. 
 
Depending on local availability, a consultation with a coagulation expert should be considered in case 
of major bleedings. 
 
Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of edoxaban. 
 
There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals 
receiving edoxaban. There is neither scientific rationale for benefit nor experience with the use of 
systemic haemostatics (desmopressin, aprotinin) in individuals receiving edoxaban. Due to the high 
plasma protein binding edoxaban is not expected to be dialysable. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors; ATC code: B01AF03 
 
Mechanism of action 
 
Edoxaban is a highly selective, direct and reversible inhibitor of FXa, the serine protease located in the 
final common pathway of the coagulation cascade. Edoxaban inhibits free FXa, and prothrombinase 
activity. Inhibition of FXa in the coagulation cascade reduces thrombin generation, prolongs clotting 
time and reduces the risk of thrombus formation. 
 



16 

Pharmacodynamic effects 
 
Edoxaban produces rapid onset of pharmacodynamic effects within 1 - 2 hours, which corresponds 
with peak edoxaban exposure (Cmax). The pharmacodynamic effects measured by anti-FXa assay are 
predictable and correlate with the dose and the concentration of edoxaban. As a result of FXa 
inhibition, edoxaban also prolongs clotting time in tests such as PT, and aPTT. Changes observed in 
these clotting tests are expected at the therapeutic dose, however, these changes are small, subject to a 
high degree of variability, and not useful in monitoring the anticoagulation effect of edoxaban. 
 
Effects of coagulation markers when switching from rivaroxaban, dabigatran, or apixaban to 
edoxaban 
In clinical pharmacology studies, healthy subjects received rivaroxaban 20 mg once daily, dabigatran 
150 mg twice daily, or apixaban 5 mg twice daily, followed by a single dose of edoxaban 60 mg on 
day 4. The effect on PT and other coagulation biomarkers (e.g. anti-FXa, aPTT) was measured. 
Following the switch to edoxaban on day 4 the PT was equivalent to day 3 of rivaroxaban and 
apixaban. For dabigatran higher aPTT activity was observed after edoxaban administration with prior 
dabigatran treatment compared to that after treatment with edoxaban alone. This is considered to be 
due to the carry-over effect of dabigatran treatment, however, this did not lead to a prolongation of 
bleeding time. 
Based on these data, when switching from these anticoagulants to edoxaban, the first dose of edoxaban 
can be initiated at the time of the next scheduled dose of the previous anticoagulant (see section 4.2). 
 
Clinical efficacy and safety 
 
Prevention of stroke and systemic embolism 
The edoxaban clinical programme for atrial fibrillation was designed to demonstrate the efficacy and 
safety of two dose groups of edoxaban compared to warfarin for the prevention of stroke and systemic 
embolism in subjects with NVAF and at moderate to high risk of stroke and systemic embolic events 
(SEE). 
 
In the pivotal ENGAGE AF-TIMI 48 study (an event-driven, Phase 3, multi-centre, randomised, 
double-blind double-dummy parallel-group study), 21,105 subjects, with a mean congestive heart 
failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke (CHADS2) score of 2.8, were 
randomised to either edoxaban 30 mg once daily treatment group, or edoxaban 60 mg once daily 
treatment group or warfarin. Subjects in both edoxaban treatment groups had their dose halved if one 
or more of the following clinical factors were present: moderate renal impairment  
(CrCl 30 – 50 mL/min), low body weight (≤ 60 kg) or concomitant use of specific P-gp inhibitors 
(verapamil, quinidine, dronedarone). 
 
The primary efficacy endpoint was the composite of stroke and SEE. Secondary efficacy endpoints 
included: composite of stroke, SEE, and cardiovascular (CV) mortality; major adverse cardiovascular 
event (MACE), which is the composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-
fatal SEE, and death due to CV cause or bleeding; composite of stroke, SEE, and all-cause mortality. 
 
The median study medicinal product exposure for both the edoxaban 60 mg and 30 mg treatment 
groups was 2.5 years. The median study follow-up for both the edoxaban 60 mg and 30 mg treatment 
groups was 2.8 years. The median subject-year exposure was 15,471, and 15,840 for the 60 mg and 
30 mg treatment groups, respectively; and the median subject-year follow-up was 19,191 and 19,216 
for the 60 mg and 30 mg treatment groups, respectively. 
 
In the warfarin group, the median TTR (time in therapeutic range, INR 2.0 to 3.0) was 68.4%. 
 
The main analysis of efficacy was aimed to show the non-inferiority of edoxaban versus warfarin on 
first stroke or SEE that occurred during treatment or within 3 days from the last dose taken in the 
modified intention to treat (mITT) population. Edoxaban 60 mg was non-inferior to warfarin for the 
primary efficacy endpoint of stroke or SEE (upper limit of the 97.5% CI of the hazard ratio (HR) was 
below the pre-specified non-inferiority margin of 1.38) (Table 4).  



17 

Table 4: Strokes and SEE in the ENGAGE AF–TIMI 48 study - mITT, on-treatment 

Primary endpoint 
Edoxaban 60 mg 

(30 mg dose reduced) 
(N = 7,012) 

Warfarin 
(N = 7,012) 

First stroke/SEEa   
n 182 232 
Event rate (%/yr)b 1.18 1.50 
HR (97.5% CI) 0.79 (0.63, 0.99)  
p-value for non-inferiorityc <0.0001  
First ischaemic stroke   
n 135 144 
Event rate (%/yr)b 0.87 0.93 
HR (95% CI) 0.94 (0.75, 1.19)  
First haemorrhagic stroke   
n 40 76 
Event rate (%/yr)b 0.26 0.49 
HR (95% CI) 0.53 (0.36, 0.78)  
First SEE    
n (%/yr)a 8 (0.05) 13 (0.08) 
HR (95% CI) 0.62 (0.26, 1.50)  
Abbreviations: HR = hazard ratio versus warfarin, CI = confidence interval, n = number of events, 
mITT = modified intent to treat, N = number of subjects in mITT population, 
SEE = systemic embolic event, yr = year. 
a A subject can be represented in multiple rows. 
b The event rate (%/yr) is calculated as number of events/subject-year exposure. 
c The two-sided p-value is based on the non-inferiority margin of 1.38. 

 
During the overall study period in the ITT population (analysis set to show superiority), adjudicated 
stroke or SEE occurred in 296 subjects in the edoxaban 60 mg group (1.57% per year), and 
337 subjects in the warfarin group (1.80% per year). Compared to warfarin-treated subjects, the HR in 
the edoxaban 60 mg group was 0.87 (99% CI: 0.71, 1.07, p = 0.08 for superiority).  
 
In subgroup analyses, for subjects in the 60 mg treatment group who were dose reduced to 30 mg in 
the ENGAGE AF-TIMI 48 study (for body weight ≤ 60 kg, moderate renal impairment, or 
concomitant use of P-gp inhibitors), the event rate was: 2.29% per year for the primary endpoint, 
compared to the event rate of 2.66% per year for the matching subjects in the warfarin group [HR 
(95% CI): 0.86 (0.66, 1.13)]. 
 
The efficacy results for pre-specified major subgroups (with dose reduction as required), including 
age, body weight, gender, status of renal function, prior stroke or TIA, diabetes and P-gp inhibitors 
were generally consistent with the primary efficacy results for the overall population studied in the 
trial. 
 
The HR (edoxaban 60 mg vs. warfarin) for the primary endpoint in the centres with a lower average 
time of INR in the therapeutic range (INR TTR) for warfarin was 0.73 – 0.80 for the lowest 3 quartiles 
(INR TTR ≤ 57.7% to ≤ 73.9%). It was 1.07 in centres with the best control of warfarin therapy (4th 
quartile with > 73.9% of INR values in the therapeutic range). 
 
There was a statistically significant interaction between the effect of edoxaban versus warfarin on the 
main study outcome (stroke/SEE) and renal function (p-value 0.0042; mITT, overall study period). 
 
Table 5 shows ischaemic strokes/SEE by CrCl category in NVAF patients in ENGAGE AF-TIMI 48. 
There is a decreasing event rate at increasing CrCl in both treatment groups. 



18 

Table 5: Number of ischaemic strokes/SEE by CrCl category in the ENGAGE AF-TIMI 48, 
mITT analysis set overall study 

CrCl 
subgroup 
(mL/min) 

Edoxaban 60 mg 
(N = 7,012) 

Warfarin 
(N = 7,012) 

 

n Number 
of events 

Event 
rate 

(%/year) 

n Number 
of events 

Event 
rate 

(%/year) 

HR (95% CI) 

≥ 30 to ≤ 50 1,302 63 1.89 1,305 67 2.05 0.93 (0.66, 1.31) 
> 50 to ≤ 70 2,093 85 1.51 2,106 95 1.70 0.88 (0.66, 1.18) 
> 70 to ≤ 90 1,661 45 0.99 1,703 50 1.08 0.92 (0.61, 1.37) 
> 90 to ≤ 110 927 27 1.08 960 26 0.98 1.10 (0.64, 1.89) 
> 110 to ≤ 130 497 14 1.01 469 10 0.78 1.27 (0.57, 2.85) 
> 130 462 10 0.78 418 3 0.25 --* 
Abbreviations: CrCl = creatinine clearance; N = number of subjects in mITT population overall study 
period; mITT = modified intent to treat; n = number of patients in subgroup; HR = hazard ratio 
versus warfarin; CI = confidence interval. 
*HR not computed if number of events < 5 in one treatment group. 

 
Within renal function subgroups, results for the secondary efficacy endpoints were consistent with 
those for the primary endpoint. 
 
Superiority testing was performed on the ITT overall study period. 
Stroke and SEE occurred in fewer subjects in the edoxaban 60 mg treatment group than in the warfarin 
group (1.57% and 1.80% per year, respectively), with a HR of 0.87 (99% CI: 0.71, 1.07, p = 0.0807 
for superiority). 
 
The pre-specified composite endpoints for the comparison of the edoxaban 60 mg treatment group to 
warfarin for stroke, SEE, and CV mortality HR (99% CI) was 0.87 (0.76, 0.99), MACE 0.89 
(0.78, 1.00), and stroke, SEE, and all-cause mortality 0.90 (0.80, 1.01). 
 
The results for all-cause mortality (adjudicated deaths) in the ENGAGE AF-TIMI 48 study were 769 
(3.99% per year) for subjects taking edoxaban 60 mg (30 mg dose reduced) as opposed to 836 (4.35% 
per year) for warfarin [HR (95% CI): 0.91 (0.83, 1.01)]. 
All-cause mortality (adjudicated deaths) per renal subgroups (edoxaban vs. warfarin): CrCl 30 to 
≤ 50 mL/min [HR (95% CI): 0.81 (0.68, 0.97)]; CrCl > 50 to < 80 mL/min [HR (95% CI): 0.87 (0.75, 
1.02)]; CrCl ≥ 80 mL/min [HR (95% CI): 1.15 (0.95, 1.40)]. 
 
Edoxaban 60 mg (30 mg dose reduced) resulted in a lower rate of cardiovascular mortality compared 
to warfarin [HR (95% CI): 0.86 (0.77, 0.97)]. 
Adjudicated efficacy cardiovascular mortality per renal subgroups (edoxaban vs. warfarin): CrCl 30 to 
≤ 50 mL/min [HR (95% CI): 0.80 (0.65, 0.99)]; CrCl > 50 to < 80 mL/min [HR (95% CI): 0.75 (0.62, 
0.90)]; CrCl ≥ 80 mL/min [HR (95% CI): 1.16 (0.92, 1.46)]. 
 
The primary safety endpoint was major bleeding.  
 
There was a significant risk reduction in the edoxaban 60 mg treatment group compared with the 
warfarin group in major bleeding (2.75%, and 3.43% per year, respectively) [HR (95% CI): 0.80 (0.71, 
0.91); p = 0.0009], ICH (0.39%, and 0.85% per year, respectively) [HR (95% CI): 0.47 (0.34, 0.63); 
p < 0.0001], and other types of bleeding (Table 6).  
 
The reduction in fatal bleeds was also significant for the edoxaban 60 mg treatment group compared 
with the warfarin group (0.21%, and 0.38%) [HR (95% CI): 0.55 (0.36, 0.84); p = 0.0059 for 
superiority], primarily because of the reduction in fatal ICH bleeds [HR (95% CI): 0.58 (0.35, 0.95); 
p = 0.0312]. 



19 

 
Table 6: Bleeding events in ENGAGE AF-TIMI 48 study - safety analysis on-treatment 

 Edoxaban 60 mg 
(30 mg dose reduced) 

(N = 7,012) 

Warfarin 
(N = 7,012) 

Major bleeding   
n 418 524 
Event rate (%/yr)a 2.75 3.43 
HR (95% CI) 0.80 (0.71, 0.91)  
p-value 0.0009  

ICHb   
n 61 132 
Event rate (%/yr)a 0.39 0.85 
HR (95% CI) 0.47 (0.34, 0.63)  

Fatal bleeding   
n 32 59 
Event rate (%/yr)a 0.21 0.38 
HR (95% CI) 0.55 (0.36, 0.84)  
CRNM Bleeding   
n 1,214 1,396 
Event rate (%/yr)a 8.67 10.15 
HR (95% CI) 0.86 (0.80, 0.93)  
Any confirmed bleedingc   
n 1,865 2,114 
Event rate (%/yr)a 14.15 16.40 
HR (95% CI) 0.87 (0.82, 0.92)  

Abbreviations: ICH = intracranial haemorrhage, HR = hazard ratio versus warfarin, 
CI = confidence interval, CRNM = clinically relevant non-major, n = number of subjects with 
events, N = number of subjects in safety population, yr = year. 
a The event rate (%/yr) is calculated as number of events/subject-year exposure.  
b ICH includes primary haemorrhagic stroke, subarachnoid haemorrhage, epi-/subdural haemorrhage, 

and ischaemic stroke with major haemorrhagic conversion. All ICHs reported on the adjudicated 
cerebrovascular and non-intracranial bleed electronic case report forms (eCRF) confirmed by the 
adjudicators are included in ICH counts. 

c Any confirmed bleeding includes those that the adjudicator defined as clinically overt. 
 
Note: A subject can be included in multiple sub-categories if he/she had an event for those categories. 
The first event of each category is included in the analysis. 

 
Tables 7, 8 and 9 show major, fatal and intracranial bleedings, respectively, by CrCl category in 
NVAF patients in ENGAGE AF-TIMI 48. There is a decreasing event rate at increasing CrCl in both 
treatment groups. 
 
 



20 

Table 7: Number of major bleeding events by CrCl category in ENGAGE AF-TIMI 48, safety 
analysis on-treatmenta 

CrCl 
subgroup 
(mL/min) 

Edoxaban 60 mg 
(N = 7,012) 

Warfarin 
(N = 7,012) 

 

n Number 
of events 

Event 
rate 

(%/year) 

n Number 
of events 

Event 
rate 

(%/year) 

HR (95% CI) 

≥ 30 to ≤ 50 1,302 96 3.91 1,305 128 5.23 0.75 (0.58, 0.98) 
> 50 to ≤ 70 2,093 148 3.31 2,106 171 3.77 0.88 (0.71, 1.10) 
> 70 to ≤ 90 1,661 108 2.88 1,703 119 3.08 0.93 (0.72, 1.21) 
> 90 to ≤ 110 927 29 1.33 960 56 2.48 0.54 (0.34, 0.84) 
> 110 to ≤ 130 497 20 1.70 469 24 2.14 0.79 (0.44, 1.42) 
> 130 462 13 1.18 418 21 2.08 0.58 (0.29, 1.15) 

 
Table 8: Number of fatal bleeding events by CrCl category in ENGAGE AF-TIMI 48, safety 

analysis on-treatmenta 

CrCl 
subgroup 
(mL/min) 

Edoxaban 60 mg 
(N = 7,012) 

Warfarin 
(N = 7,012) 

 

n Number 
of events 

Event 
rate 

(%/year) 

n Number 
of events 

Event 
rate 

(%/year) 

HR (95% CI) 

≥ 30 to ≤ 50 1,302 9 0.36 1,305 18 0.72 0.51 (0.23, 1.14) 
> 50 to ≤ 70 2,093 8 0.18 2,106 23 0.50 0.35 (0.16, 0.79) 
> 70 to ≤ 90 1,661 10 0.26 1,703 9 0.23 1.14 (0.46, 2.82) 
> 90 to ≤ 110 927 2 0.09 960 3 0.13 --* 
> 110 to ≤ 130 497 1 0.08 469 5 0.44 --* 
> 130 462 2 0.18 418 0 0.00 --* 

 
Table 9: Number of intracranial bleeding events by CrCl category in ENGAGE AF-TIMI 48, 

safety analysis on-treatmenta 

CrCl 
subgroup 
(mL/min) 

Edoxaban 60 mg 
(N = 7,012) 

Warfarin 
(N = 7,012) 

 

n Number 
of events 

Event 
rate 

(%/year) 

n Number 
of events 

Event 
rate 

(%/year) 

HR (95% CI) 

≥ 30 to ≤ 50 1,302 16 0.64 1,305 35 1.40 0.45 (0.25, 0.81) 
> 50 to ≤ 70 2,093 19 0.42 2,106 51 1.10 0.38 (0.22, 0.64) 
> 70 to ≤ 90 1,661 17 0.44 1,703 35 0.89 0.50 (0.28, 0.89) 
> 90 to ≤ 110 927 5 0.23 960 6 0.26 0.87 (0.27, 2.86) 
> 110 to ≤ 130 497 2 0.17 469 3 0.26 --* 
> 130 462 1 0.09 418 1 0.10 --* 
Abbreviations: N = number of subjects in mITT population overall study period; mITT = modified 
intent to treat; n = number of patients in subgroup; HR = hazard ratio versus warfarin; 
CI = confidence interval. 
*HR not computed if number of events < 5 in one treatment group. 
a On-Treatment: Time from first dose of study medicinal product to last dose plus 3 days. 

 



21 

In subgroup analyses, for subjects in the 60 mg treatment group who were dose reduced to 30 mg in 
the ENGAGE AF-TIMI 48 study for body weight ≤ 60 kg, moderate renal impairment, or concomitant 
use of P-gp inhibitors, 104 (3.05% per year) of edoxaban 30 mg dose reduced subjects and 166 (4.85% 
per year) of warfarin dose reduced subjects had a major bleeding event [HR (95% CI): 0.63 (0.50, 
0.81)]. 
 
In the ENGAGE AF-TIMI 48 study there was a significant improvement in net clinical outcome (first 
stroke, SEE, major bleed, or all-cause mortality; mITT population, overall study period) in favour of 
edoxaban, HR (95% CI): 0.89 (0.83, 0.96); p = 0.0024, when edoxaban 60 mg treatment group was 
compared to warfarin. 
 
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTE) 
The edoxaban clinical programme for VTE was designed to demonstrate the efficacy and safety of 
edoxaban in the treatment of DVT and PE, and the prevention of recurrent DVT and PE. 
 
In the pivotal Hokusai-VTE study, 8,292 subjects were randomised to receive initial heparin therapy 
(enoxaparin or unfractionated heparin) followed by edoxaban 60 mg once daily or the comparator. In 
the comparator arm, subjects received initial heparin therapy concurrently with warfarin, titrated to a 
target INR of 2.0 to 3.0, followed by warfarin alone. The treatment duration was from 3 months up to 
12 months, determined by the investigator based on the patient’s clinical features. 
 
The majority of edoxaban treated patients were Caucasians (69.6%) and Asians (21.0%); 3.8% were 
Black, and 5.3% were categorised as Other race. 
 
The duration of therapy was at least 3 months for 3,718 (91.6%) edoxaban subjects versus 3,727 
(91.4%) of warfarin subjects; at least 6 months for 3,495 (86.1%) of edoxaban subjects versus 3,491 
(85.6%) of warfarin subjects; and 12 months for 1,643 (40.5%) edoxaban subjects versus 1,659 
(40.4%) of warfarin subjects. 
 
The primary efficacy endpoint was the recurrence of symptomatic VTE, defined as the composite of 
recurrent symptomatic DVT, non-fatal symptomatic PE and fatal PE in subjects during the 12-month 
study period. Secondary efficacy outcomes included the composite clinical outcome of recurrent VTE 
and all-cause mortality. 
 
Edoxaban 30 mg once daily was used for subjects with one or more of the following clinical factors: 
moderate renal impairment (CrCl 30 - 50 mL/min); body weight ≤ 60 kg; concomitant use of specific 
P-gp inhibitors. 
 
In the Hokusai-VTE study (Table 10) edoxaban was demonstrated to be non-inferior to warfarin for 
the primary efficacy outcome, recurrent VTE, which occurred in 130 of 4,118 subjects (3.2%) in the 
edoxaban group versus 146 of 4,122 subjects (3.5%) in the warfarin group [HR (95% CI): 0.89 (0.70, 
1.13); p < 0.0001 for non-inferiority]. In the warfarin group, the median TTR (INR 2.0 to 3.0) was 
65.6%. For subjects presenting with PE (with or without DVT), 47 (2.8%) of edoxaban and 65 (3.9%) 
of warfarin subjects had a recurrent VTE [HR (95% CI): 0.73 (0.50, 1.06)].  
 



22 

Table 10: Efficacy results from the Hokusai-VTE study - mITT population, overall study period 

Primary endpointa Edoxaban 60 mg 
(30 mg dose reduced) 

(N = 4,118) 
Warfarin 

(N = 4,122) 

Edoxaban vs 
Warfarin 

HR (95% CI)b 
p-valuec 

All subjects with 
symptomatic recurrent 
VTEc, n (%) 

130 (3.2) 146 (3.5) 0.89 (0.70, 1.13) 
p-value < 0.0001 
(non-inferiority) 

PE with or without DVT 73 (1.8) 83 (2.0)  
Fatal PE or death where 
PE cannot be ruled out 

24 (0.6) 24 (0.6)  

Non-fatal PE 49 (1.2) 59 (1.4)  
DVT only 57 (1.4) 63 (1.5)  

Abbreviations: CI = confidence interval; DVT = deep vein thrombosis; mITT = modified intent-to-
treat; HR = Hazard ratio vs. warfarin; n = number of subjects with events; N = number of subjects in 
mITT population; PE = pulmonary embolism; VTE = venous thromboembolic events. 
a The primary efficacy endpoint is adjudicated symptomatic recurrent VTE (i.e., the composite 

endpoint of DVT, non-fatal PE, and fatal PE). 
b The HR, two-sided CI are based on the Cox proportional hazards regression model including 

treatment and the following randomisation stratification factors as covariates: presenting diagnosis 
(PE with or without DVT, DVT only), baseline risk factors (temporary factors, all others), and the 
need for 30 mg edoxaban/edoxaban placebo dose at randomisation (yes/no).  

c The p-value is for the pre-defined non-inferiority margin of 1.5. 
 
For the subjects who were dose reduced to 30 mg (predominantly low body weight or renal function) 
15 (2.1%) edoxaban and 22 (3.1%) of warfarin subjects had a recurrent VTE [HR (95% CI): 0.69 
(0.36, 1.34)]. 
 
The secondary composite endpoint of recurrent VTE and all-cause mortality occurred in 138 subjects 
(3.4%) in the edoxaban group and 158 subjects (3.9%) in the warfarin group [HR (95% CI): 0.87 
(0.70, 1.10)]. 
 
The results for all-cause mortality (adjudicated deaths) in Hokusai-VTE were 136 (3.3%) for subjects 
taking edoxaban 60 mg (30 mg dose reduced) as opposed to 130 (3.2%) for warfarin.  
 
In a pre-specified subgroup analysis of PE subjects 447 (30.6%) and 483 (32.2%) of edoxaban and 
warfarin treated subjects, respectively, were identified as having PE and N-terminal pro–B-type 
natriuretic peptide (NT-proBNP) ≥ 500 pg/mL. The primary efficacy outcome occurred in 14 (3.1%) 
and 30 (6.2%) of edoxaban and warfarin subjects, respectively [HR (95% CI): 0.50 (0.26, 0.94)]. 
 
The efficacy results for pre-specified major subgroups (with dose reduction as required), including 
age, body weight, gender and status of renal function were consistent with the primary efficacy results 
for the overall population studied in the trial. 
 
The primary safety endpoint was clinically relevant bleeding (major or clinically relevant non-major).  
 
Table 11 summarises adjudicated bleeding events for the safety analysis set on-treatment period. 
There was a significant risk reduction in the edoxaban group compared with warfarin for the primary 
safety endpoint of clinically relevant bleeding, a composite of major bleeding or clinically relevant 
non-major (CRNM) bleeding, which occurred in 349 of 4,118 subjects (8.5%) in the edoxaban group 
and in 423 of 4,122 subjects (10.3%) in the warfarin group [HR (95% CI): 0.81 (0.71, 0.94); p = 0.004 
for superiority]. 
 



23 

Table 11: Bleeding events in Hokusai-VTE study - safety analysis on-treatment perioda 

 Edoxaban 60 mg 
(30 mg dose reduced) 

(N = 4,118) 

Warfarin 
(N = 4,122) 

Clinically relevant bleeding  
(Major and CRNM)b, n (%) 

  

n 349 (8.5) 423 (10.3) 
HR (95% CI) 0.81 (0.71, 0.94)  
p-value 0.004 (for superiority)  
Major bleeding n (%)   
n 56 (1.4) 66 (1.6) 
HR (95% CI) 0.84 (0.59, 1.21)  

ICH fatal 0 6 (0.1) 
ICH non-fatal 5 (0.1) 12 (0.3) 

CRNM bleeding   
n 298 (7.2) 368 (8.9) 
HR (95% CI) 0.80 (0.68, 0.93)  
All bleeding   
n 895 (21.7) 1,056 (25.6) 
HR (95% CI) 0.82 (0.75, 0.90)  

Abbreviations: ICH = intracranial haemorrhage, HR = hazard ratio vs. warfarin; CI = confidence 
interval; N = number of subjects in safety population; n = number of events; CRNM = clinically 
relevant non-major 
a On-treatment period: time from first dose of study medicinal product to last dose plus 3 days. 
b Primary safety endpoint: clinically relevant bleeding (composite of major and clinically relevant 
non-major bleeding). 

 
In subgroup analyses, for subjects who were dose reduced to 30 mg in the Hokusai-VTE study for 
body weight ≤ 60 kg, moderate renal impairment, or concomitant use of P-gp inhibitors, 58 (7.9%) of 
edoxaban 30 mg dose reduced subjects and 92 (12.8%) of warfarin subjects had a major bleeding or 
CRNM event [HR (95%): 0.62 (0.44, 0.86)]. 
 
In the Hokusai-VTE study the net clinical outcome (recurrent VTE, major bleed, or all-cause 
mortality; mITT population, overall study period) HR (95% CI) was 1.00 (0.85, 1.18) when edoxaban 
was compared to warfarin. 
 
Prevention of stroke and systemic embolism in NVAF patients with high CrCl (CrCl > 100 mL/min) 
A dedicated randomised, double-blind trial (E314) was conducted in 607 NVAF patients with high 
CrCl (CrCl > 100 mL/min as measured by the Cockcroft-Gault formula) with the primary aim to 
evaluate the PK/PD of an edoxaban 60 mg once daily vs 75 mg once daily regimen. In addition to the 
primary PK/PD endpoint, the study included the evaluation of clinical endpoints of stroke and 
bleeding over a 12-months treatment period.  
 
An edoxaban dose of 75 mg QD in the high CrCl sub-group (> 100 mL/min) provided an ~25% 
increase in exposure as compared to an edoxaban dose of 60 mg QD as predicted.  
 
The number of subjects experiencing the adjudicated composite endpoint of stroke/transient ischaemic 
attack (TIA)/systemic embolic event (SEE) efficacy events was limited and included 2 stroke events in 
the edoxaban 60 mg group (0.7%; 95% CI: 0.1% to 2.4%) and 3 stroke events in the edoxaban 75 mg 
group (1%; 95% CI: 0.2% to 2.9%).  



24 

Adjudicated major bleeding events occurred in 2 (0.7%; 95% CI: 0.1% to 2.4%) subjects in the 
edoxaban 60 mg group compared to 3 (1.0%; 95% CI: 0.2% to 2.9%) subjects in the edoxaban 75 mg 
group. Of the 2 major bleeds in the edoxaban 60 mg group, one was in a critical area/organ 
(intraocular) and the other major bleed was an intramuscular bleed. Of the 3 major bleeds in the 
edoxaban 75 mg group, 2 occurred in a critical area/organ (intracerebral/ 1 fatal outcome) and 1 was 
an upper gastrointestinal (GI) bleed (life-threatening). There were also 9 (3%) clinically relevant non-
major (CRNM) bleedings in the edoxaban 60 mg group and 7 (2.3%) CRNM bleedings in the 
edoxaban 75 mg group.  
 
In addition to the E314 clinical trial, a prospective, multinational, multi-centre, post authorisation, 
observational study (ETNA-AF) was conducted in 10 European countries and has included 13,980 
subjects. Within this population 1,826 had a CrCl > 100 ml/min and received edoxaban 60 mg in 
accordance with dosing criteria outlined in the SmPC. The annual rates of the composite of ischaemic 
stroke or systemic embolism were 0.39%/y, and major bleeding events occurred in 0.73%/y. 
 
Given the totality of the data from ENGAGE AF, E314 and ETNA-AF, patients with NVAF and high 
CrCl treated with edoxaban 60 mg are expected to have an annual rate of ischaemic stroke/systemic 
embolism ≤ 1%. Increasing the dose above 60 mg in NVAF patients with high CrCl (> 100 mL/min) is 
not expected to provide more protection against stroke and can be associated with increased adverse 
effects. As such, an edoxaban 60 mg once daily regimen is recommended in these patients after a 
careful evaluation of the individual thromboembolic and bleeding risk (see section 4.4.).  
 
Patients undergoing cardioversion 
A multicentre, prospective, randomised, open-label study with blinded endpoint evaluation (ENSURE-
AF) was conducted which randomised 2199 subjects (oral anticoagulant naïve and pre-treated) with 
NVAF scheduled for cardioversion, to compare edoxaban 60 mg once daily with enoxaparin/warfarin 
to maintain a therapeutic INR of 2.0 to 3.0 (randomised 1:1), mean TTR on warfarin was 70.8%. A 
total of 2149 subjects were treated with either edoxaban (N = 1067) or enoxaparin/warfarin 
(N = 1082). Subjects in the edoxaban treatment group received 30 mg once daily if one or more of the 
following clinical factors were present: moderate renal impairment (CrCl 30 – 50 mL/min), low body 
weight (≤ 60 kg) or concomitant use of specific P-gp inhibitors. The majority of subjects in the 
edoxaban and warfarin groups had cardioversion performed (83.7% and 78.9%, respectively) or were 
auto-converted (6.6% and 8.6%, respectively). TEE-guided (within 3 days of initiation) or 
conventional cardioversion (at least 21 days of pre-treatment) was employed. Subjects were 
maintained on treatment for 28 days post cardioversion. 
 
The primary efficacy outcome consisted of a composite of all stroke, SEE, MI and CV mortality. A 
total of 5 (0.5%, 95% CI 0.15% - 1.06%) events occurred in subjects in the edoxaban group 
(N = 1095) and 11 (1.0%, 95% CI 0.50% - 1.78%) events in the warfarin group (N = 1104); odds ratio 
(OR) 0.46 (95% CI 0.12 - 1.43); ITT analysis set overall study period with mean duration of 66 days. 
 
The primary safety outcome was a composite of major and CRNM bleeding. A total of 16 (1.5%, 95% 
CI 0.86% - 2.42%) events occurred in subjects in the edoxaban (N = 1067) group and 11 (1.0%, 95% 
CI 0.51% - 1.81%) events in the warfarin (N = 1082) group; OR 1.48 (95% CI 0.64 - 3.55); safety 
analysis set on-treatment period. 
 
This exploratory study showed low rates of major and CRNM bleeding and thromboembolism in the 
two treatment groups in the setting of cardioversion. 
 
Paediatric population 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
edoxaban in one or more subsets of the paediatric population in prevention of arterial thrombosis, 
treatment of thromboembolism and prevention of thromboembolism (see section 4.2 for information 
on paediatric use). 
 



25 

5.2 Pharmacokinetic properties 
 
Absorption 
 
Edoxaban is absorbed with peak plasma concentrations within 1 - 2 hours. The absolute bioavailability 
is approximately 62%. Food increases peak exposure to a varying extent, but has minimal effect on 
total exposure. Edoxaban was administered with or without food in the ENGAGE AF-TIMI 48 and the 
Hokusai-VTE studies. Edoxaban is poorly soluble at pH of 6.0 or higher. Co-administration of proton-
pump inhibitors had no relevant impact on edoxaban exposure. 
 
In a study with 30 healthy subjects, both mean AUC and Cmax values for 60 mg edoxaban administered 
as a crushed tablet orally mixed in apple puree or via nasogastric tube suspended in water were 
bioequivalent to the intact tablet. Given the predictable, dose-proportional pharmacokinetic profile of 
edoxaban, the bioavailability results from this study are likely applicable to lower edoxaban doses. 
 
Distribution 
 
Disposition is biphasic. The volume of distribution is 107 (19.9) L mean (SD). 
In vitro plasma protein binding is approximately 55%. There is no clinically relevant accumulation of 
edoxaban (accumulation ratio 1.14) with once daily dosing. Steady state concentrations are achieved 
within 3 days. 
 
Biotransformation 
 
Unchanged edoxaban is the predominant form in plasma. Edoxaban is metabolised via hydrolysis 
(mediated by carboxylesterase 1), conjugation or oxidation by CYP3A4/5 (< 10%). Edoxaban has 
three active metabolites, the predominant metabolite (M-4), formed by hydrolysis, is active and 
reaches less than 10% of the exposure of the parent compound in healthy subjects. Exposure to the 
other metabolites is less than 5%. Edoxaban is a substrate for the efflux transporter P-gp, but not a 
substrate for uptake transporters such as organic anion transporter polypeptide OATP1B1, organic 
anion transporters OAT1 or OAT3 or organic cation transporter OCT2. Its active metabolite is a 
substrate for OATP1B1. 
 
Elimination 
 
In healthy subjects, the total clearance is estimated as 22 (± 3) L/hour; 50% is renally cleared 
(11 L/hour). Renal clearance accounts for approximately 35% of the administered dose. Metabolism 
and biliary/intestinal excretion account for the remaining clearance. The t½ for oral administration is 
10 - 14 hours. 
 
Linearity/non-linearity 
 
Edoxaban displays approximately dose-proportional pharmacokinetics for doses of 15 mg to 60 mg in 
healthy subjects. 
 
Special populations 
 
Elderly 
After taking renal function and body weight into account, age had no additional clinically significant 
effect on edoxaban pharmacokinetics in a population pharmacokinetic analysis of the pivotal Phase 3 
study in NVAF (ENGAGE AF-TIMI 48). 
 
Renal impairment 
The plasma AUCs for subjects with mild (CrCl > 50 - 80 mL/min), moderate (CrCl 30 - 50 mL/min) 
and severe (CrCl < 30 mL/min but not undergoing dialysis) renal impairment were increased by 32%, 
74%, and 72%, respectively, relative to subjects with normal renal function. In patients with renal 
impairment the metabolite profile changes and a higher quantity of active metabolites are formed. 



26 

There is a linear correlation between edoxaban plasma concentration and anti-FXa activity regardless 
of renal function. 
Subjects with ESRD undergoing peritoneal dialysis had 93% higher total exposure compared with 
healthy subjects.  
Population PK modeling indicates that exposure approximately doubles in patients with severe renal 
impairment (CrCl 15 – 29 mL/min) relative to patients with normal renal function. 
 
Table 12 below shows the edoxaban anti-FXa activity by CrCl category for each indication. 
 
Table 12: Edoxaban anti-FXa activity by CrCl 

Edoxaban 
dose 

CrCl 
(mL/min) 

Edoxaban 
Anti-FXa activity  

post-dose (IU/mL)1 

Edoxaban 
Anti-FXa activity 
pre-dose (IU/mL)2  

Median [2.5 – 97.5% range] 
Prevention of stroke and systemic embolism: NVAF 
30 mg once daily  ≥ 30 to ≤ 50 2.92 

[0.33 – 5.88] 
0.53 

[0.11 – 2.06] 
60 mg once daily*  > 50 to ≤ 70 4.52 

[0.38 – 7.64] 
0.83 

[0.16 – 2.61] 
> 70 to ≤ 90 4.12 

[0.19 – 7.55] 
0.68 

[0.05 – 2.33] 
> 90 to ≤ 110 3.82 

[0.36 – 7.39] 
0.60 

[0.14 – 3.57] 
> 110 to ≤ 130 3.16 

[0.28 – 6.71] 
0.41 

[0.15 – 1.51] 
> 130 2.76 

[0.12 – 6.10] 
0.45 

[0.00 – 3.10] 
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTE) 
30 mg once daily ≥ 30 to ≤ 50 2.21 

[0.14 – 4.47] 
0.22 

[0.00 – 1.09] 
60 mg once daily* > 50 to ≤ 70 3.42 

[0.19 – 6.13] 
0.34 

[0.00 – 3.10] 
> 70 to ≤ 90 2.97 

[0.24 – 5.82] 
0.24 

[0.00 – 1.77] 
> 90 to ≤ 110 2.82 

[0.14 – 5.31] 
0.20 

[0.00 – 2.52] 
> 110 to ≤ 130 2.64 

[0.13 – 5.57] 
0.17 

[0.00 – 1.86] 
> 130 2.39 

[0.10 – 4.92] 
0.13 

[0.00 – 2.43] 
*Dose reduction to 30 mg for low body weight ≤ 60 kg or specific concomitant P-gp inhibitors 
1 Post-dose is equivalent to Cmax (post-dose samples were drawn 1 – 3 hours after edoxaban 
 administration) 
2 Pre-dose is equivalent to Cmin 
 
Although treatment with edoxaban does not require routine monitoring, the effect on anticoagulation 
can be estimated by a calibrated quantitative anti-FXa assay which may be useful in exceptional 
situations where knowledge of edoxaban exposure may help to inform clinical decisions, e.g. overdose 
and emergency surgery (see also section 4.4). 
 
A 4 hour haemodialysis session reduced total edoxaban exposures by less than 9%. 
 



27 

Hepatic impairment 
Patients with mild or moderate hepatic impairment exhibited comparable pharmacokinetics and 
pharmacodynamics to their matched healthy control group. Edoxaban has not been studied in patients 
with severe hepatic impairment (see section 4.2). 
 
Gender 
After accounting for body weight, gender had no additional clinically significant effect on edoxaban 
pharmacokinetics in a population pharmacokinetic analysis of the Phase 3 study in NVAF (ENGAGE 
AF-TIMI 48). 
 
Ethnic origin 
In a population pharmacokinetic analysis of the ENGAGE AF-TIMI 48 study, peak and total exposure 
in Asian patients and non-Asian patients were comparable. 
 
Body weight 
In a population pharmacokinetic analysis of the ENGAGE AF-TIMI 48 study in NVAF, Cmax and 
AUC in patients with median low body weight (55 kg) were increased by 40% and 13%, respectively, 
as compared with patients with median high body weight (84 kg). In Phase 3 clinical studies (both 
NVAF and VTE indications) patients with body weight ≤ 60 kg had a 50% edoxaban dose reduction 
and had similar efficacy and less bleeding when compared to warfarin. 
 
Pharmocokinetic/pharmacodynamic relationship(s) 
PT, INR, aPTT and anti-FXa correlate linearly with edoxaban concentrations. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, or phototoxicity. 
 
Reproductive toxicology 
Edoxaban showed vaginal haemorrhage at higher doses in rats and rabbits but had no effects in the 
reproductive performance of parent rats. 
 
In rats, no effects on male or female fertility were seen. 
 
In animal reproduction studies, rabbits showed increased incidence of gallbladder variations at a 
dosage of 200 mg/kg which is approximately 65 times the maximum recommended human dose 
(MRHD) of 60 mg/day based on total body surface area in mg/m2. Increased post-implantation 
pregnancy losses occurred in rats at 300 mg/kg/day (approximately 49 times the MRHD) and in 
rabbits at 200 mg/kg/day (approximately 65 times the MRHD) respectively. 
 
Edoxaban was excreted in the breast milk of lactating rats. 
 
Environmental risk assessment (ERA) 
The active substance edoxaban tosilate is persistent in the environment (for instructions on disposal 
see section 6.6). 
 
 



28 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
Mannitol (E421) 
Pregelatinised starch 
Crospovidone (E1202) 
Hydroxypropyl cellulose (E463) 
Magnesium stearate (E470b) 
 
Film-coat: 
Hypromellose (E464) 
Macrogol (8000) 
Titanium dioxide (E171) 
Talc (E553b) 
Carnauba wax 
 
Roteas 15 mg film-coated tablets 
Iron oxide yellow (E172) 
Iron oxide red (E172) 
 
Roteas 30 mg film-coated tablets 
Iron oxide red (E172) 
 
Roteas 60 mg film-coated tablets 
Iron oxide yellow (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Roteas 15 mg film-coated tablets 
PVC/Aluminium blisters in cartons of 10 film-coated tablets. 
PVC/Aluminium perforated unit dose blisters in cartons of 10 x 1 film-coated tablets. 
 
Roteas 30 mg film-coated tablets 
PVC/Aluminium blisters in cartons of 10, 14, 28, 30, 56, 60, 84, 90, 98, 100 film-coated tablets. 
PVC/Aluminium perforated unit dose blisters in cartons of 10 x 1, 50 x 1 and 100 x 1 film-coated 
tablets. 
HDPE bottles with a PP screw cap containing 90 film-coated tablets. 
 
Roteas 60 mg film-coated tablets 
PVC/Aluminium blisters in cartons of 10, 14, 28, 30, 56, 60, 84, 90, 98, 100 film-coated tablets. 
PVC/Aluminium perforated unit dose blisters in cartons of 10 x 1, 50 x 1 and 100 x 1 film-coated 
tablets. 
HDPE bottles with a PP screw cap containing 90 film-coated tablets. 



29 

 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Berlin-Chemie AG 
Glienicker Weg 125 
12489 Berlin 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
Roteas 15 mg film-coated tablets 
EU/1/16/1152/001-002 
 
Roteas 30 mg film-coated tablets 
EU/1/16/1152/003-015, EU/1/16/1152/029 
 
Roteas 60 mg film-coated tablets 
EU/1/16/1152/016-028, EU/1/16/1152/030 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 April 2017 
 
 
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/


30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 

 



31 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Daiichi Sankyo Europe GmbH 
Luitpoldstrasse 1 
85276 Pfaffenhofen, Bayern 
Germany 
 
 
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. 

 
 



32 

• Additional risk minimisation measures  
 
Prior to launch of Roteas in each Member State, the MAH must agree the content and format of the 
educational programme, including communication media, distribution modalities, and any other 
aspects of the programme, with the national competent authority (NCA).  
 
The educational programme is aimed at mitigating the risk of serious bleeds or haemorrhage in 
patients treated with Roteas by ensuring prescriber awareness and providing guidance on appropriate 
patient selection, correct dosing as well as management of the risk. 
The programme is also aimed at ensuring that the healthcare professionals who intend to prescribe 
Roteas are aware of the patient alert card and that the card is to be given to and reviewed with all 
patients treated with Roteas. 
 
The MAH shall ensure that in each Member State where Roteas is marketed, all healthcare 
professionals who are expected to use Roteas are provided with the following educational material: 

• The Summary of Product Characteristics (SmPC) 
• Prescriber guide for healthcare professionals 
• Patient alert card 

 
The prescriber guide for healthcare professionals shall contain the following key elements: 

• Relevant information on the risk of bleeding 
• Details of the population potentially at higher risk of bleeding 
• Contraindications 
• Recommendations for dose adjustment in at risk populations, including patients with renal or 

hepatic impairment, low body weight and concomitant use of some P-gp inhibitors 
• Guidance on switching from or to Roteas treatment 
• Guidance regarding surgery or invasive procedure, and temporary discontinuation 
• Management of overdose situations and haemorrhage 
• Use of coagulation tests and their interpretation 
• That all patients should be provided with a patient alert card and be counselled about: 
 The signs or symptoms of bleeding and when to seek attention from a healthcare 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 Roteas if they need to 

have any surgery or invasive procedure 
 
The patient alert card should contain the following key safety messages: 

• The signs or symptoms of bleeding and when to seek attention  
• 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 Roteas if they need to have 

any surgery or invasive procedure 
 
 



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



34 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



35 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR 15 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 15 mg film-coated tablets  
edoxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 15 mg edoxaban (as tosilate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
10 x 1 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 
 
 



36 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Berlin-Chemie AG 
Glienicker Weg 125 
12489 Berlin  
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1152/001    10 film-coated tablets 
EU/1/16/1152/002    10 x 1 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Roteas 15 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
  



37 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 10 FILM-COATED TABLETS FOR 15 MG  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 15 mg film-coated tablets 
edoxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Berlin-Chemie (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
  



38 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE BLISTER OF 10 x 1 FILM-COATED TABLETS FOR 15 MG  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 15 mg film-coated tablets 
edoxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Berlin-Chemie (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
  



39 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR 30 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 30 mg film-coated tablets  
edoxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 30 mg edoxaban (as tosilate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
84 film-coated tablets 
90 film-coated tablets 
98 film-coated tablets 
100 film-coated tablets 
10 x 1 film-coated tablets 
50 x 1 film-coated tablets 
100 x 1 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 
 



40 

 
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 
 
Berlin-Chemie AG 
Glienicker Weg 125 
12489 Berlin  
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1152/003    10 film-coated tablets 
EU/1/16/1152/004    14 film-coated tablets 
EU/1/16/1152/005    28 film-coated tablets 
EU/1/16/1152/006    30 film-coated tablets 
EU/1/16/1152/007    56 film-coated tablets 
EU/1/16/1152/008    60 film-coated tablets 
EU/1/16/1152/009    84 film-coated tablets 
EU/1/16/1152/010    90 film-coated tablets 
EU/1/16/1152/011    98 film-coated tablets 
EU/1/16/1152/012    100 film-coated tablets 
EU/1/16/1152/013    10 x 1 film-coated tablets 
EU/1/16/1152/014    50 x 1 film-coated tablets 
EU/1/16/1152/015    100 x 1 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Roteas 30 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



41 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
  



42 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 10 FILM-COATED TABLETS FOR 30 MG  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 30 mg film-coated tablets 
edoxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Berlin-Chemie (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 
  



43 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 14 FILM-COATED TABLETS FOR 30 MG  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 30 mg film-coated tablets 
edoxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Berlin-Chemie (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
MON, TUE, WED, THU, FRI, SAT, SUN 
 
 
  



44 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE BLISTER OF 10 x 1 FIML-COATED TABLETS FOR 30 MG  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 30 mg film-coated tablets 
edoxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Berlin-Chemie (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
  



45 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR HDPE BOTTLE FOR 30 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 30 mg film-coated tablets  
edoxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 30 mg edoxaban (as tosilate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
90 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 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 



46 

 
Berlin-Chemie AG 
Glienicker Weg 125 
12489 Berlin 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1152/029 90 film-coated tablets (HDPE Bottle) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. (only applicable for bottle label) 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Roteas 30 mg (only applicable for outer carton, not applicable for bottle label) 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. (only applicable for outer carton, not applicable 
for bottle label) 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC (only applicable for outer carton, not applicable for bottle label) 
SN (only applicable for outer carton, not applicable for bottle label) 
NN (only applicable for outer carton, not applicable for bottle label) 
 
  



47 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR 60 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 60 mg film-coated tablets  
edoxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 60 mg edoxaban (as tosilate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
84 film-coated tablets 
90 film-coated tablets 
98 film-coated tablets 
100 film-coated tablets 
10 x 1 film-coated tablets 
50 x 1 film-coated tablets 
100 x 1 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 
 



48 

 
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 
 
Berlin-Chemie AG 
Glienicker Weg 125 
12489 Berlin 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1152/016    10 film-coated tablets 
EU/1/16/1152/017    14 film-coated tablets 
EU/1/16/1152/018    28 film-coated tablets 
EU/1/16/1152/019    30 film-coated tablets 
EU/1/16/1152/020    56 film-coated tablets 
EU/1/16/1152/021    60 film-coated tablets 
EU/1/16/1152/022    84 film-coated tablets 
EU/1/16/1152/023    90 film-coated tablets 
EU/1/16/1152/024    98 film-coated tablets 
EU/1/16/1152/025    100 film-coated tablets 
EU/1/16/1152/026    10 x 1 film-coated tablets 
EU/1/16/1152/027    50 x 1 film-coated tablets 
EU/1/16/1152/028    100 x 1 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Roteas 60 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



49 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
  



50 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 10 FILM-COATED TABLETS FOR 60 MG  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 60 mg film-coated tablets 
edoxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Berlin-Chemie (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 
  



51 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 14 FILM-COATED TABLETS FOR 60 MG  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 60 mg film-coated tablets 
edoxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Berlin-Chemie (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
MON, TUE, WED, THU, FRI, SAT, SUN 
 
 
  



52 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE BLISTER OF 10 x 1 FIML-COATED TABLETS FOR 60 MG  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 60 mg film-coated tablets 
edoxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Berlin-Chemie (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
  



53 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR HDPE BOTTLE FOR 60 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Roteas 60 mg film-coated tablets  
edoxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 60 mg edoxaban (as tosilate). 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
90 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 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 



54 

 
Berlin-Chemie AG 
Glienicker Weg 125 
12489 Berlin 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1152/030 90 film-coated tablets (HDPE Bottle) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. (only applicable for bottle label) 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Roteas 60 mg (only applicable for outer carton, not applicable for bottle label) 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. (only applicable for outer carton, not applicable 
for bottle label) 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC (only applicable for outer carton, not applicable for bottle label) 
SN (only applicable for outer carton, not applicable for bottle label) 
NN (only applicable for outer carton, not applicable for bottle label) 
 
 
  



55 

PATIENT ALERT CARD 
 
PATIENT ALERT CARD 
 
Roteas 
film-coated tablets 
edoxaban  
 
Please keep this card with you at all times. 
 
Present it to your healthcare professional, pharmacist, surgeon or dentist before any medical treatment 
or intervention. 
 
 
PATIENT INFORMATION 
 
Patient name: 
 
Date of birth: 
 
In case of emergency, please contact: 
 
Name: 
 
Phone no: 
 
 
TREATMENT INFORMATION 
(To be completed by physician) 
 
Roteas has been prescribed at a once-daily dose of: mg 
 
Started on: / (mm/yy) 
 
Blood type:  
 
Other medicines/conditions:  
 
 
PRESCRIBER INFORMATION 
 
For more information or in case of emergency, please contact: 
 
Physician’s name: 
 
Phone number, practice stamp: 
 
Signature of physician: 
 
 
INFORMATION FOR HEALTHCARE PROFESSIONALS 
 
• Roteas is an oral anticoagulant factor Xa inhibitor. 
• When an invasive procedure is required, Roteas should be stopped at least 24 hours beforehand, 

and appropriate caution exercised. 
• Roteas may increase the risk of bleeding. In case of clinically significant bleeding, stop treatment 

immediately. 



56 

• Coagulation tests such as international normalised ratio (INR), prothrombin time (PT), or activated 
partial thromboplastin time (aPTT) are not a useful measure of the effect of Roteas. However, a 
calibrated anti-Factor Xa assay may help inform clinical decisions. 

 
Please consult the Summary of Product Characteristics (SmPC) for more information. 
 
Berlin-Chemie [LOGO] 
 
 
ABOUT YOUR TREATMENT 
 
You have been prescribed Roteas, an anticoagulant medicine, which thins your blood and helps 
prevent you from suffering blood clots. It is important that you take your medicine exactly as 
instructed by your doctor. 
 
• If you miss a dose, take it immediately and then continue the following day as normal – do not take 

double the prescribed dose in a single day. 
• Do not start any other medications (including over the counter) without consulting your doctor. 
• Do not stop taking Roteas without consulting your doctor as this can increase your risk of 

developing a blood clot. 
• Please read the Patient Information Leaflet found inside each pack of Roteas. 
 
 
WHEN TO SEEK MEDICAL ADVICE 
 
RISK OF BLEEDING 
 
Taking an anticoagulant medicine such as Roteas can increase your risk of bleeding. It is therefore 
important to be aware of the possible signs and symptoms of bleeding and to speak to your doctor 
immediately if you experience any of the following: 
 
• Bruising or bleeding under the skin 
• Blood in the urine 
• Coughing up blood 
• Vomiting blood or material that looks like ground coffee 
• Nose bleeds or cuts that take a long time to stop bleeding 
• Tar-coloured stools 
• Dizziness or sudden headache 
• Unexplained tiredness 
• Abnormal vaginal bleeding, including heavier or prolonged menses  
 
Please talk to your doctor if you experience any unusual symptoms. 
 
 
  



57 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



58 

Package leaflet: Information for the user 
 

Roteas 15 mg film-coated tablets 
Roteas 30 mg film-coated tablets 
Roteas 60 mg film-coated tablets 

edoxaban 
 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
 
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 or pharmacist. 
- 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 or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
1. What Roteas is and what it is used for  
2. What you need to know before you take Roteas  
3. How to take Roteas  
4. Possible side effects  
5. How to store Roteas  
6. Contents of the pack and other information 
 
 
1. What Roteas is and what it is used for 
 
Roteas contains the active substance edoxaban and belongs to a group of medicines called 
anticoagulants. This medicine helps to prevent blood clots from forming. It works by blocking the 
activity of factor Xa, which is an important component of blood clotting. 
 
Roteas is used in adults to: 
- prevent blood clots in the brain (stroke) and other blood vessels in the body if you have a 

form of irregular heart rhythm called nonvalvular atrial fibrillation and at least one additional 
risk factor, such as heart failure, previous stroke or high blood pressure; 

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

 
 



59 

2. What you need to know before you take Roteas 
 
Do not take Roteas 

- if you are allergic to edoxaban or any of the other ingredients of this medicine (listed in 
section 6); 

- if you are actively bleeding; 
- if you have a disease or condition that increases the risk of serious bleeding  

(e.g. stomach ulcer, injury or bleeding in the brain, or recent surgery of the brain or eyes); 
- if you are taking other medicines to prevent blood clotting (e.g. warfarin, dabigatran, 

rivaroxaban, apixaban or heparin), except when changing anticoagulant treatment or while 
getting heparin through a venous or arterial line to keep it open; 

- if you have a liver disease which leads to an increased risk of bleeding; 
- if you have uncontrolled high blood pressure; 
- if you are pregnant or breast feeding. 
 
Warnings and precautions  

Talk to your doctor or pharmacist before taking Roteas, 

- if you have an increased risk of bleeding, as could be the case if you have any of the following 
conditions: 

• endstage kidney disease or if you are on dialysis; 
• severe liver disease; 
• bleeding disorders; 
• a problem with the blood vessels in the back of your eyes (retinopathy); 
• recent bleeding in your brain (intracranial or intracerebral bleeding); 
• problems with the blood vessels in your brain or spinal column; 

- if you have a mechanical heart valve. 
 
Roteas 15 mg is only to be used when changing from Roteas 30 mg to a vitamin K antagonist (e.g. 
warfarin) (see section 3. How to take Roteas). 
 
Take special care with Roteas, 
- if you know that you have a disease called antiphospholipid syndrome (a disorder of the immune 

system that causes an increased risk for blood clots), tell your doctor who will decide if the 
treatment may need to be changed. 

 
If you need to have an operation, 
- it is very important to take Roteas before and after the operation exactly at the times you have 

been told by your doctor. If possible, Roteas should be stopped at least 24 hours before an 
operation. Your doctor will determine when to restart Roteas. 
In emergency situations your physician will help determine the appropriate actions regarding 
Roteas. 

 
Children and adolescents 
Roteas is not recommended in children and adolescents under 18 years of age. There is no information 
on its use in children and adolescents. 
 



60 

Other medicines and Roteas 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
If you are taking any of the following: 
• some medicines for fungal infections (e.g. ketoconazole); 
• medicines to treat abnormal heart beat (e.g. dronedarone, quinidine, verapamil); 
• other medicines to reduce blood clotting (e.g. heparin, clopidogrel or vitamin K antagonists such 

as warfarin, acenocoumarol, phenprocoumon or dabigatran, rivaroxaban, apixaban); 
• antibiotic medicines (e.g. erythromycin); 
• medicines to prevent organ rejection after transplantation (e.g. ciclosporin); 
• anti-inflammatory and pain-relieving medicines (e.g. naproxen or acetylsalicylic acid); 
• antidepressant medicines called selective serotonin reuptake inhibitors or serotonin-

norepinephrine reuptake inhibitors; 
 
If any of the above apply to you, tell your doctor before taking Roteas, because these medicines 
may increase the effects of Roteas and the chance of unwanted bleeding. Your doctor will decide, if 
you should be treated with Roteas and if you should be kept under observation. 
 
If you are taking any of the following: 
• some medicines for treatment of epilepsy (e.g. phenytoin, carbamazepine, phenobarbital); 
• St John’s Wort, a herbal product used for anxiety and mild depression; 
• rifampicin, an antibiotic medicine. 
 
If any of the above apply to you, tell your doctor before taking Roteas, because the effect of Roteas 
may be reduced. Your doctor will decide if you should be treated with Roteas and if you should be 
kept under observation. 
 
Pregnancy and breast-feeding 
Do not take Roteas if you are pregnant or breast-feeding. If there is a chance that you could become 
pregnant, use a reliable contraceptive while you are taking Roteas. If you become pregnant while you 
are taking Roteas, immediately tell your doctor, who will decide how you should be treated. 
 
Driving and using machines 
Roteas has no or negligible effects on your ability to drive or use machines. 
 
 
3. How to take Roteas 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
How much to take 

The recommended dose is one 60 mg tablet once daily. 
 
- If you have impaired kidney function, the dose may be reduced to one 30 mg tablet once daily 

by your doctor; 
- if your body weight is 60 kg or lower, the recommended dose is one 30 mg tablet once daily; 
- if your doctor has prescribed medicines known as P-gp inhibitors: ciclosporin, dronedarone, 

erythromycin, or ketoconazole, the recommended dose is one 30 mg tablet once daily. 
 
How to take the tablet 
Swallow the tablet, preferably with water. 
Roteas can be taken with or without food. 
 



61 

If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take Roteas. 
The tablet may be crushed and mixed with water or apple puree immediately before you take it. If 
necessary, your doctor may also give you the crushed Roteas tablet through a stomach tube. 
 
Your doctor may change your anticoagulant treatment as follows: 
Changing from vitamin K antagonists (e.g. warfarin) to Roteas 
Stop taking the vitamin K antagonist (e.g. warfarin). Your doctor will need to do blood measurements 
and will instruct you when to start taking Roteas. 
 
Changing from non-VKA oral anticoagulants (dabigatran, rivaroxaban, or apixaban) to Roteas 
Stop taking the previous medicines (e.g. dabigatran, rivaroxaban, or apixaban) and start Roteas at the 
time of the next scheduled dose. 
 
Changing from parenteral anticoagulants (e.g. heparin) to Roteas 
Stop taking the anticoagulant (e.g. heparin) and start Roteas at the time of the next scheduled 
anticoagulant dose. 
 
Changing from Roteas to vitamin K antagonists (e.g. warfarin) 
If you currently take 60 mg Roteas: 
Your doctor will tell you to reduce your dose of Roteas to a 30 mg tablet once daily and to take it 
together with a vitamin K antagonist (e.g. warfarin). Your doctor will need to do blood measurements 
and will instruct you when to stop taking Roteas. 
If you currently take 30 mg (dose reduced) Roteas: 
Your doctor will tell you to reduce your dose of Roteas to a 15 mg tablet once daily and to take it 
together with a vitamin K antagonist (e.g. warfarin). Your doctor will need to do blood measurements 
and will instruct you when to stop taking Roteas. 
 
Changing from Roteas to non-VKA oral anticoagulants (dabigatran, rivaroxaban, or apixaban) 
Stop taking Roteas and start the non-VKA anticoagulant (e.g. dabigatran, rivaroxaban, or apixaban) at 
the time of the next scheduled dose of Roteas. 
 
Changing from Roteas to parenteral anticoagulants (e.g. heparin) 
Stop taking Roteas and start the parenteral anticoagulant (e.g. heparin) at the time of the next 
scheduled dose of Roteas. 
 
Patients undergoing cardioversion:  
If your abnormal heartbeat needs to be restored to normal by a procedure called cardioversion, take 
Roteas at the times your doctor tells you to prevent blood clots in the brain and other blood vessels in 
your body. 
 
If you take more Roteas than you should 
Tell your doctor immediately if you have taken too many Roteas tablets. 
If you take more Roteas than recommended, you may have an increased risk of bleeding. 
 
If you forget to take Roteas 
You should take the tablet immediately and then continue the following day with the once daily tablet 
as usual. Do not take a double dose on the same day to make up for a forgotten dose. 
 
If you stop taking Roteas 
Do not stop taking Roteas without talking to your doctor first, because Roteas treats and prevents 
serious conditions. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 



62 

4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Like other similar medicines (medicines to reduce blood clotting), Roteas may cause bleeding which 
may potentially be life-threatening. In some cases the bleeding may not be obvious. 
 
If you experience any bleeding event that does not stop by itself or if you experience signs of excessive 
bleeding (exceptional weakness, tiredness, paleness, dizziness, headache or unexplained swelling) 
consult your doctor immediately.  
Your doctor may decide to keep you under closer observation or change your medicine. 
 
Overall list of possible side effects: 
 
Common (may affect up to 1 in 10 people): 
• stomach ache; 
• abnormal liver blood tests; 
• bleeding from the skin or under the skin; 
• anaemia (low levels of red blood cells); 
• bleeding from the nose; 
• bleeding from the vagina; 
• rash; 
• bleeding in the bowel; 
• bleeding from the mouth and/or throat; 
• blood found in your urine; 
• bleeding following an injury (puncture); 
• bleeding in the stomach; 
• dizziness; 
• feeling sick; 
• headache; 
• itching. 
 
Uncommon (may affect up to 1 in 100 people): 
 
• bleeding in the eyes; 
• bleeding from a surgical wound following an operation; 
• blood in the spit when coughing; 
• bleeding in the brain; 
• other types of bleeding; 
• reduced number of platelets in your blood (which can affect clotting); 
• allergic reaction; 
• hives. 
 
Rare (may affect up to 1 in 1,000 people): 
• bleeding in the muscles; 
• bleeding in joints; 
• bleeding in the abdomen; 
• bleeding in the heart; 
• bleeding inside the skull; 
• bleeding following a surgical procedure; 
• allergic shock; 
• swelling of any part of the body due to allergic reaction. 
 
 



63 

Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. 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 Roteas 
 
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 each blister or 
bottle 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 Roteas contains  
- The active substance is edoxaban (as tosilate). 
Roteas 15 mg film-coated tablets 
Each tablet contains 15 mg edoxaban (as tosilate). 
 
Roteas 30 mg film-coated tablets 
Each tablet contains 30 mg edoxaban (as tosilate). 
 
Roteas 60 mg film-coated tablets 
Each tablet contains 60 mg edoxaban (as tosilate). 
 
- The other ingredients are: 
Roteas 15 mg film-coated tablets 
Tablet core: mannitol (E421), pregelatinised starch, crospovidone (E1202), hydroxypropyl cellulose 
(E463), magnesium stearate (E470b). 
Film coat: hypromellose (E464), macrogol (8000), titanium dioxide (E171), talc (E553b), carnauba 
wax, iron oxide red (E172), iron oxide yellow (E172). 
 
Roteas 30 mg film-coated tablets 
Tablet core: mannitol (E421), pregelatinised starch, crospovidone (E1202), hydroxypropyl cellulose 
(E463), magnesium stearate (E470b). 
Film coat: hypromellose (E464), macrogol (8000), titanium dioxide (E171), talc (E553b), carnauba 
wax, iron oxide red (E172). 
 
Roteas 60 mg film-coated tablets 
Tablet core: mannitol (E421), pregelatinised starch, crospovidone (E1202), hydroxypropyl cellulose 
(E463), magnesium stearate (E470b). 
Film coat: hypromellose (E464), macrogol (8000), titanium dioxide (E171), talc (E553b), carnauba 
wax, iron oxide yellow (E172). 
 

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


64 

What Roteas looks like and contents of the pack 
Roteas 15 mg film-coated tablets are orange, round-shaped (6.7 mm diameter) and debossed with 
“DSC L15” on one side. 
They come in blisters in cartons of 10 film-coated tablets or unit dose blisters in cartons of 10 x 1 film-
coated tablets. 
 
Roteas 30 mg film-coated tablets are pink, round-shaped (8.5 mm diameter) and debossed with 
“DSC L30” on one side. 
They come in blisters in cartons of 10, 14, 28, 30, 56, 60, 84, 90, 98 or 100 film-coated tablets or unit 
dose blisters in cartons of 10 x 1, 50 x 1, or 100 x 1 film-coated tablets, or in bottles of 90 film-coated 
tablets. 
 
Roteas 60 mg film-coated tablets are yellow, round-shaped (10.5 mm diameter) and debossed with 
“DSC L60” on one side. 
They come in blisters in cartons of 10, 14, 28, 30, 56, 60, 84, 90, 98 or 100 film-coated tablets or unit 
dose blisters in cartons of 10 x 1, 50 x 1, or 100 x 1 film-coated tablets, or in bottles of 90 film-coated 
tablets. 
 
Not all pack sizes may be marketed.  
 
Marketing Authorisation Holder  
Berlin-Chemie AG 
Glienicker Weg 125 
12489 Berlin 
Germany 
 
Manufacturer 
Daiichi Sankyo Europe GmbH 
Luitpoldstrasse 1 
85276 Pfaffenhofen 
Germany 
 



65 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Lietuva 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

България 
“Берлин-Хеми/А. Менарини  
България”  EООД 
тел.: +359 2 454 0950 

Luxembourg/Luxemburg 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Česká republika 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Magyarország 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Danmark 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Malta 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Deutschland 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Nederland 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Eesti 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Norge 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Ελλάδα 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Österreich 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

España 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Polska 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

France 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Portugal 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Hrvatska 
Berlin-Chemie Menarini Hrvatska d.o.o. 
Tel : +385 1 4821 361 

România 
Berlin-Chemie А.Menarini S.R.L. 
Tel: +40 21 232 34 32 

Ireland 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Slovenija 
Berlin-Chemie / A. Menarini Distribution 
Ljubljana d.o.o. 
Tel: +386 01 300 2160 

Ísland 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Slovenská republika 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Italia 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Suomi/Finland 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Κύπρος 
Daiichi Sankyo Europe GmbH 
Τηλ: +49-(0) 89 7808 0 

Sverige 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

Latvija 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

United Kingdom 
Daiichi Sankyo Europe GmbH 
Tel: +49-(0) 89 7808 0 

 
This leaflet was last revised in {MM/YYYY}. 

 
Detailed information on this medicine is available on the European Medicines Agency web site: 
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