Xarelto

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

0BSUMMARY OF PRODUCT CHARACTERISTICS 
 
 



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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 
 
Xarelto 2.5 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 2.5 mg rivaroxaban.  
 
Excipient with known effect 
Each film-coated tablet contains 33.92 mg lactose (as monohydrate), see section 4.4. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet)  
 
Light yellow, round biconvex tablets (6 mm diameter, 9 mm radius of curvature) marked with the 
BAYER-cross on one side and "2.5" and a triangle on the other side.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Xarelto, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or 
ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute 
coronary syndrome (ACS) with elevated cardiac biomarkers (see sections 4.3, 4.4 and 5.1). 
 
Xarelto, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of 
atherothrombotic events in adult patients with coronary artery disease (CAD) or symptomatic 
peripheral artery disease (PAD) at high risk of ischaemic events. 
 
4.2 Posology and method of administration 
 
Posology 
The recommended dose is 2.5 mg twice daily.  
 
 ACS 
Patients taking Xarelto 2.5 mg twice daily should also take a daily dose of 75 - 100 mg ASA or a daily 
dose of 75 - 100 mg ASA in addition to either a daily dose of 75 mg clopidogrel or a standard daily 
dose of ticlopidine. 
 
Treatment should be regularly evaluated in the individual patient weighing the risk for ischaemic 
events against the bleeding risks. Extension of treatment beyond 12 months should be done on an 
individual patient basis as experience up to 24 months is limited (see section 5.1). 
 
Treatment with Xarelto should be started as soon as possible after stabilisation of the ACS event 
(including revascularisation procedures); at the earliest 24 hours after admission to hospital and at the 
time when parenteral anticoagulation therapy would normally be discontinued. 



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 CAD/PAD 
Patients taking Xarelto 2.5 mg twice daily should also take a daily dose of 75 - 100 mg ASA. 
 
Duration of treatment should be determined for each individual patient based on regular evaluations 
and should consider the risk for thrombotic events versus the bleeding risks. 
 
In patients with an acute thrombotic event or vascular procedure and a need for dual antiplatelet 
therapy, the continuation of Xarelto 2.5 mg twice daily should be evaluated depending on the type of 
event or procedure and antiplatelet regimen. Safety and efficacy of Xarelto 2.5 mg twice daily in 
combination with ASA plus clopidogrel/ticlopidine has only been studied in patients with recent ACS 
(see section 4.1). Dual antiplatelet therapy has not been studied in combination with Xarelto 2.5 mg 
twice daily in patients with CAD/PAD (see sections 4.4 and 5.1).  
 
If a dose is missed the patient should continue with the regular dose as recommended at the next 
scheduled time. The dose should not be doubled to make up for a missed dose. 
 
Converting from Vitamin K Antagonists (VKA) to Xarelto 
When converting patients from VKAs to Xarelto, International Normalised Ratio (INR) values could 
be falsely elevated after the intake of Xarelto. The INR is not valid to measure the anticoagulant 
activity of Xarelto, and therefore should not be used (see section 4.5). 
 
Converting from Xarelto to Vitamin K antagonists (VKA) 
There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. 
Continuous adequate anticoagulation should be ensured during any transition to an alternate 
anticoagulant. It should be noted that Xarelto can contribute to an elevated INR.  
In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is ≥ 2.0. 
For the first two days of the conversion period, standard initial dosing of VKA should be used 
followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the 
INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of 
Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last 
dose (see sections 4.5 and 5.2). 
 
Converting from parenteral anticoagulants to Xarelto 
For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant 
and start Xarelto 0 to 2 hours before the time that the next scheduled administration of the parenteral 
medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation 
of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin). 
 
Converting from Xarelto to parenteral anticoagulants 
Give the first dose of parenteral anticoagulant at the time the next Xarelto dose would be taken.  
 
Special populations 
Renal impairment 
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) 
indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be 
used with caution in these patients. Use is not recommended in patients with creatinine clearance 
< 15 ml/min (see sections 4.4 and 5.2). 
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 
50 - 80 ml/min) or moderate renal impairment (creatinine clearance 30 - 49 ml/min) (see section 5.2). 
 
Hepatic impairment 
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically 
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2). 
 



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Elderly population  
No dose adjustment (see sections 4.4 and 5.2) 
The risk of bleeding increases with increasing age (see section 4.4). 
 
Body weight 
No dose adjustment (see sections 4.4 and 5.2) 
 
Gender 
No dose adjustment (see section 5.2) 
 
Paediatric population 
The safety and efficacy of Xarelto 2.5 mg tablets in children aged 0 to 18 years have not been 
established. No data are available. Therefore, Xarelto 2.5 mg tablets are not recommended for use in 
children below 18 years of age.  
 
Method of administration  
Xarelto is for oral use. 
The tablets can be taken with or without food (see sections 4.5 and 5.2). 
 
Crushing of tablets 
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with 
water or apple puree immediately prior to use and administered orally.  
The crushed tablet may also be given through gastric tubes (see sections 5.2 and 6.6). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Active clinically significant bleeding. 
 
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. 
 
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low 
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral 
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of 
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain 
an open central venous or arterial catheter (see section 4.5). 
 
Concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a transient 
ischaemic attack (TIA) (see section 4.4).  
 
Concomitant treatment of CAD/PAD with ASA in patients with previous haemorrhagic or lacunar 
stroke, or any stroke within a month (see section 4.4). 
 
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic 
patients with Child Pugh B and C (see section 5.2). 
 
Pregnancy and breast-feeding (see section 4.6). 
 



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4.4 Special warnings and precautions for use 
 
In ACS patients, efficacy and safety of Xarelto 2.5 mg have been investigated in combination with the 
antiplatelet agents ASA alone or ASA plus clopidogrel/ticlopidine. Treatment in combination with 
other antiplatelet agents, e.g. prasugrel or ticagrelor, has not been studied and is not recommended. 
In patients at high risk of ischaemic events with CAD/PAD, efficacy and safety of Xarelto 2.5 mg 
have only been investigated in combination with ASA.  
 
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment 
period. 
 
Haemorrhagic risk 
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding. 
It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto 
administration should be discontinued if severe haemorrhage occurs (see section 4.9). 
 
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary 
including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently 
during long term rivaroxaban treatment on top of single or dual anti-platelet therapy. Thus, in addition 
to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to 
detect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to be 
appropriate. 
 
Several sub-groups of patients, as detailed below, are at increased risk of bleeding. Therefore, the use 
of Xarelto in combination with dual antiplatelet therapy in patients at known increased risk for 
bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. In 
addition 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. 
 
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban 
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional 
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. 
overdose and emergency surgery (see sections 5.1 and 5.2). 
 
Renal impairment 
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels 
may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. 
Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not 
recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).  
In patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) concomitantly 
receiving other medicinal products which increase rivaroxaban plasma concentrations Xarelto is to be 
used with caution (see section 4.5). 
 
Interaction with other medicinal products 
The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with 
azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV 
protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and 
P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree 
(2.6 fold on average) which may lead to an increased bleeding risk (see section 4.5). 
 
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis 
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) and 
platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotonin 
norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease 
an appropriate prophylactic treatment may be considered (see sections 4.5 and 5.1). 



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Patients on treatment with Xarelto and ASA or with Xarelto and ASA plus clopidogrel/ticlopidine 
should only receive concomitant treatment with NSAIDs if the benefit outweighs the bleeding risk. 
 
Other haemorrhagic risk factors 
As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding 
risk such as: 
 congenital or acquired bleeding disorders 
 uncontrolled severe arterial hypertension 
 other gastrointestinal disease without active ulceration that can potentially lead to bleeding 

complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal 
reflux disease) 

 vascular retinopathy 
 bronchiectasis or history of pulmonary bleeding 
 
It should be used with caution in ACS and CAD/PAD patients: 
 ≥ 75 years of age if co-administered with ASA alone or with ASA plus clopidogrel or ticlopidine. 

The benefit-risk of the treatment should be individually assessed on a regular basis. 
 with lower body weight (< 60 kg) if co-administered with ASA alone or with ASA plus 

clopidogrel or ticlopidine. 
 CAD patients with severe symptomatic heart failure. Study data indicate that such patients may 

benefit less from treatment with rivaroxaban (see section 5.1). 
 
Patients with prosthetic valves 
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone 
transcatheter aortic valve replacement (TAVR). Safety and efficacy of Xarelto have not been studied 
in patients with prosthetic heart valves; therefore, there are no data to support that Xarelto provides 
adequate anticoagulation in this patient population. Treatment with Xarelto is not recommended for 
these patients. 
 
Patients with antiphospholipid syndrome 
Direct acting Oral Anticoagulants (DOACs) including rivaroxaban 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. 
 
Patients with prior stroke and/or TIA 
Patients with ACS 
Xarelto 2.5 mg is contraindicated for the treatment of ACS in patients with a prior stroke or TIA (see 
section 4.3). Few ACS patients with a prior stroke or TIA have been studied but the limited efficacy 
data available indicate that these patients do not benefit from treatment. 
 
Patients with CAD/PAD 
CAD/PAD patients with previous haemorrhagic or lacunar stroke, or an ischaemic, non-lacunar stroke 
with in the previous month were not studied (see section 4.3).  
 
Spinal/epidural anaesthesia or puncture 
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, 
patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk 
of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. 
The risk of these events may be increased by the post-operative use of indwelling epidural catheters or 
the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by 
traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and 
symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder 
dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior 
to neuraxial intervention the physician should consider the potential benefit versus the risk in 
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical 



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experience with the use of Xarelto 2.5 mg with ASA alone or with ASA plus clopidogrel or ticlopidine 
in these situations. 
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and 
neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of 
rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when 
the anticoagulant effect of rivaroxaban is estimated to be low (see section 5.2). However, the exact 
timing to reach a sufficiently low anticoagulant effect in each patient is not known.  
Platelet aggregation inhibitors should be discontinued as suggested by the manufacturer’s prescribing 
information.  
 
Dosing recommendations before and after invasive procedures and surgical intervention  
If an invasive procedure or surgical intervention is required, Xarelto 2.5 mg should be stopped at least 
12 hours before the intervention, if possible and based on the clinical judgement of the physician. If a 
patient is to undergo elective surgery and anti-platelet effect is not desired, platelet aggregation 
inhibitors should be discontinued as directed by the manufacturer’s prescribing information.  
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the 
urgency of the intervention. 
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention 
provided the clinical situation allows and adequate haemostasis has been established as determined by 
the treating physician (see section 5.2). 
 
Elderly population 
Increasing age may increase haemorrhagic risk (see sections 5.1 and 5.2).  
 
Dermatological reactions 
Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS 
syndrome, have been reported during post-marketing surveillance in association with the use of 
rivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in the 
course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of 
treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. 
spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal 
lesions. 
 
Information about excipients 
Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose-galactose malabsorption should not take this medicinal product. 
This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially “sodium-free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
CYP3A4 and P-gp inhibitors 
Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a 
day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in 
mean rivaroxaban CRmaxR, with significant increases in pharmacodynamic effects which may lead to an 
increased bleeding risk. Therefore, the use of Xarelto is not recommended in patients receiving 
concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, 
voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong 
inhibitors of both CYP3A4 and P-gp (see section 4.4).  
 
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either 
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. 
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and 
moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in 
CRmaxR. The interaction with clarithromycin is likely not clinically relevant in most patients but can be 
potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). 
 



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Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 
1.3 fold increase in mean rivaroxaban AUC and CRmaxR. The interaction with erythromycin is likely not 
clinically relevant in most patients but can be potentially significant in high-risk patients. 
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. The effect of erythromycin is additive to that of renal impairment (see 
section 4.4). 
 
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold 
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean CRmaxR. The interaction with 
fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-
risk patients. (For patients with renal impairment: see section 4.4). 
 
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should 
be avoided. 
 
Anticoagulants 
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single 
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on 
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban. 
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any 
other anticoagulants (see sections 4.3 and 4.4).  
 
NSAIDs/platelet aggregation inhibitors 
No clinically relevant prolongation of bleeding time was observed after concomitant administration of 
rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more 
pronounced pharmacodynamic response.  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with 500 mg acetylsalicylic acid. 
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a 
pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was 
observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or 
GPIIb/IIIa receptor levels. 
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) 
and platelet aggregation inhibitors because these medicinal products typically increase the bleeding 
risk (see section 4.4). 
 
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. When 
concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-
major clinically relevant bleeding were observed in all treatment groups. 
 
Warfarin 
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or 
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) 
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, 
inhibition of factor Xa activity and endogenous thrombin potential were additive.  
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the 
fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity 
and ETP) reflected only the effect of rivaroxaban.  
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR 
measurement can be used at the CRtroughR of rivaroxaban (24 hours after the previous intake of 
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point. 



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No pharmacokinetic interaction was observed between warfarin and rivaroxaban. 
 
CYP3A4 inducers  
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 
50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The 
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, 
phenobarbital or St. John’s Wort 16T(Hypericum perforatum)) 16T may also lead to reduced rivaroxaban 
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be 
avoided unless the patient is closely observed for signs and symptoms of thrombosis. 
 
Other concomitant therapies  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), 
atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban 
neither inhibits nor induces any major CYP isoforms like CYP3A4. 
No clinically relevant interaction with food was observed (see section 4.2). 
 
Laboratory parameters 
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of 
rivaroxaban (see section 5.1). 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
Safety and efficacy of Xarelto 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 rivaroxaban passes the placenta, Xarelto is contraindicated 
during pregnancy (see section 4.3).  
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban. 
 
Breast-feeding 
Safety and efficacy of Xarelto have not been established in breast-feeding women. Data from animals 
indicate that rivaroxaban is secreted into milk. Therefore Xarelto 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 rivaroxaban in humans 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 
 
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope 
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). 
Patients experiencing these adverse reactions should not drive or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety of rivaroxaban has been evaluated in thirteen phase III studies in adults including 
53,103 patients exposed to rivaroxaban, and in two phase II and one phase III paediatric studies 
including 412 patients. See phase III studies as listed in table 1. 
 



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Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult 
and paediatric phase III studies 

Indication Number 
of 
patients* 

Total daily dose Maximum 
treatment duration 

Prevention of venous 
thromboembolism (VTE) in adult 
patients undergoing elective hip or 
knee replacement surgery 

6,097 10 mg 39 days 

Prevention of VTE in medically ill 
patients 

3,997 10 mg 39 days 

Treatment of deep vein thrombosis 
(DVT), pulmonary embolism (PE) and 
prevention of recurrence 

6,790 Day 1 - 21: 30 mg 
Day 22 and onwards: 
20 mg 
After at least 6 months: 
10 mg or 20 mg 

21 months 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

329 Body weight-adjusted dose 
to achieve a similar 
exposure as that observed 
in adults treated for DVT 
with 20 mg rivaroxaban 
once daily 

12 months 

Prevention of stroke and systemic 
embolism in patients with non-
valvular atrial fibrillation 

7,750 20 mg 41 months 

Prevention of atherothrombotic events 
in patients after an ACS 

10,225 5 mg or 10 mg 
respectively, co-
administered with either 
ASA or ASA plus 
clopidogrel or ticlopidine 

31 months  

Prevention of atherothrombotic events 
in patients with CAD/PAD 

18,244 5 mg co-administered with 
ASA or 10 mg alone 

47 months 

* Patients exposed to at least one dose of rivaroxaban 
 
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see 
section 4.4. and ‘Description of selected adverse reactions’ below) (Table 2). The most commonly 
reported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %). 
 



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Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the 
completed adult and paediatric phase III studies 
Indication Any bleeding Anaemia 
Prevention of venous 
thromboembolism (VTE) in adult 
patients undergoing elective hip or 
knee replacement surgery 

6.8% of patients 5.9% of patients 

Prevention of venous 
thromboembolism in medically ill 
patients 

12.6% of patients 2.1% of patients 

Treatment of DVT, PE and prevention 
of recurrence 

23% of patients 1.6% of patients 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

39.5% of patients 4.6% of patients 

Prevention of stroke and systemic 
embolism in patients with 
non-valvular atrial fibrillation 

28 per 100 patient 
years 

2.5 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients after an ACS 

22 per 100 patient 
years 

1.4 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients with CAD/PAD 

6.7 per 100 patient 
years 

0.15 per 100 patient 
years**  

* For all rivaroxaban studies all bleeding events are collected, reported and 
adjudicated. 

** In the COMPASS study, there is a low anaemia incidence as a selective 
approach to adverse event collection was applied 

 
Tabulated list of adverse reactions 
The frequencies of adverse reactions reported with Xarelto in adult and paediatric patients are 
summarised in Table 3 below by system organ class (in MedDRA) and by frequency. 
 
Frequencies are defined as: 
very common (≥ 1/10)  
common (≥ 1/100 to < 1/10)  
uncommon (≥ 1/1,000 to < 1/100)  
rare (≥ 1/10,000 to < 1/1,000) 
very rare (< 1/10,000)  
not known (cannot be estimated from the available data) 
  



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Table 3: All adverse reactions reported in adult patients in phase III clinical studies or through 
post-marketing use* and in two phase II and one phase III studies in paediatric patients 
Common Uncommon Rare Very rare Not known 
Blood and lymphatic system disorders 
Anaemia (incl. 
respective 
laboratory 
parameters) 

Thrombocytosis 
(incl. platelet count 
increased)P

A
P, 

thrombocytopenia 

   

Immune system disorders 
 Allergic reaction, 

dermatitis allergic, 
angioedema and 
allergic oedema 

 Anaphylactic 
reactions including 
anaphylactic shock  

 

Nervous system disorders 
Dizziness, 
headache 

Cerebral and 
intracranial 
haemorrhage, 
syncope 

   

Eye disorders 
Eye haemorrhage 
(incl. conjunctival 
haemorrhage) 

    

Cardiac disorders 
 Tachycardia    
Vascular disorders 
Hypotension, 
haematoma 

    

Respiratory, thoracic and mediastinal disorders 
Epistaxis, 
haemoptysis 

    

Gastrointestinal disorders 
Gingival bleeding, 
gastrointestinal 
tract haemorrhage 
(incl. rectal 
haemorrhage), 
gastrointestinal and 
abdominal pains, 
dyspepsia, nausea, 
constipationP

A
P, 

diarrhoea, 
vomitingP

A 

Dry mouth    

Hepatobiliary disorders 
Increase in 
transaminases 

Hepatic 
impairment, 
increased bilirubin, 
increased blood 
alkaline 
phosphatase P

A
P, 

increased GGTP

A 

Jaundice, bilirubin 
conjugated 
increased (with or 
without 
concomitant 
increase of ALT), 
cholestasis, 
hepatitis (incl. 
hepatocellular 
injury) 

  



13 

Common Uncommon Rare Very rare Not known 
Skin and subcutaneous tissue disorders 
Pruritus (incl. 
uncommon cases of 
generalised 
pruritus), rash, 
ecchymosis, 
cutaneous and 
subcutaneous 
haemorrhage 

Urticaria  Stevens-Johnson 
syndrome/Toxic 
Epidermal 
Necrolysis, DRESS 
syndrome  

 

Musculoskeletal and connective tissue disorders 
Pain in extremity P

A Haemarthrosis Muscle 
haemorrhage 

 Compartment 
syndrome 
secondary to a 
bleeding 

Renal and urinary disorders 
Urogenital tract 
haemorrhage (incl. 
haematuria and 
menorrhagiaP

B
P), 

renal impairment 
(incl. blood 
creatinine 
increased, blood 
urea increased) 

   Renal failure/acute 
renal failure 
secondary to a 
bleeding sufficient 
to cause 
hypoperfusion 

General disorders and administration site conditions 
Fever P

A
P, peripheral 

oedema, decreased 
general strength 
and energy (incl. 
fatigue and 
asthenia) 

Feeling unwell 
(incl. malaise)  

Localised oedemaP

A   

Investigations 
 Increased LDHP

A
P, 

increased lipaseP

A
P, 

increased amylaseP

A 

   

Injury, poisoning and procedural complications 
Postprocedural 
haemorrhage (incl. 
postoperative 
anaemia, and 
wound 
haemorrhage), 
contusion, wound 
secretion P

A 

 Vascular 
pseudoaneurysmP

C 
  

A:  observed in prevention of VTE in adult patients undergoing elective hip or knee replacement 
surgery 

B:  observed in treatment of DVT, PE and prevention of recurrence as very common in women 
< 55 years 

C:  observed as uncommon in prevention of atherothrombotic events in patients after an ACS 
(following percutaneous coronary intervention) 

*  A pre-specified selective approach to adverse event collection was applied. As incidence of 
adverse reactions did not increase and no new adverse reaction was identified, COMPASS 
study data were not included for frequency calculation in this table. 

 



14 

Description of selected adverse reactions 
Due to the pharmacological mode of action, the use of Xarelto 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 “Management of 
bleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito 
urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more 
frequently during long term rivaroxaban 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 and quantify the clinical relevance of overt 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 “Haemorrhagic risk”). Menstrual bleeding may be intensified and/or prolonged. 
Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained 
swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of 
cardiac ischaemia like chest pain or angina pectoris have been observed.  
Known complications secondary to severe bleeding such as compartment syndrome and renal failure 
due to hypoperfusion have been reported for Xarelto. 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 45TAppendix V45T. 
 
4.9 Overdose 
 
Rare cases of overdose up to 600 mg have been reported without bleeding complications or other 
adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma 
exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.  
A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban is 
available (refer to the Summary of Product Characteristics of andexanet alfa). 
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.  
 
Management of bleeding 
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban 
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has 
a half-life of approximately 5 to 13 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. 
If bleeding cannot be controlled by the above measures, either the administration of a specific 
factor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of 
rivaroxaban, or a specific procoagulant reversal agent, such as prothrombin complex concentrate 
(PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), 
should be considered. However, there is currently very limited clinical experience with the use of 
these medicinal products in individuals receiving rivaroxaban. The recommendation is also based on 
limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated 
depending on improvement of bleeding. Depending on local availability, a consultation with a 
coagulation expert should be considered in case of major bleedings (see section 5.1). 
 
Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. 
There is limited experience with tranexamic acid and no experience with aminocaproic acid and 
aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor 



15 

experience with the use of the systemic haemostatic desmopressin in individuals receiving 
rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01  
 
Mechanism of action 
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of 
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting 
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin 
(activated factor II) and no effects on platelets have been demonstrated. 
 
Pharmacodynamic effects 
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is 
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations 
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. 
The readout for PT is to be done in seconds, because the INR is only calibrated and validated for 
coumarins and cannot be used for any other anticoagulant.  
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult 
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC 
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC 
reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to 
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC 
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation 
than the 4-factor PCC (see section 4.9). 
The activated partial thomboplastin time (aPTT) and HepTest are also prolonged dose-dependently; 
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no 
need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. 
However, if clinically indicated, rivaroxaban levels can be measured by calibrated quantitative anti-
factor-Xa tests (see section 5.2). 
 
Clinical efficacy and safety 
ACS 
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for the 
prevention of cardiovascular (CV) death, myocardial infarction (MI) or stroke in subjects with a 
recent ACS (ST-elevation myocardial infarction [STEMI], non- ST-elevation myocardial infarction 
[NSTEMI] or unstable angina [UA]). In the pivotal double-blind ATLAS ACS 2 TIMI 51 study, 
15,526 patients were randomly assigned in a 1:1:1 fashion to one of three treatment groups: 
rivaroxaban 2.5 mg orally twice daily, 5 mg orally twice daily or to placebo twice daily co-
administered with ASA alone or with ASA plus a thienopyridine (clopidogrel or ticlopidine). Patients 
with an ACS under the age of 55 had to have either diabetes mellitus or a previous MI. The median 
time on treatment was 13 months and overall treatment duration was up to almost 3 years. 93.2% of 
patients received ASA concomitantly plus thienopyridine treatment and 6.8% ASA only. Among 
patients receiving dual anti-platelets therapy 98.8% received clopidogrel, 0.9% received ticlopidine 
and 0.3% received prasugrel. Patients received the first dose of rivaroxaban at a minimum of 24 hours 
and up to 7 days (mean 4.7 days) after admission to the hospital, but as soon as possible after 
stabilisation of the ACS event, including revascularisation procedures and when parenteral 
anticoagulation therapy would normally be discontinued. 
Both the 2.5 mg twice daily and the 5 mg twice daily regimens of rivaroxaban were effective in 
further reducing the incidence of CV events on a background of standard antiplatelet care. The 2.5 mg 
twice daily regimen reduced mortality, and there is evidence that the lower dose had lower bleeding 
risks, therefore rivaroxaban 2.5 mg twice daily co-administered with acetylsalicylic acid (ASA) alone 



16 

or with ASA plus clopidogrel or ticlopidine is recommended for the prevention of atherothrombotic 
events in adult patients after an ACS with elevated cardiac biomarkers. 
Relative to placebo, rivaroxaban significantly reduced the primary composite endpoint of CV death, 
MI or stroke. The benefit was driven by a reduction in CV death and MI and appeared early with a 
constant treatment effect over the entire treatment period (see Table 4 and Figure 1). Also the first 
secondary endpoint (all-cause death, MI or stroke) was reduced significantly. An additional 
retrospective analysis showed a nominally significant reduction in the incidence rates of stent 
thrombosis compared with placebo (see Table 4). The incidence rates for the principal safety outcome 
(non-coronary artery bypass graft (CABG) TIMI major bleeding events) were higher in patients 
treated with rivaroxaban than in patients who received placebo (see Table 6). However the incidence 
rates were balanced between rivaroxaban and placebo for the components of fatal bleeding events, 
hypotension requiring treatment with intravenous inotropic agents and surgical intervention for 
ongoing bleeding.  
In Table 5 the efficacy results of patients undergoing percutaneous coronary intervention (PCI) are 
presented. The safety results in this subgroup of patients undergoing PCI were comparable to the 
overall safety results.  
Patients with elevated biomarkers (troponin or CK-MB) and without a prior stroke/TIA constituted 
80% of the study population. The results of this patient population were also consistent with the 
overall efficacy and safety results.  
 
Table 4: Efficacy results from phase III ATLAS ACS 2 TIMI 51 

Study population 
 

Patients with a recent acute coronary syndrome P

a) 
 

Treatment dose 
 

Rivaroxaban 2.5 mg, twice daily, 
N=5,114 
n (%)  
Hazard Ratio (HR) (95% CI) p-
value P

b) 

Placebo 
N=5,113  
n (%) 

Cardiovascular death, MI or stroke 313 (6.1%) 
0.84 (0.72, 0.97) p = 0.020* 

376 (7.4%) 
 

All-cause death, MI or stroke 320 (6.3%) 
0.83 (0.72, 0.97) p = 0.016* 

386 (7.5%) 

Cardiovascular death 94 (1.8%) 
0.66 (0.51, 0.86) p = 0.002** 

143 (2.8%) 
 

All-cause death 103 (2.0%) 
0.68 (0.53, 0.87) p = 0.002** 

153 (3.0%) 

MI 205 (4.0%) 
0.90 (0.75, 1.09) p = 0.270 

229 (4.5%) 

Stroke 46 (0.9%) 
1.13 (0.74, 1.73) p = 0.562 

41 (0.8%) 

Stent thrombosis 61 (1.2%) 
0.70 (0.51, 0.97) p = 0.033** 

87 (1.7%) 

a) modified intent to treat analysis set (intent to treat total analysis set for stent thrombosis) 
b) vs placebo; Log-Rank p-value 
* statistically superior  
** nominally significant 

 



17 

Table 5: Efficacy results from phase III ATLAS ACS 2 TIMI 51 in patients undergoing PCI 
Study population 
 

Patients with recent acute coronary syndrome 
undergoing PCI P

a) 
Treatment dose 
 

Rivaroxaban 2.5 mg, twice daily, 
N=3114 
n (%)  
HR (95% CI) p-value P

b) 

Placebo 
N=3096  
n (%) 

Cardiovascular death, MI or stroke 153 (4.9%) 
0.94 (0.75, 1.17) p = 0.572 

165 (5.3%) 

Cardiovascular death 24 (0.8%) 
0.54 (0.33, 0.89) p = 0.013** 

45 (1.5%) 

All-cause death 31 (1.0%) 
0.64 (0.41, 1.01) p = 0.053 

49 (1.6%) 

MI 115 (3.7%) 
1.03 (0.79, 1.33) p = 0.829 

113 (3.6%) 

Stroke 27 (0.9%) 
1.30 (0.74, 2.31) p = 0.360 

21 (0.7%) 

Stent thrombosis 47 (1.5%) 
0.66 (0.46, 0.95) p = 0.026** 

71 (2.3%) 

a) modified intent to treat analysis set (intent to treat total analysis set for stent thrombosis) 
b) vs placebo; Log-Rank p-value 
** nominally significant 

 
Table 6: Safety results from phase III ATLAS ACS 2 TIMI 51 

Study population Patients with recent acute coronary syndrome P

a) 
Treatment dose 
 

Rivaroxaban 2.5 mg, twice daily, 
N=5,115 
n (%) 
HR (95% CI) p-value P

b) 

Placebo 
N=5,125 
n(%) 

Non-CABG TIMI major bleeding 
event 

65 (1.3%) 
3.46 (2.08, 5.77) p = < 0.001* 

19 (0.4%) 

Fatal bleeding event 6 (0.1%) 
0.67 (0.24, 1.89) p = 0.450   

9 (0.2%) 

Symptomatic intracranial 
haemorrhage 

14 (0.3%) 
2.83 (1.02, 7.86) p = 0.037   

5 (0.1%) 

Hypotension requiring treatment 
with intravenous inotropic agents 

3 (0.1%) 3 (0.1%) 

Surgical intervention for ongoing 
bleeding 

7 (0.1%) 9 (0.2%) 

Transfusion of 4 or more units of 
blood over a 48 hour period 

19 (0.4%) 6 (0.1%) 

a) safety population, on treatment  
b) vs placebo; Log-Rank p-value 
* statistically significant 

 



18 

Figure 1: Time to first occurrence of primary efficacy endpoint (CV death, MI or stroke)  

 
 
CAD/PAD 
The phase III COMPASS study (27,395 patients, 78.0% male, 22.0% female) demonstrated the 
efficacy and safety of rivaroxaban for the prevention of a composite of CV death, MI, stroke in 
patients with CAD or symptomatic PAD at high risk of ischaemic events. Patients were followed for a 
median of 23 months and maximum of 3.9 years.  
 
Subjects without a continuous need for treatment with a proton pump inhibitor were randomised to 
pantoprazole or placebo. All patients were then randomised 1:1:1 to rivaroxaban 2.5 mg twice 
daily/ASA 100 mg once daily, to rivaroxaban 5 mg twice daily, or ASA 100 mg once daily alone, and 
their matching placebos.  
 
CAD patients had multivessel CAD and/or prior MI. For patients < 65 years of age atherosclerosis 
involving at least two vascular beds or at least two additional cardiovascular risk factors were 
required.  
 
PAD patients had previous interventions such as bypass surgery or percutaneous transluminal 
angioplasty or limb or foot amputation for arterial vascular disease or intermittent claudication with 
ankle/arm blood pressure ratio < 0.90 and/ or significant peripheral artery stenosis or previous carotid 
revascularisation or asymptomatic carotid artery stenosis ≥ 50%.  
 
Exclusion criteria included the need for dual antiplatelet or other non-ASA antiplatelet or oral 
anticoagulant therapy and patients with high bleeding risk, or heart failure with ejection fraction 
< 30% or New York Heart Association class III or IV, or any ischaemic, non-lacunar stroke within 
1 month or any history of haemorrhagic or lacunar stroke.  
 
Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily was superior to ASA 
100 mg, in the reduction of the primary composite outcome of CV death, MI, stroke (see Table 7 and 
Figure 2).  
 
There was a significant increase of the primary safety outcome (modified ISTH major bleeding events) 
in patients treated with rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily 
compared to patients who received ASA 100 mg (see Table 8).  

0 90 180 270 360 450 540 630 720 810

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

C
u
m

u
la

ti
ve

 E
ve

n
t 

R
at

e 
(%

)

Relative Days from the RandomizationNo. of Patients at Risk
XARELTO 5114 4431 3943 3199 2609 2005 1425 878 415 89

Placebo 5113 4437 3974 3253 2664 2059 1460 878 421 87

XARELTO 2.5 mg twice daily
Placebo

Hazard Ratio: 0.84
95% CI:  (0.72, 0.97)
P-value=0.020*



19 

For the primary efficacy outcome, the observed benefit of rivaroxaban 2.5 mg twice daily plus ASA 
100 mg once daily compared with ASA 100 mg once daily was HR=0.89 (95% CI 0.7-1.1) in patients 
≥75 years (incidence: 6.3% vs 7.0%) and HR=0.70 (95% CI 0.6-0.8) in patients < 75 years (3.6% vs 
5.0%). For modified ISTH major bleeding, the observed risk increase was HR=2.12 (95% CI 1.5-3.0) 
in patients ≥75 years (5.2% vs 2.5%) and HR=1.53 (95% CI 1.2-1.9) in patients < 75 years (2.6% vs 
1.7%).  
 
The use of pantoprazole 40 mg once daily in addition to antithrombotic study medication in patients 
with no clinical need for a proton pump inhibitor showed no benefit in the prevention of upper 
gastrointestinal events (i.e. composite of upper gastrointestinal bleeding, upper gastrointestinal 
ulceration, or upper gastrointestinal obstruction or perforation); the incidence rate of upper 
gastrointestinal events was 0.39/100 patient-years in the pantoprazole 40 mg once daily group and 
0.44/100 patient-years in the placebo once daily group. 
 
Table 7: Efficacy results from phase III COMPASS 

Study 
population 

Patients with CAD/PAD P

a) 

Treatment dose Rivaroxaban 2.5 mg bid 
in combination with 
ASA 100 mg od 
N=9152 

ASA 100 mg od 
 
 
N=9126 

 

 Patients with 
events 

KM % Patients 
with events 

KM % HR  
(95% CI) 

p-value P

b) 

 
Stroke, MI or 
CV death 

379 (4.1%) 5.20% 496 (5.4%) 7.17% 
0.76  
(0.66;0.86) 

p = 0.00004* 

- Stroke 83 (0.9%) 1.17% 142 (1.6%) 2.23% 
0.58  
(0.44;0.76) 

p = 0.00006 

- MI 178 (1.9%) 2.46% 205 (2.2%) 2.94% 
0.86  
(0.70;1.05) 

p = 0.14458 

- CV death 160 (1.7%) 2.19% 203 (2.2%) 2.88% 
0.78  
(0.64;0.96) 

p = 0.02053 

 
All-cause 
mortality 

313 (3.4%) 4.50% 378 (4.1%) 5.57% 
0.82  
(0.71;0.96) 

 

Acute limb 
ischaemia  

22 (0.2%) 0.27% 40 (0.4%) 0.60% 
0.55 
(0.32;0.92) 

 

a) intention to treat analysis set, primary analyses 
b) vs ASA 100 mg; Log-Rank p-value 
* The reduction in the primary efficacy outcome was statistically superior. 
bid: twice daily; CI: confidence interval; KM %: Kaplan-Meier estimates of cumulative incidence 
risk calculated at 900 days; CV: cardiovascular; MI: myocardial infarction; od: once daily 

 



20 

Table 8: Safety results from phase III COMPASS 
Study population Patients with CAD/PAD P

a) 
Treatment dose 
 

Rivaroxaban 2.5 mg 
bid in combination 
with ASA 100 mg 
od, N=9152 
n (Cum. risk %) 

ASA 100 mg od 
 
 
N=9126 
n (Cum.risk %) 

Hazard Ratio 
(95 % CI) 
 
p-value P

b) 

Modified ISTH major bleeding 288 (3.9%)   170 (2.5%)  1.70 (1.40;2.05) 
p < 0.00001 

- Fatal bleeding event 15 (0.2%)  10 (0.2%)  1.49 (0.67;3.33) 
p = 0.32164 

- Symptomatic bleeding in 
critical organ (non-fatal) 

63 (0.9%)  49 (0.7%)  1.28 (0.88;1.86) 
p = 0.19679 

- Bleeding into the surgical site 
requiring reoperation (non-
fatal, not in critical organ) 

10 (0.1%) 8 (0.1%)  1.24 (0.49;3.14)
  
p = 0.65119 

- Bleeding leading to 
hospitalisation (non-fatal, not 
in critical organ, not requiring 
reoperation) 

208 (2.9%)  109 (1.6%)   1.91 (1.51;2.41) 
p < 0.00001 

- With overnight stay 172 (2.3%) 90 (1.3%) 1.91 (1.48;2.46) 
p < 0.00001 

- Without overnight stay 36 (0.5%) 21 (0.3%) 1.70 (0.99;2.92) 
p = 0.04983 

Major gastrointestinal bleeding 140 (2.0%) 65 (1.1%)  2.15 (1.60;2.89) 
p < 0.00001 

Major intracranial bleeding 28 (0.4%)  24 (0.3%) 1.16 (0.67;2.00) 
p = 0.59858 

a) intention-to-treat analysis set, primary analyses  
b) vs ASA 100 mg; Log-Rank p-value 
bid: twice daily; CI: confidence interval; Cum. Risk: Cumulative incidence risk (Kaplan-Meier 
estimates) at 30 months; ISTH: 1TInternational Society on Thrombosis and Haemostasis; 1Tod: 
once daily 

 



21 

Figure 2: Time to first occurrence of primary efficacy outcome (stroke, myocardial infarction, 
cardiovascular death) in COMPASS 

 
bid: twice daily; od: once daily; CI: confidence interval 
 
CAD with heart failure  
The COMMANDER HF study included 5,022 patients with heart failure and significant coronary 
artery disease (CAD) following a hospitalisation of decompensated heart failure (HF) which were 
randomly assigned into one of the two treatment groups: rivaroxaban 2.5 mg twice daily (N=2,507) or 
matching placebo (N=2,515), respectively. The overall median study treatment duration was 504 days.  
Patients must have had symptomatic HF for at least 3 months and left ventricular ejection fraction 
(LVEF) of ≤40% within one year of enrollment. At baseline, the median ejection fraction was 34% 
(IQR: 28%-38%) and 53% of subjects were NYHA Class III or IV.  
The primary efficacy analysis (i.e. composite of all-cause mortality, MI, or stroke) showed no 
statistically significant difference between the rivaroxaban 2.5 mg twice daily group and the placebo 
group with a HR=0.94 (95% CI 0.84 - 1.05), p=0.270. For all-cause mortality, there was no difference 
between rivaroxaban and placebo in the number of events (event rate per 100 patient-years; 11.41 vs 
11.63, HR: 0.98; 95% CI: 0.87 to 1.10; p=0.743). The event rates for MI per 100 patient-years 
(rivaroxaban vs placebo) were 2.08 vs 2.52 (HR 0.83; 95% CI: 0.63 to 1.08; p=0.165) and for stroke 
the event rates per 100 patient-years were 1.08 vs 1.62 (HR: 0.66; 95% CI: 0.47 to 0.95; p=0.023). The 
principal safety outcome (i.e. composite of fatal bleeding or bleeding into a critical space with a 
potential for permanent disability), occurred in 18 (0.7%) patients in the rivaroxaban 2.5 mg twice 
daily treatment group and in 23 (0.9%) patients in the placebo group, respectively (HR=0.80; 95% CI 
0.43 - 1.49; p=0.484). There was a statistically significant increase in ISTH major bleeding in the 
rivaroxaban group compared with placebo (event rate per 100 patient-years: 2.04 vs 1.21, HR 1.68; 
95% CI: 1.18 to 2.39; p=0.003). 
In patients with mild and moderate heart failure the treatment effects for the COMPASS study 
subgroup were similar to those of the entire study population (see section CAD/PAD). 
 
Patients with high risk triple positive antiphospholipid syndrome 
In an investigator sponsored, randomised open-label multicentre study with blinded endpoint 
adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, 
diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for 
all 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and 
anti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of 

Kaplan-Meier Estimates (%) at 30 months:  
Xarelto 2.5mg bid + ASA 100mg od: 5.2 (4.7 - 5.8)  
ASA 100mg od: 7.2 (6.5 - 7.9) 



22 

120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 
569 days. 59 patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinine 
clearance (CrCl) < 50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 
12% of patients randomised to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No 
events were reported in patients randomised to warfarin. Major bleeding occurred in 4 patients (7%) 
of the rivaroxaban group and 2 patients (3%) of the warfarin group. 
 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
Rivaroxaban is rapidly absorbed with maximum concentrations (CRmaxR) appearing 2 - 4 hours after 
tablet intake.  
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect 
rivaroxaban AUC or CRmaxR at the 2.5 mg and 10 mg dose. Rivaroxaban 2.5 mg and 10 mg tablets can be 
taken with or without food.  
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily. At higher doses 
rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased 
absorption rate with increased dose. This is more marked in fasting state than in fed state. Variability 
in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 
30% to 40%. 
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% 
and 56% decrease in AUC and CRmaxR compared to tablet was reported when rivaroxaban granulate is 
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in 
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the 
stomach should be avoided since this can result in reduced absorption and related rivaroxaban 
exposure. 
Bioavailability (AUC and CRmaxR) was comparable for 20 mg rivaroxaban administered orally as a 
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube 
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional 
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable 
to lower rivaroxaban doses. 
 
Distribution 
Plasma protein binding in humans is high at approximately 92% to 95%, with serum albumin being 
the main binding component. The volume of distribution is moderate with VRssR being approximately 
50 litres. 
 
Biotransformation and elimination  
Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half 
then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the 
administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly 
via active renal secretion. 
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative 
degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of 
biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter 
proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein). 
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active 
circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be 
classified as a low-clearance substance. After intravenous administration of a 1 mg dose the 
elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption 



23 

rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in 
young individuals, and with terminal half-lives of 11 to 13 hours in the elderly. 
 
Special populations 
Gender 
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between 
male and female patients. 
 
Elderly population 
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values 
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No 
dose adjustment is necessary. 
 
Different weight categories 
Extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasma 
concentrations (less than 25%). No dose adjustment is necessary. 
 
Inter-ethnic differences 
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, 
Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and 
pharmacodynamics. 
 
Hepatic impairment 
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor 
changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly 
comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic 
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also 
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. 
There are no data in patients with severe hepatic impairment. 
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic 
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor 
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a 
steeper PK/PD relationship between concentration and PT.  
Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and 
clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see 
section 4.3). 
 
Renal impairment 
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via 
creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min), 
moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal 
impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold 
respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In 
individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa 
activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; 
prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no 
data in patients with creatinine clearance < 15 ml/min. 
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. 
Use is not recommended in patients with creatinine clearance < 15 ml/min. Rivaroxaban is to be used 
with caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4). 
 
Pharmacokinetic data in patients 
In patients receiving rivaroxaban 2.5 mg twice daily for the prevention of atherothrombotic events in 
patients with ACS the geometric mean concentration (90% prediction interval) 2 - 4 h and about 12 h 
after dose (roughly representing maximum and minimum concentrations during the dose interval) was 
47 (13 - 123) and 9.2 (4.4 - 18) mcg/l, respectively. 



24 

 
Pharmacokinetic/pharmacodynamic relationship 
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma 
concentration and several PD endpoints (factor-Xa inhibition, PT, aPTT, Heptest) has been evaluated 
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between 
rivaroxaban concentration and factor-Xa activity was best described by an ERmaxR model. For PT, the 
linear intercept model generally described the data better. Depending on the different PT reagents 
used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and 
the slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses in Phase II and III were 
consistent with the data established in healthy subjects.  
 
Paediatric population 
Safety and efficacy have not been established in the indications ACS and CAD/PAD for children and 
adolescents up to 18 years.  
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile 
toxicity. 
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic 
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant 
exposure levels. 
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive 
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic 
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, 
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as 
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Microcrystalline cellulose 
Croscarmellose sodium 
Lactose monohydrate 
Hypromellose (2910) 
Sodium laurilsulfate 
Magnesium stearate 
 
Film-coat 
Macrogol (3350) 
Hypromellose (2910) 
Titanium dioxide (E 171) 
Iron oxide yellow (E 172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 



25 

Crushed tablets 
Crushed rivaroxaban tablets are stable in water and in apple puree for up to 4 hours. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Cartons containing 14, 20, 28, 30, 56, 60, 98, 168 or 196 film-coated tablets in PP/Alu foil blisters.  
Cartons containing 10 x 1 or 100 x 1 film-coated tablets in PP/Alu foil perforated unit dose blisters.  
Multipacks containing 10 packs of 10 x 1 (100 film-coated tablets) in PP/Alu foil perforated unit dose 
blisters.  
Cartons containing 14 film-coated tablets in PVC/PVDC/Alu foil blisters . 
HDPE bottles with a PP screw cap containing 100 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Crushing of tablets 
Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via a 
nasogastric tube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, the 
tube should be flushed with water. Since rivaroxaban absorption is dependent on the site of active 
substance release, administration of rivaroxaban distal to the stomach should be avoided, as this can 
result in reduced absorption and thereby, reduced active substance exposure. Enteral feeding is not 
required immediately after administration of the 2.5 mg tablets. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/025-035, EU/1/08/472/041, EU/1/08/472/046-047 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 30 September 2008  
Date of latest renewal: 22 May 2018 
 
 
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. 
 



26 

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 
 
Xarelto 10 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 10 mg rivaroxaban. 
 
Excipient with known effect 
Each film-coated tablet contains 26.51 mg lactose (as monohydrate), see section 4.4. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet) 
 
Light red, round biconvex tablets (6 mm diameter, 9 mm radius of curvature) marked with the 
BAYER-cross on one side and "10" and a triangle on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee 
replacement surgery. 
 
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent 
DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.) 
 
4.2 Posology and method of administration 
 
Posology 
 
Prevention of VTE in adult patients undergoing elective hip or knee replacement surgery 
The recommended dose is 10 mg rivaroxaban taken orally once daily. The initial dose should be taken 
6 to 10 hours after surgery, provided that haemostasis has been established.  
 
The duration of treatment depends on the individual risk of the patient for venous thromboembolism 
which is determined by the type of orthopaedic surgery. 
 For patients undergoing major hip surgery, a treatment duration of 5 weeks is recommended. 
 For patients undergoing major knee surgery, a treatment duration of 2 weeks is recommended. 
 
If a dose is missed the patient should take Xarelto immediately and then continue the following day 
with once daily intake as before. 
 
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE  
The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first 
three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent 
DVT and PE.  



27 

Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE 
provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration of 
therapy should be considered in patients with provoked DVT or PE not related to major transient risk 
factors, unprovoked DVT or PE, or a history of recurrent DVT or PE.   
 
When extended prevention of recurrent DVT and PE is indicated (following completion of at least 
6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom 
the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or 
who have developed recurrent DVT or PE on extended prevention with Xarelto 10 mg once daily, a 
dose of Xarelto 20 mg once daily should be considered.  
 
The duration of therapy and dose selection should be individualised after careful assessment of the 
treatment benefit against the risk for bleeding (see section 4.4).  
 

 Time period Dosing schedule Total daily dose 

Treatment and 
prevention of recurrent 
DVT and PE 

Day 1-21 15 mg twice daily  30 mg 

Day 22 onwards 20 mg once daily  20 mg 
Prevention of recurrent 
DVT and PE  

Following completion 
of at least 6 months 
therapy for DVT or PE 

10 mg once daily or  
20 mg once daily  

10 mg  
or 20 mg 

 
To support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment initiation pack 
of Xarelto for treatment of DVT/PE is available. 
 
If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take 
Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be 
taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended 
on the following day.  
 
If a dose is missed during the once daily treatment phase, the patient should take Xarelto immediately, 
and continue on the following day with the once daily intake as recommended. The dose should not be 
doubled within the same day to make up for a missed dose. 
 
Converting from Vitamin K Antagonists (VKA) to Xarelto 
For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be stopped and 
Xarelto therapy should be initiated once the INR is ≤ 2.5.  
 
When converting patients from VKAs to Xarelto, International Normalised Ratio (INR) values will be 
falsely elevated after the intake of Xarelto. The INR is not valid to measure the anticoagulant activity 
of Xarelto, and therefore should not be used (see section 4.5). 
 
Converting from Xarelto to Vitamin K antagonists (VKA) 
There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. 
Continuous adequate anticoagulation should be ensured during any transition to an alternate 
anticoagulant. It should be noted that Xarelto can contribute to an elevated INR. 
In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is ≥ 2.0. 
For the first two days of the conversion period, standard initial dosing of VKA should be used 
followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the 
INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of 
Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last 
dose (see sections 4.5 and 5.2). 
 
Converting from parenteral anticoagulants to Xarelto 
For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant 
and start Xarelto 0 to 2 hours before the time that the next scheduled administration of the parenteral 



28 

medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation 
of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin). 
 
Converting from Xarelto to parenteral anticoagulants 
Give the first dose of parenteral anticoagulant at the time the next Xarelto dose would be taken. 
 
Special populations 
Renal impairment 
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) 
indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be 
used with caution in these patients. Use is not recommended in patients with creatinine clearance 
< 15 ml/min (see sections 4.4 and 5.2). 
 
- For the prevention of VTE in adult patients undergoing elective hip or knee replacement 

surgery, no dose adjustment is necessary in patients with mild renal impairment (creatinine 
clearance 50 - 80 ml/min) or moderate renal impairment (creatinine clearance 30- 49 ml/min) 
(see section 5.2). 

 
- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE, no dose 

adjustment from the recommended dose is necessary in patients with mild renal impairment 
(creatinine clearance 50 - 80 ml/min) (see section 5.2).  
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 
15 - 29 ml/min) renal impairment: patients should be treated with 15 mg twice daily for the first 
3 weeks. Thereafter, when the recommended dose is 20 mg once daily, a reduction of the dose 
from 20 mg once daily to 15 mg once daily should be considered if the patient’s assessed risk 
for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 
15 mg is based on PK modelling and has not been studied in this clinical setting (see 
sections 4.4, 5.1 and 5.2).  
When the recommended dose is 10 mg once daily, no dose adjustment from the recommended 
dose is necessary. 

 
Hepatic impairment 
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically 
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2). 
 
Elderly population 
No dose adjustment (see section 5.2) 
 
Body weight 
No dose adjustment (see section 5.2) 
 
Gender 
No dose adjustment (see section 5.2) 
 
Paediatric population 
The safety and efficacy of Xarelto 10 mg tablets in children aged 0 to 18 years have not been 
established. No data are available. Therefore, Xarelto 10 mg tablets are not recommended for use in 
children below 18 years of age. 
 
Method of administration 
Xarelto is for oral use.  
The tablets can be taken with or without food (see sections 4.5 and 5.2). 
 
Crushing of tablets 
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with 
water or apple puree immediately prior to use and administered orally.  
The crushed tablet may also be given through gastric tubes (see sections 5.2 and 6.6). 



29 

 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Active clinically significant bleeding. 
 
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. 
 
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low 
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral 
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of 
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain 
an open central venous or arterial catheter (see section 4.5). 
 
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic 
patients with Child Pugh B and C (see section 5.2). 
 
Pregnancy and breast-feeding (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment 
period. 
 
Haemorrhagic risk 
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding. 
It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto 
administration should be discontinued if severe haemorrhage occurs (see section 4.9). 
 
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary 
including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently 
during long term rivaroxaban 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 and quantify the clinical relevance of overt 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). In patients receiving Xarelto for VTE prevention following 
elective hip or knee replacement surgery, this may be done by regular physical examination of the 
patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin. 
Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. 
 
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban 
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional 
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. 
overdose and emergency surgery (see sections 5.1 and 5.2). 
 
Renal impairment 
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels 
may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. 
Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not 
recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2). 



30 

In patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) concomitantly 
receiving other medicinal products which increase rivaroxaban plasma concentrations Xarelto is to be 
used with caution (see section 4.5). 
 
Interaction with other medicinal products 
The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with 
azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV 
protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and 
P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree 
(2.6 fold on average) which may lead to an increased bleeding risk (see section 4.5). 
 
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis 
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) and 
platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotonin 
norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease 
an appropriate prophylactic treatment may be considered (see section 4.5). 
 
Other haemorrhagic risk factors 
As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding 
risk such as: 
 congenital or acquired bleeding disorders 
 uncontrolled severe arterial hypertension 
 other gastrointestinal disease without active ulceration that can potentially lead to bleeding 

complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal 
reflux disease) 

 vascular retinopathy 
 bronchiectasis or history of pulmonary bleeding 
 
Patients with prosthetic valves 
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone 
transcatheter aortic valve replacement (TAVR). Safety and efficacy of Xarelto have not been studied 
in patients with prosthetic heart valves; therefore, there are no data to support that Xarelto provides 
adequate anticoagulation in this patient population. Treatment with Xarelto is not recommended for 
these patients. 
 
Patients with antiphospholipid syndrome 
Direct acting Oral Anticoagulants (DOACs) including rivaroxaban 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. 
 
Hip fracture surgery 
Rivaroxaban has not been studied in interventional clinical studies in patients undergoing hip fracture 
surgery to evaluate efficacy and safety. 
 
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary 
embolectomy 
Xarelto is not recommended as an alternative to unfractionated heparin in patients with pulmonary 
embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary 
embolectomy since the safety and efficacy of Xarelto have not been established in these clinical 
situations.  
 
Spinal/epidural anaesthesia or puncture 
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, 
patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk 
of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. 



31 

The risk of these events may be increased by the post-operative use of indwelling epidural catheters or 
the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by 
traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and 
symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder 
dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior 
to neuraxial intervention the physician should consider the potential benefit versus the risk in 
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. 
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and 
neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of 
rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when 
the anticoagulant effect of rivaroxaban is estimated to be low (see section 5.2). 
At least 18 hours should elapse after the last administration of rivaroxaban before removal of an 
epidural catheter. Following removal of the catheter, at least 6 hours should elapse before the next 
rivaroxaban dose is administered. 
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours. 
 
Dosing recommendations before and after invasive procedures and surgical intervention other than 
elective hip or knee replacement surgery 
If an invasive procedure or surgical intervention is required, Xarelto 10 mg should be stopped at least 
24 hours before the intervention, if possible and based on the clinical judgement of the physician.  
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the 
urgency of the intervention. 
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention 
provided the clinical situation allows and adequate haemostasis has been established as determined by 
the treating physician (see section 5.2). 
 
Elderly population 
Increasing age may increase haemorrhagic risk (see section 5.2). 
 
Dermatological reactions 
Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS 
syndrome, have been reported during post-marketing surveillance in association with the use of 
rivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in the 
course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of 
treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. 
spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal 
lesions. 
 
Information about excipients 
Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose-galactose malabsorption should not take this medicinal product. 
This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially “sodium-free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
CYP3A4 and P-gp inhibitors 
Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a 
day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in 
mean rivaroxaban CRmaxR, with significant increases in pharmacodynamic effects which may lead to an 
increased bleeding risk. Therefore, the use of Xarelto is not recommended in patients receiving 
concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, 
voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong 
inhibitors of both CYP3A4 and P-gp (see section 4.4).  
 
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either 
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. 



32 

Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and 
moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in 
CRmaxR. The interaction with clarithromycin is likely not clinically relevant in most patients but can be 
potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). 
 
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 
1.3 fold increase in mean rivaroxaban AUC and CRmaxR. The interaction with erythromycin is likely not 
clinically relevant in most patients but can be potentially significant in high-risk patients. 
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. The effect of erythromycin is additive to that of renal impairment (see 
section 4.4). 
 
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold 
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. The interaction with 
fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-
risk patients. (For patients with renal impairment: see section 4.4). 
 
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should 
be avoided. 
 
Anticoagulants 
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single 
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on 
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban. 
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any 
other anticoagulants (see sections 4.3 and 4.4).  
 
NSAIDs/platelet aggregation inhibitors 
No clinically relevant prolongation of bleeding time was observed after concomitant administration of 
rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more 
pronounced pharmacodynamic response.  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with 500 mg acetylsalicylic acid. 
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a 
pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was 
observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or 
GPIIb/IIIa receptor levels. 
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) 
and platelet aggregation inhibitors because these medicinal products typically increase the bleeding 
risk (see section 4.4). 
 
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. When 
concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-
major clinically relevant bleeding were observed in all treatment groups. 
 
Warfarin 
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or 
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) 
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, 
inhibition of factor Xa activity and endogenous thrombin potential were additive.  
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the 



33 

fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity 
and ETP) reflected only the effect of rivaroxaban.  
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR 
measurement can be used at the CRtroughR of rivaroxaban (24 hours after the previous intake of 
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point. 
No pharmacokinetic interaction was observed between warfarin and rivaroxaban. 
 
CYP3A4 inducers  
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 
50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The 
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, 
phenobarbital or St. John’s Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban 
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be 
avoided unless the patient is closely observed for signs and symptoms of thrombosis. 
 
Other concomitant therapies  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), 
atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban 
neither inhibits nor induces any major CYP isoforms like CYP3A4. 
No clinically relevant interaction with food was observed (see section 4.2). 
 
Laboratory parameters 
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of 
rivaroxaban (see section 5.1).  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy  
Safety and efficacy of Xarelto 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 rivaroxaban passes the placenta, Xarelto is contraindicated 
during pregnancy (see section 4.3).  
Women of child bearing potential should avoid becoming pregnant during treatment with rivaroxaban. 
 
Breast-feeding 
Safety and efficacy of Xarelto have not been established in breast-feeding women. Data from animals 
indicate that rivaroxaban is secreted into milk. Therefore Xarelto 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 rivaroxaban in humans 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 
 
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope 
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). 
Patients experiencing these adverse reactions should not drive or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety of rivaroxaban has been evaluated in thirteen phase III studies in adults including 
53,103 patients exposed to rivaroxaban and in two phase II and one phase III paediatric studies 
including 412 patients . See phase III studies as listed in table 1. 



34 

 
Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult 
and paediatric phase III studies 

Indication Number of 
patients* 

Total daily dose Maximum 
treatment 
duration 

Prevention of venous thromboembolism 
(VTE) in adult patients undergoing 
elective hip or knee replacement surgery 

6,097 10 mg 39 days 

Prevention of VTE in medically ill 
patients 

3,997 10 mg 39 days 

Treatment of DVT, PE and prevention 
of recurrence 

6,790 Day 1 - 21: 30 mg 
Day 22 and onwards: 
20 mg 
After at least 6 
months: 10 mg or 20 
mg 

21 months 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

329 Body weight-adjusted 
dose to achieve a 
similar exposure as 
that observed in adults 
treated for DVT with 
20 mg rivaroxaban 
once daily 

12 months 

Prevention of stroke and systemic 
embolism in patients with non-valvular 
atrial fibrillation 

7,750 20 mg 41 months 

Prevention of atherothrombotic events 
in patients after an acute coronary 
syndrome (ACS) 

10,225 5 mg or 10 mg 
respectively, co-
administered with 
either ASA or ASA 
plus clopidogrel or 
ticlopidine 

31 months  

Prevention of atherothrombotic events 
in patients with CAD/PAD 

18,244 5 mg co-administered 
with ASA or 10 mg 
alone 

47 months 

* Patients exposed to at least one dose of rivaroxaban 
 
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see 
section 4.4. and ‘Description of selected adverse reactions’ below) (Table 2). The most commonly 
reported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %). 
 



35 

Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the 
completed adult and paediatric phase III studies 
Indication Any bleeding Anaemia 
Prevention of venous 
thromboembolism (VTE) in adult 
patients undergoing elective hip or 
knee replacement surgery 

6.8% of patients 5.9% of patients 

Prevention of VTE in medically ill 
patients 

12.6% of patients 2.1% of patients 

Treatment of DVT, PE and prevention 
of recurrence 

23% of patients 1.6% of patients 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

39.5% of patients 4.6% of patients 

Prevention of stroke and systemic 
embolism in patients with 
non-valvular atrial fibrillation 

28 per 100 patient 
years 

2.5 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients after an ACS 

22 per 100 patient 
years 

1.4 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients with CAD/PAD 

6.7 per 100 patient 
years 

0.15 per 100 patient 
years**  

* For all rivaroxaban studies all bleeding events are collected, reported and 
adjudicated.   

**  In the COMPASS study, there is a low anaemia incidence as a selective 
approach to adverse event collection was applied 

 
Tabulated list of adverse reactions 
The frequencies of adverse reactions reported with Xarelto in adult and paediatric patients are 
summarised in Table 3 below by system organ class (in MedDRA) and by frequency. 
 
Frequencies are defined as: 
very common (≥ 1/10) 
common (≥ 1/100 to < 1/10) 
uncommon (≥ 1/1,000 to < 1/100) 
rare (≥ 1/10,000 to < 1/1,000) 
very rare (< 1/10,000) 
not known (cannot be estimated from the available data) 
 



36 

Table 3: All adverse reactions reported in adult patients in phase III clinical studies or through 
post-marketing use* and in two phase II and one phase III studies in paediatric patients 
Common Uncommon Rare Very rare Not known 
Blood and lymphatic system disorders 
Anaemia (incl. 
respective 
laboratory 
parameters) 

Thrombocytosis 
(incl. platelet count 
increased)P

A
P, 

thrombocytopenia 

   

Immune system disorders 
 Allergic reaction, 

dermatitis allergic, 
angioedema and 
allergic oedema 

 Anaphylactic 
reactions including 
anaphylactic shock  

 

Nervous system disorders 
Dizziness, 
headache 

Cerebral and 
intracranial 
haemorrhage, 
syncope 

   

Eye disorders 
Eye haemorrhage 
(incl. conjunctival 
haemorrhage) 

    

Cardiac disorders 
 Tachycardia    
Vascular disorders 
Hypotension, 
haematoma 

    

Respiratory, thoracic and mediastinal disorders 
Epistaxis, 
haemoptysis 

    

Gastrointestinal disorders 
Gingival bleeding, 
gastrointestinal 
tract haemorrhage 
(incl. rectal 
haemorrhage), 
gastrointestinal and 
abdominal pains, 
dyspepsia, nausea, 
constipationP

A
P, 

diarrhoea, 
vomitingP

A 

Dry mouth    

Hepatobiliary disorders 
Increase in 
transaminases 

Hepatic 
impairment, 
increased bilirubin, 
increased blood 
alkaline 
phosphatase P

A
P, 

increased GGTP

A 

Jaundice, bilirubin 
conjugated 
increased (with or 
without 
concomitant 
increase of ALT), 
cholestasis, 
hepatitis (incl. 
hepatocellular 
injury) 

  



37 

Common Uncommon Rare Very rare Not known 
Skin and subcutaneous tissue disorders 
Pruritus (incl. 
uncommon cases of 
generalised 
pruritus), rash, 
ecchymosis, 
cutaneous and 
subcutaneous 
haemorrhage 

Urticaria  Stevens-Johnson 
syndrome/Toxic 
Epidermal 
Necrolysis, DRESS 
syndrome  

 

Musculoskeletal and connective tissue disorders 
Pain in extremity P

A Haemarthrosis Muscle 
haemorrhage 

 Compartment 
syndrome 
secondary to a 
bleeding 

Renal and urinary disorders 
Urogenital tract 
haemorrhage (incl. 
haematuria and 
menorrhagiaP

B
P), 

renal impairment 
(incl. blood 
creatinine 
increased, blood 
urea increased) 

   Renal failure/acute 
renal failure 
secondary to a 
bleeding sufficient 
to cause 
hypoperfusion 

General disorders and administration site conditions 
Fever P

A
P, peripheral 

oedema, decreased 
general strength 
and energy (incl. 
fatigue and 
asthenia) 

Feeling unwell 
(incl. malaise)  

Localised oedemaP

A   

Investigations 
 Increased LDHP

A
P, 

increased lipaseP

A
P, 

increased amylaseP

A 

   

Injury, poisoning and procedural complications 
Postprocedural 
haemorrhage (incl. 
postoperative 
anaemia, and 
wound 
haemorrhage), 
contusion, wound 
secretion P

A 

 Vascular 
pseudoaneurysmP

C 
  

A:  observed in prevention of VTE in adult patients undergoing elective hip or knee replacement 
surgery 

B:  observed in treatment of DVT, PE and prevention of recurrence as very common in women 
< 55 years 

C:  observed as uncommon in prevention of atherothrombotic events in patients after an ACS 
(following percutaneous coronary intervention) 

*   A pre-specified selective approach to adverse event collection was applied. As incidence of 
adverse reactions did not increase and no new adverse reaction was identified, COMPASS 
study data were not included for frequency calculation in this table. 

 



38 

Description of selected adverse reactions 
Due to the pharmacological mode of action, the use of Xarelto 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 “Management of 
bleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito 
urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more 
frequently during long term rivaroxaban 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 and quantify the clinical relevance of overt 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 “Haemorrhagic risk”). Menstrual bleeding may be intensified and/or prolonged. 
Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained 
swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of 
cardiac ischaemia like chest pain or angina pectoris have been observed.  
Known complications secondary to severe bleeding such as compartment syndrome and renal failure 
due to hypoperfusion have been reported for Xarelto. 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. 
 
4.9 Overdose 
 
Rare cases of overdose up to 600 mg have been reported without bleeding complications or other 
adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma 
exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.  
A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban is 
available (refer to the Summary of Product Characteristics of andexanet alfa). 
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.  
 
Management of bleeding 
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban 
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has 
a half-life of approximately 5 to 13 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. 
If bleeding cannot be controlled by the above measures, either the administration of a specific 
factor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of 
rivaroxaban, or a specific procoagulant reversal agent, such as prothrombin complex concentrate 
(PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), 
should be considered. However, there is currently very limited clinical experience with the use of 
these medicinal products in individuals receiving rivaroxaban. The recommendation is also based on 
limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated 
depending on improvement of bleeding. Depending on local availability, a consultation with a 
coagulation expert should be considered in case of major bleedings (see section 5.1). 
 
Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. 
There is limited experience with tranexamic acid and no experience with aminocaproic acid and 
aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor 



39 

experience with the use of the systemic haemostatic desmopressin in individuals receiving 
rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01  
 
Mechanism of action 
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of 
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting 
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin 
(activated factor II) and no effects on platelets have been demonstrated. 
 
Pharmacodynamic effects 
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is 
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations 
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. 
The readout for PT is to be done in seconds, because the INR is only calibrated and validated for 
coumarins and cannot be used for any other anticoagulant. In patients undergoing major orthopaedic 
surgery, the 5/95 percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of 
maximum effect) ranged from 13 to 25 s (baseline values before surgery 12 to 15 s). 
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult 
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC 
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC 
reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to 
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC 
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation 
than the 4-factor PCC (see section 4.9). 
The activated partial thomboplastin time (aPTT) and HepTest are also prolonged dose-dependently; 
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no 
need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. 
However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-
factor Xa tests (see section 5.2). 
 
Clinical efficacy and safety 
Prevention of VTE in adult patients undergoing elective hip or knee replacement surgery  
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for the 
prevention of VTE, i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism 
(PE) in patients undergoing major orthopaedic surgery of the lower limbs. Over 9,500 patients (7,050 
in total hip replacement surgery and 2,531 in total knee replacement surgery) were studied in 
controlled randomised double-blind phase III clinical studies, the RECORD-programme.  
Rivaroxaban 10 mg once daily (od) started no sooner than 6 hours post-operatively was compared 
with enoxaparin 40 mg once daily started 12 hours pre-operatively. 
In all three phase III studies (see table 4), rivaroxaban significantly reduced the rate of total VTE (any 
venographically detected or symptomatic DVT, non-fatal PE and death) and major VTE (proximal 
DVT, non-fatal PE and VTE-related death), the pre-specified primary and major secondary efficacy 
endpoints. Furthermore, in all three studies the rate of symptomatic VTE (symptomatic DVT, non-
fatal PE, VTE-related death) was lower in rivaroxaban treated patients compared to patients treated 
with enoxaparin. 
The main safety endpoint, major bleeding, showed comparable rates for patients treated with 
rivaroxaban 10 mg compared to enoxaparin 40 mg. 
 



40 

Table 4: Efficacy and safety results from phase III clinical studies 
 RECORD 1 RECORD 2 RECORD 3 

Study 
population 

4,541 patients undergoing 
total hip replacement surgery 

2,509 patients undergoing total 
hip replacement surgery 

2,531 patients undergoing 
total knee replacement 
surgery 

Treatment 
dose and 
duration 
after 
surgery 

Rivaroxab
an 
10 mg od 
35 ± 4 da
ys 

Enoxapari
n 
40 mg od 
35 ± 4 day
s 

p Rivaroxab
an 
10 mg od 
35 ± 4 da
ys 

Enoxaparin 
40 mg od 
12 ± 2 days 

p Rivaroxab
an 
10 mg od 
12 ± 2 day
s 

Enoxapari
n 
40 mg od 
12 ± 2 day
s 

p 

Total VTE 18 
(1.1%) 

58 
(3.7%) 

< 0.001 17 
(2.0%)  

81 (9.3%) < 0.001 79 
(9.6%) 

166 
(18.9%) 

< 0.001 

Major 
VTE 

4 (0.2%) 33 
(2.0%) 

< 0.001 6 (0.6%) 49 (5.1%) < 0.001 9 (1.0%) 24 (2.6%) 0.01 

Symptomati
c VTE  

6 (0.4%) 11 
(0.7%) 

 3 (0.4%) 15 (1.7%)  8 (1.0%) 24 (2.7%)  

Major 
bleedings 

6 (0.3%) 2 (0.1%)  1 (0.1%) 1 (0.1%)  7 (0.6%) 6 (0.5%)  

 
The analysis of the pooled results of the phase III studies corroborated the data obtained in the 
individual studies regarding reduction of total VTE, major VTE and symptomatic VTE with 
rivaroxaban 10 mg once daily compared to enoxaparin 40 mg once daily. 
  
In addition to the phase III RECORD programme, a post-authorisation, non-interventional, open-label 
cohort study (XAMOS) has been conducted in 17,413 patients undergoing major orthopaedic surgery 
of the hip or knee, to compare rivaroxaban with other pharmacological thromboprophylaxis (standard-
of-care) under real-life setting. Symptomatic VTE occurred in 57 (0.6%) patients in the rivaroxaban 
group (n=8,778) and 88 (1.0%) of patients in the standard-of-care group (n=8,635; HR 0.63; 95% CI 
0.43-0.91); safety population). Major bleeding occurred in 35 (0.4%) and 29 (0.3%) of patients in the 
rivaroxaban and standard-of-care groups (HR 1.10; 95% CI 0.67-1.80). Thus, the results were 
consistent with the results of the pivotal randomised studies. 
 
Treatment of DVT, PE and prevention of recurrent DVT and PE 
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban in the 
initial and continued treatment of acute DVT and PE and prevention of recurrence. 
Over 12,800 patients were studied in four randomised controlled phase III clinical studies (Einstein 
DVT, Einstein PE, Einstein Extension and Einstein Choice). and additionally a predefined pooled 
analysis of the Einstein DVT and Einstein PE studies was conducted. The overall combined treatment 
duration in all studies was up to 21 months.  
 
In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the 
prevention of recurrent DVT and PE (patients who presented with symptomatic PE were excluded 
from this study). The treatment duration was for 3, 6 or 12 months depending on the clinical 
judgement of the investigator. 
For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. This 
was followed by 20 mg rivaroxaban once daily.  
 
In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention of 
recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinical 
judgement of the investigator. 
For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks. 
This was followed by 20 mg rivaroxaban once daily.  
 
In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted of 
enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until 
the PT/INR was in therapeutic range ( 2.0). Treatment was continued with a vitamin K antagonist 
dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0. 



41 

 
In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent 
DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who had 
completed 6 to 12 months of treatment for venous thromboembolism depending on the clinical 
judgment of the investigator. Rivaroxaban 20 mg once daily was compared with placebo.  
 
Einstein DVT, PE and Extension used the same pre-defined primary and secondary efficacy outcomes. 
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent 
DVT or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of 
recurrent DVT, non-fatal PE and all-cause mortality.  
In Einstein Choice, 3,396 patients with confirmed symptomatic DVT and/or PE who completed 6-12 
months of anticoagulant treatment were studied for the prevention of fatal PE or non-fatal 
symptomatic recurrent DVT or PE. Patients with an indication for continued therapeutic-dosed 
anticoagulation were excluded from the study. The treatment duration was up to 12 months depending 
on the individual randomisation date (median: 351 days). Rivaroxaban 20 mg once daily and 
rivaroxaban 10 mg once daily were compared with 100 mg acetylsalicylic acid once daily. 
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent 
DVT or fatal or non-fatal PE.  
In the Einstein DVT study (see Table 5) rivaroxaban was demonstrated to be non-inferior to 
enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); Hazard Ratio 
(HR): 0.680 (0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit 
(primary efficacy outcome plus major bleeding events) was reported with a HR of 0.67 
((95% CI: 0.47 - 0.95), nominal p value p=0.027) in favour of rivaroxaban. INR values were within 
the therapeutic range a mean of 60.3% of the time for the mean treatment duration of 189 days, and 
55.4%, 60.1%, and 62.8% of the time in the 3-, 6-, and 12-month intended treatment duration groups, 
respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean 
centre TTR (Time in Target INR Range of 2.0 – 3.0) in the equally sized tertiles and the incidence of 
the recurrent VTE (P=0.932 for interaction). Within the highest tertile according to centre, the HR 
with rivaroxaban versus warfarin was 0.69 (95% CI: 0.35 - 1.35). 
 
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding 
events) as well as the secondary safety outcome (major bleeding events) were similar for both 
treatment groups. 
 



42 

Table 5: Efficacy and safety results from phase III Einstein DVT 

Study population 
3,449 patients with symptomatic acute deep vein 
thrombosis 

Treatment dose and duration 
Rivaroxaban P

a) 

3, 6 or 12 months 
N=1,731 

Enoxaparin/VKAP

b) 
3, 6 or 12 months 
N=1,718 

Symptomatic recurrent VTE* 
36 
(2.1%) 

51 
(3.0%) 

 Symptomatic recurrent PE 
20 
(1.2%) 

18 
(1.0%) 

 Symptomatic recurrent DVT 
14 
(0.8%) 

28 
(1.6%) 

 Symptomatic PE and DVT 
1 
(0.1%) 

0 

 Fatal PE/death where PE cannot 
be ruled out 

4 
(0.2%) 

6 
(0.3%) 

Major or clinically relevant non-major 
bleeding 

139 
(8.1%) 

138 
(8.1%) 

Major bleeding events 
14 
(0.8%) 

20 
(1.2%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 
* p < 0.0001 (non-inferiority to a prespecified HR of 2.0); HR: 0.680 (0.443 - 1.042), p=0.076 

(superiority) 
 
In the Einstein PE study (see Table 6) rivaroxaban was demonstrated to be non-inferior to 
enoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority); HR: 1.123 
(0.749 – 1.684)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding 
events) was reported with a HR of 0.849 ((95% CI: 0.633 - 1.139), nominal p value p= 0.275). INR 
values were within the therapeutic range a mean of 63% of the time for the mean treatment duration of 
215 days, and 57%, 62%, and 65% of the time in the 3-, 6-, and 12-month intended treatment duration 
groups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level of 
mean centre TTR (Time in Target INR Range of 2.0 – 3.0) in the equally sized tertiles and the 
incidence of the recurrent VTE (p=0.082 for interaction). Within the highest tertile according to 
centre, the HR with rivaroxaban versus warfarin was 0.642 (95% CI: 0.277 - 1.484). 
 
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding 
events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the 
enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome 
(major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the 
enoxaparin/VKA group (2.2% (52/2405)) with a HR 0.493 (95% CI: 0.308 - 0.789). 
 



43 

Table 6: Efficacy and safety results from phase III Einstein PE 
Study population 4,832 patients with an acute symptomatic PE 

Treatment dose and duration 
Rivaroxaban P

a) 
3, 6 or 12 months 
N=2,419 

Enoxaparin/VKA P

b) 
3, 6 or 12 months 
N=2,413 

Symptomatic recurrent VTE* 
50 
(2.1%) 

44 
(1.8%) 

 Symptomatic recurrent PE 
23 
(1.0%) 

20 
(0.8%) 

 Symptomatic recurrent DVT 
18 
(0.7%) 

17 
(0.7%) 

 Symptomatic PE and DVT 0 
2 
(<0.1%) 

 Fatal PE/death where PE cannot 
be ruled out 

11 
(0.5%) 

7 
(0.3%) 

Major or clinically relevant non-major 
bleeding 

249 
(10.3%) 

274 
(11.4%) 

Major bleeding events 
26 
(1.1%) 

52 
(2.2%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 
* p < 0.0026 (non-inferiority to a prespecified HR of 2.0); HR: 1.123 (0.749 –  1.684)  

 
A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see 
Table 7). 
 
Table 7: Efficacy and safety results from pooled analysis of phase III Einstein DVT and Einstein 
PE 
Study population 8,281 patients with an acute symptomatic DVT or PE 

Treatment dose and duration 
Rivaroxaban P

a) 

3, 6 or 12 months 
N=4,150 

Enoxaparin/VKAP

b) 
3, 6 or 12 months 
N=4,131 

Symptomatic recurrent VTE* 
86 
(2.1%) 

95 
(2.3%) 

 Symptomatic recurrent PE 
43 
(1.0%) 

38 
(0.9%) 

 Symptomatic recurrent DVT 
32 
(0.8%) 

45 
(1.1%) 

 Symptomatic PE and DVT 
1 
(<0.1%) 

2 
(<0.1%) 

 Fatal PE/death where PE 
cannot be ruled out 

15 
(0.4%) 

13 
(0.3%) 

Major or clinically relevant non-
major bleeding 

388 
(9.4%) 

412 
(10.0%) 

Major bleeding events 
40 
(1.0%) 

72 
(1.7%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 

* p < 0.0001 (non-inferiority to a prespecified HR of 1.75); HR: 0.886 (0.661 – 1.186) 
 
The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the 
pooled analysis was reported with a HR of 0.771 ((95% CI: 0.614 – 0.967), nominal p value 
p = 0.0244). 
 
In the Einstein Extension study (see Table 8) rivaroxaban was superior to placebo for the primary and 
secondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was a 



44 

non-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once 
daily compared to placebo. The secondary safety outcome (major or clinically relevant non-major 
bleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared 
to placebo.  
 
Table 8: Efficacy and safety results from phase III Einstein Extension 

Study population 
1,197 patients continued treatment and prevention 
of recurrent venous thromboembolism 

Treatment dose and duration 
Rivaroxaban P

a)
P  

6 or 12 months 
N=602 

Placebo 
6 or 12 months 
N=594 

Symptomatic recurrent VTE* 
8 
(1.3%) 

42 
(7.1%) 

 Symptomatic recurrent PE 
2 
(0.3%) 

13 
(2.2%) 

 Symptomatic recurrent DVT 
5 
(0.8%) 

31 
(5.2%) 

 Fatal PE/death where PE cannot 
be ruled out 

1 
(0.2%) 

1 
(0.2%) 

Major bleeding events 
4 
(0.7%) 

0 
(0.0%) 

Clinically relevant non-major bleeding 
32 
(5.4%) 

7 
(1.2%) 

a) Rivaroxaban 20 mg once daily 

* p < 0.0001 (superiority), HR: 0.185 (0.087 - 0.393) 
 
In the Einstein Choice study (Table 9) rivaroxaban 20 mg and 10 mg were both superior to 100 mg 
acetylsalicylic acid for the primary efficacy outcome. The principal safety outcome (major bleeding 
events) was similar for patients treated with rivaroxaban 20 mg and 10 mg once daily compared to 
100 mg acetylsalicylic acid.  
 



45 

Table 9: Efficacy and safety results from phase III Einstein Choice 

Study population 
3,396 patients continued prevention of 
recurrent venous thromboembolism 

Treatment dose  
Rivaroxaban 20 mg 
once daily 
N=1,107 

Rivaroxaban 
10 mg once daily 
N=1,127 

ASA 100 mg once 
daily 
N=1,131 

Treatment duration median 
[interquartile range] 

349 [189-362] days 353 [190-362] days 350 [186-362] days 

Symptomatic recurrent VTE 
17 
(1.5%)* 

13 
(1.2%)** 

50 
(4.4%) 

Symptomatic recurrent 
PE 

6 
(0.5%) 

6 
(0.5%) 

19 
(1.7%) 

Symptomatic recurrent 
DVT 

9 
(0.8%) 

8 
(0.7%) 

30 
(2.7%) 

Fatal PE/death where PE 
cannot be ruled out 

2 
(0.2%) 

0 
 

2 
(0.2%) 

Symptomatic recurrent VTE, 
MI, stroke, or non-CNS 
systemic embolism 

19 
(1.7%) 

18 
(1.6%) 

56 
(5.0%) 

Major bleeding events 
6 
(0.5%) 

5 
(0.4%) 

3 
(0.3%) 

Clinically relevant non-major 
bleeding 

30  
(2.7) 

22  
(2.0) 

20 
(1.8) 

Symptomatic recurrent VTE 
or major bleeding (net 
clinical benefit) 

23 
(2.1%) P

+ 
17  
(1.5%) P

++ 
53  
(4.7%) 

*  p<0.001(superiority) rivaroxaban 20 mg od vs ASA 100 mg od; HR=0.34 (0.20–0.59) 
**  p<0.001 (superiority) rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.26 (0.14–0.47) 
P

+   
PRivaroxaban 20 mg od vs ASA 100 mg od; HR=0.44 (0.27–0.71), p=0.0009 (nominal)  

P

++   
PRivaroxaban 10 mg od vs ASA 100 mg od; HR=0.32 (0.18–0.55), p<0.0001 (nominal) 

 
In addition to the phase III EINSTEIN programme, a prospective, non-interventional, open-label 
cohort study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and 
death has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-term 
safety of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice. 
Rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 
0.5%, respectively. There were differences in patient baseline characteristics including age, cancer and 
renal impairment. A pre-specified propensity score stratified analysis was used to adjust for measured 
baseline differences but residual confounding may, in spite of this, influence the results. Adjusted HRs 
comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-cause mortality 
were 0.77 (95% CI 0.40 - 1.50), 0.91 (95% CI 0.54 - 1.54) and 0.51 (95% CI 0.24 - 1.07), respectively.  
These results in clinical practice are consistent with the established safety profile in this indication. 
 
Patients with high risk triple positive antiphospholipid syndrome 
In an investigator sponsored, randomised open-label multicentre study with blinded endpoint 
adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, 
diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for 
all 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and 
anti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of 
120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 
569 days. 59 patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinine 
clearance (CrCl) < 50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 
12% of patients randomised to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No 
events were reported in patients randomised to warfarin. Major bleeding occurred in 4 patients (7%) 
of the rivaroxaban group and 2 patients (3%) of the warfarin group. 



46 

 
Paediatric population 
 The European Medicines Agency has waived the obligation to submit the results of studies with 
Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
Rivaroxaban is rapidly absorbed with maximum concentrations (CRmaxR) appearing 2 - 4 hours after 
tablet intake. 
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect 
rivaroxaban AUC or CRmaxR at the 2.5 mg and 10 mg dose. Rivaroxaban 2.5 mg and 10 mg tablets can be 
taken with or without food. Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg 
once daily. At higher doses rivaroxaban displays dissolution limited absorption with decreased 
bioavailability and decreased absorption rate with increased dose. This is more marked in fasting state 
than in fed state. Variability in rivaroxaban pharmacokinetics is moderate with inter-individual 
variability (CV%) ranging from 30% to 40%, apart from on the day of surgery and the following day 
when variability in exposure is high (70%). 
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% 
and 56% decrease in AUC and CRmaxR compared to tablet was reported when rivaroxaban granulate is 
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in 
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the 
stomach should be avoided since this can result in reduced absorption and related rivaroxaban 
exposure. 
Bioavailability (AUC and CRmaxR) was comparable for 20 mg rivaroxaban administered orally as a 
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube 
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional 
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable 
to lower rivaroxaban doses. 
 
Distribution 
Plasma protein binding in humans is high at approximately 92% to 95%, with serum albumin being 
the main binding component. The volume of distribution is moderate with VRssR being approximately 
50 litres. 
 
Biotransformation and elimination  
Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half 
then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the 
administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly 
via active renal secretion. 
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative 
degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of 
biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter 
proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein). 
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active 
circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be 
classified as a low-clearance substance. After intravenous administration of a 1 mg dose the 
elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption 
rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in 
young individuals, and with terminal half-lives of 11 to 13 hours in the elderly. 
 
Special populations 
Gender 
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between 
male and female patients. 



47 

 
Elderly population  
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values 
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No 
dose adjustment is necessary. 
 
Different weight categories 
Extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasma 
concentrations (less than 25%). No dose adjustment is necessary. 
 
Inter-ethnic differences 
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, 
Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and 
pharmacodynamics. 
 
Hepatic impairment 
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor 
changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly 
comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic 
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also 
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. 
There are no data in patients with severe hepatic impairment. 
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic 
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor 
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a 
steeper PK/PD relationship between concentration and PT.  
Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and 
clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see 
section 4.3). 
 
Renal impairment 
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via 
creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min), 
moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal 
impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold 
respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In 
individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa 
activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; 
prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no 
data in patients with creatinine clearance < 15 ml/min. 
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. 
Use is not recommended in patients with creatinine clearance < 15 ml/min. Rivaroxaban is to be used 
with caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4). 
 
Pharmacokinetic data in patients 
In patients receiving rivaroxaban for prevention of VTE 10 mg once daily the geometric mean 
concentration (90% prediction interval) 2 - 4 h and about 24 h after dose (roughly representing 
maximum and minimum concentrations during the dose interval) was 101 (7 - 273) and 
14 (4 ‑ 51) mcg/l, respectively. 
 
Pharmacokinetic/pharmacodynamic relationship 
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma 
concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated 
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between 
rivaroxaban concentration and factor Xa activity was best described by an ERmaxR model. For PT, the 
linear intercept model generally described the data better. Depending on the different PT reagents 



48 

used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and 
the slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses in Phase II and III were 
consistent with the data established in healthy subjects. In patients, baseline factor Xa and PT were 
influenced by the surgery resulting in a difference in the concentration-PT slope between the day post-
surgery and steady state.  
 
Paediatric population 
Safety and efficacy have not been established in the indication primary prevention of VTE for children 
and adolescents up to 18 years.  
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile 
toxicity. 
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic 
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant 
exposure levels. 
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive 
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic 
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, 
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as 
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Microcrystalline cellulose 
Croscarmellose sodium 
Lactose monohydrate 
Hypromellose (2910) 
Sodium laurilsulfate 
Magnesium stearate 
 
Film-coat 
Macrogol (3350) 
Hypromellose (2910) 
Titanium dioxide (E 171) 
Iron oxide red (E 172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
Crushed tablets  
Crushed rivaroxaban tablets are stable in water and in apple puree for up to 4 hours. 
 



49 

6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Cartons containing 5, 10, 14, 28, 30 or 98 film-coated tablets in PP/Alu foil blisters.  
Cartons containing 10 x 1 or 100 x 1 film-coated tablets in PP/Alu foil perforated unit dose blisters.  
Multipacks containing 10 packs of 10 x 1 (100 film-coated tablets) in PP/Alu foil perforated unit dose 
blisters.  
Cartons containing 5, 10 or 30 film-coated tablets in PVC/PVDC/Alu foil blisters . 
HDPE bottles with a PP screw cap containing 100 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Crushing of tablets 
Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via a 
nasogastric tube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, the 
tube should be flushed with water. Since rivaroxaban absorption is dependent on the site of active 
substance release, administration of rivaroxaban distal to the stomach should be avoided, as this can 
result in reduced absorption and thereby, reduced active substance exposure. Enteral feeding is not 
required immediately after administration of the 10 mg tablets. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/001-010, EU/1/08/472/022, EU/1/08/472/042-045. 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 30 September 2008 
Date of latest renewal: 22 May 2018 
 
 
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. 
 



50 

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 
 
Xarelto 15 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 15 mg rivaroxaban.  
 
Excipient with known effect 
Each film-coated tablet contains 24.13 mg lactose (as monohydrate), see section 4.4. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet)  
 
Red, round biconvex tablets (6 mm diameter, 9 mm radius of curvature) marked with the BAYER-
cross on one side and “15” and a triangle on the other side.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Adults 
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with 
one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes 
mellitus, prior stroke or transient ischaemic attack.  
 
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent 
DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.) 
 
Paediatric population  
Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and 
adolescents aged less than 18 years and weighing from 30 kg to 50 kg after at least 5 days of initial 
parenteral anticoagulation treatment. 
 
4.2 Posology and method of administration 
 
Posology 
Prevention of stroke and systemic embolism in adults 
The recommended dose is 20 mg once daily, which is also the recommended maximum dose.  
 
Therapy with Xarelto should be continued long term provided the benefit of prevention of stroke and 
systemic embolism outweighs the risk of bleeding (see section 4.4).  
 
If a dose is missed the patient should take Xarelto immediately and continue on the following day with 
the once daily intake as recommended. The dose should not be doubled within the same day to make 
up for a missed dose.  



51 

 
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE in adults 
The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first 
three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent 
DVT and PE.  
 
Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE 
provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration of 
therapy should be considered in patients with provoked DVT or PE not related to major transient risk 
factors, unprovoked DVT or PE, or a history of recurrent DVT or PE.   
 
When extended prevention of recurrent DVT and PE is indicated (following completion of at least 
6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom 
the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or 
who have developed recurrent DVT or PE on extended prevention with Xarelto 10 mg once daily, a 
dose of Xarelto 20 mg once daily should be considered.  
 
The duration of therapy and dose selection should be individualised after careful assessment of the 
treatment benefit against the risk for bleeding (see section 4.4).  
 

 Time period Dosing schedule Total daily dose 

Treatment and 
prevention of recurrent 
DVT and PE 

Day 1 - 21 15 mg twice daily  30 mg 

Day 22 onwards 20 mg once daily  20 mg 

Prevention of recurrent 
DVT and PE  

Following completion 
of at least 6 months 
therapy for DVT or PE  

10 mg once daily or  
20 mg once daily  

10 mg  
or 20 mg 

 
To support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment initiation pack 
of Xarelto for treatment of DVT/PE is available. 
 
If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take 
Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be 
taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended 
on the following day.  
 
If a dose is missed during the once daily treatment phase, the patient should take Xarelto immediately, 
and continue on the following day with the once daily intake as recommended. The dose should not be 
doubled within the same day to make up for a missed dose.  
 
Treatment of VTE and prevention of VTE recurrence in children and adolescents 
Xarelto treatment in children and adolescents aged less than 18 years should be initiated following at 
least 5 days of initial parenteral anticoagulation treatment (see section 5.1).  
 
The dose for children and adolescent is calculated based on body weight.  
- Body weight from 30 to 50 kg: 

a once daily dose of 15 mg rivaroxaban is recommended. This is the maximum daily dose.  
- Body weight of 50 kg or more: 

a once daily dose of 20 mg rivaroxaban is recommended. This is the maximum daily dose.  
- For patients with body weight less 30 kg refer to the Summary of Product Characteristics of 

Xarelto granules for oral suspension.  
 
The weight of a child should be monitored and the dose reviewed regularly. This is to ensure a 
therapeutic dose is maintained. Dose adjustments should be made based on changes in body weight 
only. 
 



52 

Treatment should be continued for at least 3 months in children and adolescents. Treatment can be 
extended up to 12 months when clinically necessary. There is no data available in children to support a 
dose reduction after 6 months treatment. The benefit-risk of continued therapy after 3 months should 
be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the 
potential bleeding risk.  
 
If a dose is missed, the missed dose should be taken as soon as possible after it is noticed, but only on 
the same day. If this is not possible, the patient should skip the dose and continue with the next dose as 
prescribed. The patient should not take two doses to make up for a missed dose.  
 
Converting from Vitamin K Antagonists (VKA) to Xarelto 
- Prevention of stroke and systemic embolism:  

VKA treatment should be stopped and Xarelto therapy should be initiated when the 
International Normalised Ratio (INR) is ≤ 3.0.  

- Treatment of DVT, PE and prevention of recurrence in adults and treatment of VTE and 
prevention of recurrence in paediatric patients:  
VKA treatment should be stopped and Xarelto therapy should be initiated once the INR is ≤ 2.5.  

When converting patients from VKAs to Xarelto, INR values will be falsely elevated after the intake 
of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and therefore should 
not be used (see section 4.5). 
 
Converting from Xarelto to Vitamin K antagonists (VKA) 
There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. 
Continuous adequate anticoagulation should be ensured during any transition to an alternate 
anticoagulant. It should be noted that Xarelto can contribute to an elevated INR.  
In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is ≥ 2.0. 
For the first two days of the conversion period, standard initial dosing of VKA should be used 
followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the 
INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of 
Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last 
dose (see sections 4.5 and 5.2). 
 
Paediatric patients:  
Children who convert from Xarelto to VKA need to continue Xarelto for 48 hours after the first dose 
of VKA. After 2 days of co-administration an INR should be obtained prior to the next scheduled dose 
of Xarelto. Co-administration of Xarelto and VKA is advised to continue until the INR is ≥ 2.0. Once 
Xarelto is discontinued INR testing may be done reliably 24 hours after the last dose (see above and 
section 4.5). 
 
Converting from parenteral anticoagulants to Xarelto 
For adult and paediatric patients currently receiving a parenteral anticoagulant, discontinue the 
parenteral anticoagulant and start Xarelto 0 to 2 hours before the time that the next scheduled 
administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due 
or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. 
intravenous unfractionated heparin). 
 
Converting from Xarelto to parenteral anticoagulants 
Discontinue Xarelto and give the first dose of parenteral anticoagulant at the time the next Xarelto 
dose would be taken.  
 
Special populations 
Renal impairment 
Adults:  
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) 
indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be 
used with caution in these patients. Use is not recommended in patients with creatinine clearance 
< 15 ml/min (see sections 4.4 and 5.2). 



53 

 
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 15-
29 ml/min) renal impairment the following dose recommendations apply: 
 
- For the prevention of stroke and systemic embolism in patients with non-valvular atrial 

fibrillation, the recommended dose is 15 mg once daily (see section 5.2). 
 

- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: patients 
should be treated with 15 mg twice daily for the first 3 weeks. Thereafter, when the 
recommended dose is 20 mg once daily, a reduction of the dose from 20 mg once daily to 15 mg 
once daily should be considered if the patient’s assessed risk for bleeding outweighs the risk for 
recurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling and 
has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).  
When the recommended dose is 10 mg once daily, no dose adjustment from the recommended 
dose is necessary.  

 
No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 
50 - 80 ml/min) (see section 5.2).  
 
Paediatric population:  
- Children and adolescents with mild renal impairment (glomerular filtration rate 

50 - 80 mL/min/1.73 mP

2
P): no dose adjustment is required, based on data in adults and limited 

data in paediatric patients (see section 5.2). 
- Children and adolescents with moderate or severe renal impairment (glomerular filtration rate 

< 50 mL/min/1.73 mP

2
P): Xarelto is not recommended as no clinical data is available (see 

section 4.4). 
 
Hepatic impairment 
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically 
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2). 
No clinical data is available in children with hepatic impairment.  
 
Elderly population  
No dose adjustment (see section 5.2) 
 
Body weight 
No dose adjustment for adults (see section 5.2) 
For paediatric patients the dose is determined based on body weight.  
 
Gender 
No dose adjustment (see section 5.2) 
 
Patients undergoing cardioversion 
Xarelto can be initiated or continued in patients who may require cardioversion.  
For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated 
with anticoagulants, Xarelto treatment should be started at least 4 hours before cardioversion to ensure 
adequate anticoagulation (see sections 5.1 and 5.2). For all patients, confirmation should be sought 
prior to cardioversion that the patient has taken Xarelto as prescribed. Decisions on initiation and 
duration of treatment should take established guideline recommendations for anticoagulant treatment 
in patients undergoing cardioversion into account. 
 
Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) 
with stent placement 
There is limited experience of a reduced dose of 15 mg Xarelto once daily (or 10 mg Xarelto once 
daily for patients with moderate renal impairment [creatinine clearance 30 - 49 ml/min]) in addition to 
a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrial fibrillation who 
require oral anticoagulation and undergo PCI with stent placement (see sections 4.4 and 5.1).  



54 

 
Paediatric population 
The safety and efficacy of Xarelto in children aged 0 to < 18 years have not been established in the 
indication prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. 
No data are available. Therefore, it is not recommended for use in children below 18 years of age in 
indications other than the treatment of VTE and prevention of VTE recurrence.  
 
Method of administration  
Adults 
Xarelto is for oral use.  
The tablets are to be taken with food (see section 5.2). 
 
Crushing of tablets 
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with 
water or apple puree immediately prior to use and administered orally. After the administration of 
crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by 
food. 
The crushed tablet may also be given through gastric tubes (see sections 5.2 and 6.6). 
 
Children and adolescents weighing 30 kg to 50 kg 
Xarelto is for oral use.  
49TThe patient should be advised to 49Tswallow the tablet with liquid. It should also be taken with food (see 
section 5.2). The tablets should be taken approximately 24 hours apart. 
 
In case the patient immediately spits up the dose or vomits within 30 minutes after receiving the dose, 
a new dose should be given. However, if the patient vomits more than 30 minutes after the dose, the 
dose should not be re-administered and the next dose should be taken as scheduled. 
 
The tablet must not be split in an attempt to provide a fraction of a tablet dose.  
 
Crushing of tablets 
For patients who are unable to swallow whole tablets, Xarelto granules for oral suspension should be 
used.  
If the oral suspension is not immediately available, when doses of 15 mg or 20 mg rivaroxaban are 
prescribed, these could be provided by crushing the 15 mg or 20 mg tablet and mixing it with water or 
apple puree immediately prior to use and administering orally. 
The crushed tablet may be given through a nasogastric or gastric feeding tube (see sections 5.2 
and 6.6).  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Active clinically significant bleeding. 
 
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. 
 
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low 
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral 
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of 
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain 
an open central venous or arterial catheter (see section 4.5). 
 



55 

Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic 
patients with Child Pugh B and C (see section 5.2). 
 
Pregnancy and breast-feeding (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment 
period. 
 
Haemorrhagic risk 
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding. 
It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto 
administration should be discontinued if severe haemorrhage occurs (see section 4.9). 
 
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary 
including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently 
during long term rivaroxaban 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 and quantify the clinical relevance of overt 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. 
 
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban 
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional 
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. 
overdose and emergency surgery (see sections 5.1 and 5.2). 
 
Paediatric population 
There is limited data in children with cerebral vein and sinus thrombosis who have a CNS infection 
(see section 5.1). The risk of bleeding should be carefully evaluated before and during therapy with 
rivaroxaban. 
 
Renal impairment 
In adult patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma 
levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding 
risk. Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not 
recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2). 
Xarelto should be used with caution in patients with renal impairment concomitantly receiving other 
medicinal products which increase rivaroxaban plasma concentrations (see section 4.5). 
Xarelto is not recommended in children and adolescents with moderate or severe renal impairment 
(glomerular filtration rate < 50 mL/min/1.73 mP

2
P), as no clinical data is available.  

 
Interaction with other medicinal products 
The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with 
azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV 
protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and 
P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree 
(2.6 fold on average) which may lead to an increased bleeding risk. No clinical data is available in 
children receiving concomitant systemic treatment with strong inhibitors of both CYP 3A4 and P-gp 
(see section 4.5). 
 
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis 
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and 



56 

platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotonin 
norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease 
an appropriate prophylactic treatment may be considered (see section 4.5).  
 
Other haemorrhagic risk factors 
As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding 
risk such as: 
 congenital or acquired bleeding disorders 
 uncontrolled severe arterial hypertension 
 other gastrointestinal disease without active ulceration that can potentially lead to bleeding 

complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal 
reflux disease) 

 vascular retinopathy 
 bronchiectasis or history of pulmonary bleeding 
 
Patients with prosthetic valves 
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone 
transcatheter aortic valve replacement (TAVR). Safety and efficacy of Xarelto have not been studied 
in patients with prosthetic heart valves; therefore, there are no data to support that Xarelto provides 
adequate anticoagulation in this patient population. Treatment with Xarelto is not recommended for 
these patients. 
 
Patients with antiphospholipid syndrome 
Direct acting Oral Anticoagulants (DOACs) including rivaroxaban 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. 
 
Patients with non-valvular atrial fibrillation who undergo PCI with stent placement 
Clinical data are available from an interventional study with the primary objective to assess safety in 
patients with non-valvular atrial fibrillation who undergo PCI with stent placement. Data on efficacy 
in this population are limited (see sections 4.2 and 5.1). No data are available for such patients with a 
history of stroke/ transient ischaemic attack (TIA).  
 
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary 
embolectomy 
Xarelto is not recommended as an alternative to unfractionated heparin in patients with pulmonary 
embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary 
embolectomy since the safety and efficacy of Xarelto have not been established in these clinical 
situations.  
 
Spinal/epidural anaesthesia or puncture 
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, 
patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk 
of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. 
The risk of these events may be increased by the post-operative use of indwelling epidural catheters or 
the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by 
traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and 
symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder 
dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior 
to neuraxial intervention the physician should consider the potential benefit versus the risk in 
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical 
experience with the use of 15 mg rivaroxaban in these situations. 
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and 
neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of 
rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when 



57 

the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a 
sufficiently low anticoagulant effect in each patient is not known and should be weighed against the 
urgency of a diagnostic procedure. 
For the removal of an epidural catheter and based on the general PK characteristics at least 2x half-
life, i.e. at least 18 hours in young adult patients and 26 hours in elderly patients should elapse after 
the last administration of rivaroxaban (see section 5.2). Following removal of the catheter, at least 
6 hours should elapse before the next rivaroxaban dose is administered. 
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.  
No data is available on the timing of the placement or removal of neuraxial catheter in children while 
on Xarelto. In such cases, discontinue rivaroxaban and consider a short acting parenteral 
anticoagulant. 
 
Dosing recommendations before and after invasive procedures and surgical intervention  
If an invasive procedure or surgical intervention is required, Xarelto 15 mg should be stopped at least 
24 hours before the intervention, if possible and based on the clinical judgement of the physician.  
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the 
urgency of the intervention. 
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention 
provided the clinical situation allows and adequate haemostasis has been established as determined by 
the treating physician (see section 5.2). 
 
Elderly population 
Increasing age may increase haemorrhagic risk (see section 5.2). 
 
Dermatological reactions 
Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS 
syndrome, have been reported during post-marketing surveillance in association with the use of 
rivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in the 
course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of 
treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. 
spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal 
lesions. 
 
Information about excipients 
Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose-galactose malabsorption should not take this medicinal product. 
This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially “sodium-free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
The extent of interactions in the paediatric population is not known. The below mentioned interaction 
data was obtained in adults and the warnings in section 4.4 should be taken into account for the 
paediatric population. 
 
CYP3A4 and P-gp inhibitors 
Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a 
day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in 
mean rivaroxaban CRmaxR, with significant increases in pharmacodynamic effects which may lead to an 
increased bleeding risk. Therefore, the use of Xarelto is not recommended in patients receiving 
concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, 
voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong 
inhibitors of both CYP3A4 and P-gp (see section 4.4).  
 
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either 
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. 
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and 



58 

moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in 
CRmaxR. The interaction with clarithromycin is likely not clinically relevant in most patients but can be 
potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). 
 
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 
1.3 fold increase in mean rivaroxaban AUC and CRmaxR. The interaction with erythromycin is likely not 
clinically relevant in most patients but can be potentially significant in high-risk patients. 
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. The effect of erythromycin is additive to that of renal impairment (see 
section 4.4). 
 
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold 
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean CRmaxR. The interaction with 
fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-
risk patients. (For patients with renal impairment: see section 4.4). 
 
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should 
be avoided. 
 
Anticoagulants 
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single 
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on 
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban. 
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any 
other anticoagulants (see sections 4.3 and 4.4).  
 
NSAIDs/platelet aggregation inhibitors 
No clinically relevant prolongation of bleeding time was observed after concomitant administration of 
rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more 
pronounced pharmacodynamic response.  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with 500 mg acetylsalicylic acid. 
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a 
pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was 
observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or 
GPIIb/IIIa receptor levels. 
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) 
and platelet aggregation inhibitors because these medicinal products typically increase the bleeding 
risk (see section 4.4). 
 
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. When 
concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-
major clinically relevant bleeding were observed in all treatment groups. 
 
Warfarin 
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or 
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) 
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, 
inhibition of factor Xa activity and endogenous thrombin potential were additive.  
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the 



59 

fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity 
and ETP) reflected only the effect of rivaroxaban.  
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR 
measurement can be used at the CRtroughR of rivaroxaban (24 hours after the previous intake of 
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point. 
No pharmacokinetic interaction was observed between warfarin and rivaroxaban. 
 
CYP3A4 inducers  
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 
50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The 
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, 
phenobarbital or St. John’s Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban 
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be 
avoided unless the patient is closely observed for signs and symptoms of thrombosis. 
 
Other concomitant therapies  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), 
atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban 
neither inhibits nor induces any major CYP isoforms like CYP3A4. 
 
Laboratory parameters 
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of 
rivaroxaban (see section 5.1).  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
Safety and efficacy of Xarelto 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 rivaroxaban passes the placenta, Xarelto is contraindicated 
during pregnancy (see section 4.3).  
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban. 
 
Breast-feeding 
Safety and efficacy of Xarelto have not been established in breast-feeding women. Data from animals 
indicate that rivaroxaban is secreted into milk. Therefore Xarelto 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 rivaroxaban in humans 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 
 
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope 
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). 
Patients experiencing these adverse reactions should not drive or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety of rivaroxaban has been evaluated in thirteen phase III studies in adults including 
53,103 patients exposed to rivaroxaban and in two phase II and one phase III paediatric studies 
including 412 patients. See phase III studies as listed in table 1. 
 



60 

Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult 
and paediatric phase III studies 

Indication Number of 
patients* 

Total daily dose  Maximum 
treatment duration 

Prevention of venous thromboembolism 
(VTE) in adult patients undergoing 
elective hip or knee replacement surgery 

6,097 10 mg 39 days 

Prevention of VTE in medically ill 
patients 

3,997 10 mg 39 days 

Treatment of DVT, PE and prevention 
of recurrence 

6,790 Day 1 - 21: 30 mg 
Day 22 and onwards: 
20 mg 
After at least 6 
months: 10 mg or 20 
mg 

21 months 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

329 Body weight-adjusted 
dose to achieve a 
similar exposure as 
that observed in adults 
treated for DVT with 
20 mg rivaroxaban 
once daily 

12 months 

Prevention of stroke and systemic 
embolism in patients with non-valvular 
atrial fibrillation 

7,750 20 mg 41 months 

Prevention of atherothrombotic events 
in patients after an ACS 

10,225 5 mg or 10 mg 
respectively, co-
administered with 
either ASA or ASA 
plus clopidogrel or 
ticlopidine 

31 months 

Prevention of atherothrombotic events 
in patients with CAD/PAD 

18,244 5 mg co-administered 
with ASA or 10 mg 
alone 

47 months 

* Patients exposed to at least one dose of rivaroxaban 
 
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see 
section 4.4. and ‘Description of selected adverse reactions’ below) (Table 2). The most commonly 
reported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %). 
 



61 

Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the 
completed adult and paediatric phase III studies 
Indication Any bleeding Anaemia 
Prevention of VTE in adult patients 
undergoing elective hip or knee 
replacement surgery 

6.8% of patients 5.9% of patients 

Prevention of VTE in medically ill 
patients 

12.6% of patients 2.1% of patients 

Treatment of DVT, PE and prevention 
of recurrence 

23% of patients 1.6% of patients 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

39.5% of patients 4.6% of patients 

Prevention of stroke and systemic 
embolism in patients with 
non-valvular atrial fibrillation 

28 per 100 patient 
years 

2.5 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients after an ACS 

22 per 100 patient 
years 

1.4 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients with CAD/PAD 

6.7 per 100 patient 
years 

0.15 per 100 patient 
years**  

* For all rivaroxaban studies all bleeding events are collected, reported and 
adjudicated.   

**  In the COMPASS study, there is a low anaemia incidence as a selective 
approach to adverse event collection was applied 

 
Tabulated list of adverse reactions 
The frequencies of adverse reactions reported with Xarelto in adult and paediatric patients are 
summarised in Table 3 below by system organ class (in MedDRA) and by frequency.  
 
Frequencies are defined as: 
very common (≥ 1/10) 
common (≥ 1/100 to < 1/10)  
uncommon (≥ 1/1,000 to < 1/100)  
rare (≥ 1/10,000 to < 1/1,000)  
very rare (< 1/10,000) 
not known (cannot be estimated from the available data) 
  



62 

Table 3: All adverse reactions reported in adult patients in phase III clinical studies or through 
post-marketing use* and in two phase II and one phase III studies in paediatric patients  
Common Uncommon Rare Very rare Not known 
Blood and lymphatic system disorders 
Anaemia (incl. 
respective laboratory 
parameters) 

Thrombocytosis 
(incl. platelet count 
increased)P

A
P, 

thrombocytopenia 

   

Immune system disorders 
 Allergic reaction, 

dermatitis allergic, 
angioedema and 
allergic oedema 

 Anaphylactic 
reactions 
including 
anaphylactic 
shock  

 

Nervous system disorders 
Dizziness, headache Cerebral and 

intracranial 
haemorrhage, 
syncope 

   

Eye disorders 
Eye haemorrhage 
(incl. conjunctival 
haemorrhage) 

    

Cardiac disorders 
 Tachycardia    
Vascular disorders 
Hypotension, 
haematoma 

    

Respiratory, thoracic and mediastinal disorders 
Epistaxis, 
haemoptysis 

    

Gastrointestinal disorders 
Gingival bleeding, 
gastrointestinal tract 
haemorrhage (incl. 
rectal haemorrhage), 
gastrointestinal and 
abdominal pains, 
dyspepsia, nausea, 
constipationP

A
P, 

diarrhoea, vomiting P

A 

Dry mouth    

Hepatobiliary disorders 
Increase in 
transaminases 

Hepatic 
impairment, 
increased bilirubin, 
increased blood 
alkaline 
phosphataseP

A
P, 

increased GGTP

A 

Jaundice, bilirubin 
conjugated 
increased (with or 
without 
concomitant 
increase of ALT), 
cholestasis, 
hepatitis (incl. 
hepatocellular 
injury) 

  



63 

Common Uncommon Rare Very rare Not known 
Skin and subcutaneous tissue disorders 
Pruritus (incl. 
uncommon cases of 
generalised pruritus), 
rash, ecchymosis, 
cutaneous and 
subcutaneous 
haemorrhage 

Urticaria  Stevens-Johnson 
syndrome/Toxic 
Epidermal 
Necrolysis, 
DRESS syndrome  

 

Musculoskeletal and connective tissue disorders 
Pain in extremity P

A Haemarthrosis Muscle 
haemorrhage 

 Compartment 
syndrome 
secondary to a 
bleeding 

Renal and urinary disorders 
Urogenital tract 
haemorrhage (incl. 
haematuria and 
menorrhagiaP

B
P), renal 

impairment (incl. 
blood creatinine 
increased, blood urea 
increased) 

   Renal 
failure/acute 
renal failure 
secondary to a 
bleeding 
sufficient to 
cause 
hypoperfusion 

General disorders and administration site conditions 
Fever P

A
P, peripheral 

oedema, decreased 
general strength and 
energy (incl. fatigue 
and asthenia) 

Feeling unwell 
(incl. malaise)  

Localised 
oedemaP

A 
  

Investigations 
 Increased LDHP

A
P, 

increased lipaseP

A
P, 

increased amylaseP

A 

   

Injury, poisoning and procedural complications 
Postprocedural 
haemorrhage (incl. 
postoperative 
anaemia, and wound 
haemorrhage), 
contusion, wound 
secretion P

A 

 Vascular 
pseudoaneurysmP

C 
  

A:  observed in prevention of VTE in adult patients undergoing elective hip or knee replacement 
surgery 

B:  observed in treatment of DVT, PE and prevention of recurrence as very common in women 
< 55 years 

C:  observed as uncommon in prevention of atherothrombotic events in patients after an ACS 
(following percutaneous coronary intervention) 

*   A pre-specified selective approach to adverse event collection was applied. As incidence of 
adverse reactions did not increase and no new adverse reaction was identified, COMPASS 
study data were not included for frequency calculation in this table. 

 
Description of selected adverse reactions 
Due to the pharmacological mode of action, the use of Xarelto 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 “Management of 



64 

bleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito 
urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more 
frequently during long term rivaroxaban 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 and quantify the clinical relevance of overt 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 “Haemorrhagic risk”). Menstrual bleeding may be intensified and/or prolonged. 
Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained 
swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of 
cardiac ischaemia like chest pain or angina pectoris have been observed.  
Known complications secondary to severe bleeding such as compartment syndrome and renal failure 
due to hypoperfusion have been reported for Xarelto. Therefore, the possibility of haemorrhage is to 
be considered in evaluating the condition in any anticoagulated patient. 
 
Paediatric population  
The safety assessment in children and adolescents is based on the safety data from two phase II and 
one phase III open-label active controlled studies in paediatric patients aged birth to less than 18 years. 
The safety findings were generally similar between rivaroxaban and comparator in the various 
paediatric age groups. Overall, the safety profile in the 412 children and adolescents treated with 
rivaroxaban was similar to that observed in the adult population and consistent across age subgroups, 
although assessment is limited by the small number of patients. 
In paediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (very 
common, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increase in bilirubin 
(common, 1.5%) and bilirubin conjugated increased (uncommon, 0.7%) were reported more 
frequently as compared to adults. Consistent with adult population, menorrhagia was observed in 6.6% 
(common) of female adolescents after menarche. Thrombocytopenia as observed in the post-marketing 
experience in adult population was common (4.6%) in paediatric clinical studies. The adverse drug 
reactions in paediatric patients were primarily mild to moderate in severity. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In adults, rare cases of overdose up to 600 mg have been reported without bleeding complications or 
other adverse reactions. There is limited data available in children. Due to limited absorption a ceiling 
effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 
50 mg rivaroxaban or above in adults, however, no data is available at supratherapeutic doses in 
children.  
A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban is 
available for adults, but not established in children (refer to the Summary of Product Characteristics of 
andexanet alfa). 
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.  
 
Management of bleeding 
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban 
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has 
a half-life of approximately 5 to 13 hours in adults. The half life in children estimated using population 
pharmacokinetic (popPK) modelling approaches is shorter (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 



65 

products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) 
or platelets. 
If bleeding cannot be controlled by the above measures, either the administration of a specific 
factor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of 
rivaroxaban, or a specific procoagulant reversal agent, such as prothrombin complex concentrate 
(PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), 
should be considered. However, there is currently very limited clinical experience with the use of 
these medicinal products in adults and in children receiving rivaroxaban. The recommendation is also 
based on limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and 
titrated depending on improvement of bleeding. Depending on local availability, a consultation with a 
coagulation expert should be considered in case of major bleedings (see section 5.1). 
 
Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. 
There is limited experience with tranexamic acid and no experience with aminocaproic acid and 
aprotinin in adults receiving rivaroxaban. There is no experience on the use of these agents in children 
receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use of 
the systemic haemostatic desmopressin in individuals receiving rivaroxaban. Due to the high plasma 
protein binding rivaroxaban is not expected to be dialysable. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01  
 
Mechanism of action 
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of 
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting 
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin 
(activated factor II) and no effects on platelets have been demonstrated. 
 
Pharmacodynamic effects 
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is 
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations 
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. 
The readout for PT is to be done in seconds, because the INR is only calibrated and validated for 
coumarins and cannot be used for any other anticoagulant.  
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95 
percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for 
15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15 
to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 
14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s. 
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and 
systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at the 
time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in 
patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough 
(16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged 
from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 
to 26 s. 
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult 
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC 
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC 
reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to 
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC 
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation 
than the 4-factor PCC (see section 4.9). 



66 

The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently; 
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no 
need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. 
However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-
factor Xa tests (see section 5.2). 
 
Paediatric population 
PT (neoplastin reagent), aPTT, and anti-Xa assay (with a calibrated quantitative test) display a close 
correlation to plasma concentrations in children. The correlation between anti-Xa to plasma 
concentrations is linear with a slope close to 1. Individual discrepancies with higher or lower anti-Xa 
values as compared to the corresponding plasma concentrations may occur. There is no need for 
routine monitoring of coagulation parameters during clinical treatment with rivaroxaban. However, if 
clinically indicated, rivaroxaban concentrations can be measured by calibrated quantitative anti-
Factor Xa tests in mcg/L (see table 13 in section 5.2 for ranges of observed rivaroxaban plasma 
concentrations in children). The lower limit of quantifications must be considered when the anti-Xa 
test is used to quantify plasma concentrations of rivaroxaban in children. No threshold for efficacy or 
safety events has been established. 
 
Clinical efficacy and safety 
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation 
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for the 
prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.  
In the pivotal double-blind ROCKET AF study, 14,264 patients were assigned either to rivaroxaban 
20 mg once daily (15 mg once daily in patients with creatinine clearance 30 - 49 ml/min) or to 
warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0). The median time on treatment 
was 19 months and overall treatment duration was up to 41 months.  
34.9% of patients were treated with acetylsalicylic acid and 11.4% were treated with class III 
antiarrhythmic including amiodarone.  
 
Rivaroxaban was non-inferior to warfarin for the primary composite endpoint of stroke and non-CNS 
systemic embolism. In the per-protocol population on treatment, stroke or systemic embolism occurred 
in 188 patients on rivaroxaban (1.71% per year) and 241 on warfarin (2.16% per year) (HR 0.79; 
95% CI, 0.66 - 0.96; P<0.001 for non-inferiority). Among all randomised patients analysed according 
to ITT, primary events occurred in 269 on rivaroxaban (2.12% per year) and 306 on warfarin (2.42% 
per year) (HR 0.88; 95% CI, 0.74 - 1.03; P<0.001 for non-inferiority; P=0.117 for superiority). Results 
for secondary endpoints as tested in hierarchical order in the ITT analysis are displayed in Table 4. 
Among patients in the warfarin group, INR values were within the therapeutic range (2.0 to 3.0) a 
mean of 55% of the time (median, 58%; interquartile range, 43 to 71). The effect of rivaroxaban did 
not differ across the level of centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized 
quartiles (P=0.74 for interaction). Within the highest quartile according to centre, the Hazard Ratio 
(HR) with rivaroxaban versus warfarin was 0.74 (95% CI, 0.49 - 1.12). 
The incidence rates for the principal safety outcome (major and non-major clinically relevant bleeding 
events) were similar for both treatment groups (see Table 5). 
 



67 

Table 4: Efficacy results from phase III ROCKET AF 

Study population 
ITT analyses of efficacy in patients with non-valvular atrial 
fibrillation 

Treatment dose 

Rivaroxaban 
20 mg once daily  
(15 mg once daily in 
patients with moderate 
renal impairment) 
Event rate (100 pt-yr) 

Warfarin 
titrated to a target 
INR of 2.5 (therapeutic 
range 2.0 to 3.0) 
 
Event rate (100 pt-yr) 

HR (95% CI) 
p-value, test for 
superiority 

Stroke and non-CNS 
systemic embolism 

269 
(2.12) 

306 
(2.42) 

0.88 (0.74 - 1.03) 
0.117 

Stroke, non-CNS systemic 
embolism and vascular death 

572 
(4.51) 

609 
(4.81) 

0.94 (0.84 - 1.05) 
0.265 

Stroke, non-CNS systemic 
embolism, vascular death 
and myocardial infarction 

659 
(5.24) 

709 
(5.65) 

0.93 (0.83 - 1.03) 
0.158 

 Stroke 
253  
(1.99) 

281 
(2.22) 

0.90 (0.76 - 1.07) 
0.221 

 Non-CNS systemic 
embolism 

20  
(0.16) 

27 
(0.21) 

0.74 (0.42 - 1.32) 
0.308 

Myocardial infarction 
130 
(1.02) 

142 
(1.11) 

0.91 (0.72 - 1.16)  
0.464 

 



68 

Table 5: Safety results from phase III ROCKET AF 
Study population Patients with non-valvular atrial fibrillationP

a) 

Treatment dose  

Rivaroxaban 
20 mg once daily  
(15 mg once daily in 
patients with moderate 
renal impairment) 
Event rate (100 pt-yr) 

Warfarin 
titrated to a target INR 
of 2.5 (therapeutic 
range 2.0 to 3.0) 
 
Event rate (100 pt-yr) 

HR (95% CI) 
p-value  

Major and non-major 
clinically relevant bleeding 
events 

1,475 
(14.91) 

1,449 
(14.52) 

1.03 (0.96 - 1.11) 
0.442 

Major bleeding events 
395 
(3.60) 

386 
(3.45) 

1.04 (0.90 - 1.20) 
0.576 

Death due to 

bleeding* 

27 
(0.24) 

55 
(0.48) 

0.50 (0.31 - 0.79) 
0.003 

Critical organ 

bleeding* 

91 
(0.82) 

133 
(1.18) 

0.69 (0.53 - 0.91) 
0.007 

Intracranial 

haemorrhage* 

55  
(0.49) 

84 
(0.74) 

0.67 (0.47 - 0.93) 
0.019 

Haemoglobin drop* 
305 
(2.77) 

254 
(2.26) 

1.22 (1.03 - 1.44) 
0.019 

Transfusion of 2 or 
more units of packed 
red blood cells or 

whole blood* 

183 
(1.65) 

149 
(1.32) 

1.25 (1.01 - 1.55) 
0.044 

Non-major clinically 
relevant bleeding events 

1,185 
(11.80) 

1,151 
(11.37) 

1.04 (0.96 - 1.13) 
0.345 

All-cause mortality 
208 
(1.87) 

250 
(2.21) 

0.85 (0.70 - 1.02) 
0.073 

a) Safety population, on treatment 

* Nominally significant 
 
In addition to the phase III ROCKET AF study, a prospective, single-arm, post-authorisation, non-
interventional, open-label cohort study (XANTUS) with central outcome adjudication including 
thromboembolic events and major bleeding has been conducted. 6,785 patients with non-valvular 
atrial fibrillation were enrolled for prevention of stroke and non-central nervous system (CNS) 
systemic embolism in clinical practice. The mean CHADSR2R and HAS-BLED scores were both 2.0 in 
XANTUS, compared to a mean CHADSR2R and HAS-BLED score of 3.5 and 2.8 in ROCKET AF, 
respectively. Major bleeding occurred in 2.1 per 100 patient years. Fatal haemorrhage was reported in 
0.2 per 100 patient years and intracranial haemorrhage in 0.4 per 100 patient years. Stroke or non-CNS 
systemic embolism was recorded in 0.8 per 100 patient years. 
These observations in clinical practice are consistent with the established safety profile in this 
indication. 
 
Patients undergoing cardioversion 
A prospective, randomised, open-label, multicentre, exploratory study with blinded endpoint 
evaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naive and pre-treated) with 
non-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted 
VKA (randomised 2:1), for the prevention of cardiovascular events. TEE- guided (1 - 5 days of pre-
treatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies were 
employed. The primary efficacy outcome (all stroke, transient ischaemic attack, non-CNS systemic 
embolism, myocardial infarction (MI) and cardiovascular death) occurred in 5 (0.5%) patients in the 
rivaroxaban group (n = 978) and 5 (1.0%) patients in the VKA group (n = 492; RR 0.50; 95% CI 0.15-
1.73; modified ITT population). The principal safety outcome (major bleeding) occurred in 6 (0.6%) 
and 4 (0.8%) patients in the rivaroxaban (n = 988) and VKA (n = 499) groups, respectively (RR 0.76; 



69 

95% CI 0.21-2.67; safety population). This exploratory study showed comparable efficacy and safety 
between rivaroxaban and VKA treatment groups in the setting of cardioversion. 
 
Patients with non-valvular atrial fibrillation who undergo PCI with stent placement 
A randomised, open-label, multicentre study (PIONEER AF-PCI) was conducted in 2,124 patients 
with non-valvular atrial fibrillation who underwent PCI with stent placement for primary 
atherosclerotic disease to compare safety of two rivaroxaban regimens and one VKA regimen. Patients 
were randomly assigned in a 1:1:1 fashion for an overall 12-month-therapy. Patients with a history of 
stroke or TIA were excluded.  
Group 1 received rivaroxaban 15 mg once daily (10 mg once daily in patients with creatinine 
clearance 30 - 49 ml/min) plus P2Y12 inhibitor. Group 2 received rivaroxaban 2.5 mg twice daily plus 
DAPT (dual antiplatelet therapy i.e. clopidogrel 75 mg [or alternate P2Y12 inhibitor] plus low-dose 
acetylsalicylic acid [ASA]) for 1, 6 or 12 months followed by rivaroxaban 15 mg (or 10 mg for 
subjects with creatinine clearance 30 - 49 ml/min) once daily plus low-dose ASA. Group 3 received 
dose-adjusted VKA plus DAPT for 1, 6 or 12 months followed by dose-adjusted VKA plus low-dose 
ASA.  
The primary safety endpoint, clinically significant bleeding events, occurred in 109 (15.7%), 117 
(16.6%), and 167 (24.0%) subjects in group 1, group 2 and group 3, respectively (HR 0.59; 95% CI 
0.47-0.76; p<0.001, and HR 0.63; 95% CI 0.50-0.80; p<0.001, respectively). The secondary endpoint 
(composite of cardiovascular events CV death, MI, or stroke) occurred in 41 (5.9%), 36 (5.1%), and 
36 (5.2%) subjects in the group 1, group 2 and group 3, respectively. Each of the rivaroxaban 
regimens showed a significant reduction in clinically significant bleeding events compared to the 
VKA regimen in patients with non-valvular atrial fibrillation who underwent a PCI with stent 
placement. 
The primary objective of PIONEER AF-PCI was to assess safety. Data on efficacy (including 
thromboembolic events) in this population are limited.  
 
Treatment of DVT, PE and prevention of recurrent DVT and PE  
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban in the 
initial and continued treatment of acute DVT and PE and prevention of recurrence. 
Over 12,800 patients were studied in four randomised controlled phase III clinical studies (Einstein 
DVT, Einstein PE, Einstein Extension and Einstein Choice) and additionally a predefined pooled 
analysis of the Einstein DVT and Einstein PE studies was conducted. The overall combined treatment 
duration in all studies was up to 21 months. 
 
In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the 
prevention of recurrent DVT and PE (patients who presented with symptomatic PE were excluded 
from this study). The treatment duration was for 3, 6 or 12 months depending on the clinical 
judgement of the investigator. 
For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. This 
was followed by 20 mg rivaroxaban once daily.  
 
In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention of 
recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinical 
judgement of the investigator. 
For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks. 
This was followed by 20 mg rivaroxaban once daily.  
 
In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted of 
enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until 
the PT/INR was in therapeutic range ( 2.0). Treatment was continued with a vitamin K antagonist 
dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0. 
 
In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent 
DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who had 
completed 6 to 12 months of treatment for venous thromboembolism depending on the clinical 
judgment of the investigator. Rivaroxaban 20 mg once daily was compared with placebo.  



70 

 
Einstein DVT, PE and Extension used the same pre-defined primary and secondary efficacy outcomes. 
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent 
DVT or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of 
recurrent DVT, non-fatal PE and all-cause mortality.  
 
In Einstein Choice, 3,396 patients with confirmed symptomatic DVT and/or PE who completed 6-12 
months of anticoagulant treatment were studied for the prevention of fatal PE or non-fatal 
symptomatic recurrent DVT or PE. Patients with an indication for continued therapeutic-dosed 
anticoagulation were excluded from the study. The treatment duration was up to 12 months depending 
on the individual randomisation date (median: 351 days). Rivaroxaban 20 mg once daily and 
rivaroxaban 10 mg once daily were compared with 100 mg acetylsalicylic acid once daily. 
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent 
DVT or fatal or non-fatal PE.  
 
In the Einstein DVT study (see Table 6) rivaroxaban was demonstrated to be non-inferior to 
enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); HR: 0.680 
(0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primary efficacy 
outcome plus major bleeding events) was reported with a HR of 0.67 ((95% CI: 0.47 - 0.95), nominal 
p value p=0.027) in favour of rivaroxaban. INR values were within the therapeutic range a mean of 
60.3% of the time for the mean treatment duration of 189 days, and 55.4%, 60.1%, and 62.8% of the 
time in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In the 
enoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in 
Target INR Range of 2.0 - 3.0) in the equally sized tertiles and the incidence of the recurrent VTE 
(P=0.932 for interaction). Within the highest tertile according to centre, the HR with rivaroxaban 
versus warfarin was 0.69 (95% CI: 0.35 - 1.35). 
 
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding 
events) as well as the secondary safety outcome (major bleeding events) were similar for both 
treatment groups. 
 
Table 6: Efficacy and safety results from phase III Einstein DVT 

Study population 
3,449 patients with symptomatic acute deep vein 
thrombosis 

Treatment dose and duration 
Rivaroxaban P

a) 

3, 6 or 12 months 
N=1,731 

Enoxaparin/VKAP

b) 
3, 6 or 12 months 
N=1,718 

Symptomatic recurrent VTE* 
36 
(2.1%) 

51 
(3.0%) 

Symptomatic recurrent PE 
20 
(1.2%) 

18 
(1.0%) 

Symptomatic recurrent 
DVT 

14 
(0.8%) 

28 
(1.6%) 

Symptomatic PE and DVT 
1 
(0.1%) 

0 

Fatal PE/death where PE 
cannot be ruled out 

4 
(0.2%) 

6 
(0.3%) 

Major or clinically relevant non-
major bleeding 

139 
(8.1%) 

138 
(8.1%) 

Major bleeding events 
14 
(0.8%) 

20 
(1.2%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 

* p < 0.0001 (non-inferiority to a prespecified HR of 2.0); HR: 0.680 (0.443 - 1.042), p=0.076 
(superiority) 

 



71 

In the Einstein PE study (see Table 7) rivaroxaban was demonstrated to be non-inferior to 
enoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority); HR: 1.123 
(0.749 - 1.684)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding 
events) was reported with a HR of 0.849 ((95% CI: 0.633 - 1.139), nominal p value p= 0.275). INR 
values were within the therapeutic range a mean of 63% of the time for the mean treatment duration of 
215 days, and 57%, 62%, and 65% of the time in the 3-, 6-, and 12-month intended treatment duration 
groups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level of 
mean centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized tertiles and the 
incidence of the recurrent VTE (p=0.082 for interaction). Within the highest tertile according to 
centre, the HR with rivaroxaban versus warfarin was 0.642 (95% CI: 0.277 - 1.484). 
 
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding 
events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the 
enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome 
(major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the 
enoxaparin/VKA group (2.2% (52/2405)) with a HR 0.493 (95% CI: 0.308 - 0.789). 
 
Table 7: Efficacy and safety results from phase III Einstein PE 
Study population 4,832 patients with an acute symptomatic PE 

Treatment dose and duration 
Rivaroxaban P

a) 
3, 6 or 12 months 
N=2,419 

Enoxaparin/VKA P

b) 
3, 6 or 12 months 
N=2,413 

Symptomatic recurrent VTE* 
50 
(2.1%) 

44 
(1.8%) 

Symptomatic recurrent PE 
23 
(1.0%) 

20 
(0.8%) 

Symptomatic recurrent 
DVT 

18 
(0.7%) 

17 
(0.7%) 

Symptomatic PE and DVT 0 
2 
(<0.1%) 

Fatal PE/death where PE 
cannot be ruled out 

11 
(0.5%) 

7 
(0.3%) 

Major or clinically relevant non-
major bleeding 

249 
(10.3%) 

274 
(11.4%) 

Major bleeding events 
26 
(1.1%) 

52 
(2.2%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 
* p < 0.0026 (non-inferiority to a prespecified HR of 2.0); HR: 1.123 (0.749 - 1.684)  

 
A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see 
Table 8). 
 



72 

Table 8: Efficacy and safety results from pooled analysis of phase III Einstein DVT and Einstein 
PE 
Study population 8,281 patients with an acute symptomatic DVT or PE 

Treatment dose and duration 
Rivaroxaban P

a) 

3, 6 or 12 months 
N=4,150 

Enoxaparin/VKAP

b) 
3, 6 or 12 months 
N=4,131 

Symptomatic recurrent VTE* 
86 
(2.1%) 

95 
(2.3%) 

Symptomatic recurrent PE 
43 
(1.0%) 

38 
(0.9%) 

Symptomatic recurrent 
DVT 

32 
(0.8%) 

45 
(1.1%) 

Symptomatic PE and DVT 
1 
(<0.1%) 

2 
(<0.1%) 

Fatal PE/death where PE 
cannot be ruled out 

15 
(0.4%) 

13 
(0.3%) 

Major or clinically relevant non-
major bleeding 

388 
(9.4%) 

412 
(10.0%) 

Major bleeding events 
40 
(1.0%) 

72 
(1.7%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 

* p < 0.0001 (non-inferiority to a prespecified HR of 1.75); HR: 0.886 (0.661 - 1.186) 
 
The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the 
pooled analysis was reported with a HR of 0.771 ((95% CI: 0.614 - 0.967), nominal p value p= 
0.0244). 
 
In the Einstein Extension study (see Table 9) rivaroxaban was superior to placebo for the primary and 
secondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was a 
non-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once 
daily compared to placebo. The secondary safety outcome (major or clinically relevant non-major 
bleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared 
to placebo.  
 
Table 9: Efficacy and safety results from phase III Einstein Extension 

Study population 
1,197 patients continued treatment and prevention 
of recurrent venous thromboembolism 

Treatment dose and duration 
Rivaroxaban P

a)
P  

6 or 12 months 
N=602 

Placebo 
6 or 12 months 
N=594 

Symptomatic recurrent VTE* 
8 
(1.3%) 

42 
(7.1%) 

Symptomatic recurrent PE 
2 
(0.3%) 

13 
(2.2%) 

Symptomatic recurrent DVT 
5 
(0.8%) 

31 
(5.2%) 

Fatal PE/death where PE 
cannot be ruled out 

1 
(0.2%) 

1 
(0.2%) 

Major bleeding events 
4 
(0.7%) 

0 
(0.0%) 

Clinically relevant non-major 
bleeding 

32 
(5.4%) 

7 
(1.2%) 

a) Rivaroxaban 20 mg once daily 

* p < 0.0001 (superiority), HR: 0.185 (0.087 - 0.393) 
 



73 

In the Einstein Choice study (see Table 10) rivaroxaban 20 mg and 10 mg were both superior to 100 
mg acetylsalicylic acid for the primary efficacy outcome. The principal safety outcome (major 
bleeding events) was similar for patients treated with rivaroxaban 20 mg and 10 mg once daily 
compared to 100 mg acetylsalicylic acid.  
 
Table 10: Efficacy and safety results from phase III Einstein Choice 

Study population 
3,396 patients continued prevention of 
recurrent venous thromboembolism 

Treatment dose  
Rivaroxaban 20 mg 
once daily 
N=1,107 

Rivaroxaban 10 
mg once daily 
N=1,127 

ASA 100 mg once 
daily 
N=1,131 

Treatment duration median 
[interquartile range] 

349 [189-362] days 353 [190-362] days 350 [186-362] days 

Symptomatic recurrent VTE 
17 
(1.5%)* 

13 
(1.2%)** 

50 
(4.4%) 

Symptomatic recurrent 
PE 

6 
(0.5%) 

6 
(0.5%) 

19 
(1.7%) 

Symptomatic recurrent 
DVT 

9 
(0.8%) 

8 
(0.7%) 

30 
(2.7%) 

Fatal PE/death where PE 
cannot be ruled out 

2 
(0.2%) 

0 
(0.0%) 

2 
(0.2%) 

Symptomatic recurrent VTE, 
MI, stroke, or non-CNS 
systemic embolism 

19 
(1.7%) 

18 
(1.6%) 

56 
(5.0%) 

Major bleeding events 
6 
(0.5%) 

5 
(0.4%) 

3 
(0.3%) 

Clinically relevant non-major 
bleeding 

30  
(2.7) 

22  
(2.0) 

20  
(1.8) 

Symptomatic recurrent VTE 
or major bleeding (net 
clinical benefit) 

23 
(2.1%) P

+ 
17  
(1.5%) P

++ 
53  
(4.7%) 

*  p<0.001(superiority) rivaroxaban 20 mg od vs ASA 100 mg od; HR=0.34 (0.20-0.59) 
**  p<0.001 (superiority) rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.26 (0.14-0.47)P

  

P

+  
PRivaroxaban 20 mg od vs ASA 100 mg od; HR=0.44 (0.27-0.71), p=0.0009 (nominal)  

P

++
P  Rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.32 (0.18-0.55), p<0.0001 (nominal) 

 
In addition to the phase III EINSTEIN programme, a prospective, non-interventional, open-label 
cohort study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and 
death has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-term 
safety of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice. 
Rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 
0.5%, respectively. There were differences in patient baseline characteristics including age, cancer and 
renal impairment. A pre-specified propensity score stratified analysis was used to adjust for measured 
baseline differences but residual confounding may, in spite of this, influence the results. Adjusted HRs 
comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-cause mortality 
were 0.77 (95% CI 0.40 - 1.50), 0.91 (95% CI 0.54 - 1.54) and 0.51 (95% CI 0.24 - 1.07), respectively.  
These results in clinical practice are consistent with the established safety profile in this indication. 
 
Paediatric population 
Treatment of VTE and prevention of VTE recurrence in paediatric patients  
A total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in 
6 open-label, multicentre paediatric studies. Body weight-adjusted dosing in patients from birth to less 
than 18 years resulted in rivaroxaban exposure similar to that observed in adult DVT patients treated 
with rivaroxaban 20 mg once daily as confirmed in the phase III study (see section 5.2).  
 
The EINSTEIN Junior phase III study was a randomised, active-controlled, open-label multicentre 
clinical study in 500 paediatric patients (aged from birth to < 18 years) with confirmed acute VTE. 



74 

There were 276 children aged 12 to < 18 years, 101 children aged 6 to < 12 years, 69 children aged 
2 to < 6 years, and 54 children aged < 2 years.  
 
Index VTE was classified as either central venous catheter-related VTE (CVC-VTE; 90/335 patients 
in the rivaroxaban group, 37/165 patients in the comparator group), cerebral vein and sinus thrombosis 
(CVST; 74/335 patients in the rivaroxaban group, 43/165 patients in the comparator group), and all 
others including DVT and PE (non-CVC-VTE; 171/335 patients in the rivaroxaban group, 
84/165 patients in the comparator group). The most common presentation of index thrombosis in 
children aged 12 to < 18 years was non-CVC-VTE in 211 (76.4%); in children aged 6 to < 12 years 
and aged 2 to < 6 years was CVST in 48 (47.5%) and 35 (50.7%), respectively; and in children aged 
< 2 years was CVC-VTE in 37 (68.5%). There were no children < 6 months with CVST in the 
rivaroxaban group. 22 of the patients with CVST had a CNS infection (13 patients in the rivaroxaban 
group and 9 patients in comparator group). 
 
VTE was provoked by persistent, transient, or both persistent and transient risk factors in 438 (87.6%) 
children.  
 
Patients received initial treatment with therapeutic doses of UFH, LMWH, or fondaparinux for at least 
5 days, and were randomised 2:1 to receive either body weight-adjusted doses of rivaroxaban or 
comparator group (heparins, VKA) for a main study treatment period of 3 months (1 month for 
children < 2 years with CVC-VTE). At the end of the main study treatment period, the diagnostic 
imaging test, which was obtained at baseline, was repeated, if clinically feasible. The study treatment 
could be stopped at this point, or at the discretion of the Investigator continued for up to 12 months 
(for children < 2 years with CVC-VTE up to 3 months) in total. 
 
The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was the 
composite of major bleeding and clinically relevant non-major bleeding (CRNMB). All efficacy and 
safety outcomes were centrally adjudicated by an independent committee blinded for treatment 
allocation. The efficacy and safety results are shown in Tables 11 and 12 below. 
 
Recurrent VTEs occurred in the rivaroxaban group in 4 of 335 patients and in the comparator group in 
5 of 165 patients. The composite of major bleeding and CRNMB was reported in 10 of 329 patients 
(3%) treated with rivaroxaban and in 3 of 162 patients (1.9%) treated with comparator. Net clinical 
benefit (symptomatic recurrent VTE plus major bleeding events) was reported in the rivaroxaban 
group in 4 of 335 patients and in the comparator group in 7 of 165 patients. Normalisation of the 
thrombus burden on repeat imaging occurred in 128 of 335 patients with rivaroxaban treatment and in 
43 of 165 patients in the comparator group. These findings were generally similar among age groups. 
There were 119 (36.2%) children with any treatment-emergent bleeding in the rivaroxaban group and 
45 (27.8%) children in the comparator group. 
 



75 

Table 11: Efficacy results at the end of the main treatment period  
Event Rivaroxaban  

N=335* 
Comparator 
N=165* 

Recurrent VTE (primary efficacy outcome) 4 
(1.2%, 95% CI 
0.4% – 3.0%) 

5 
(3.0%, 95% CI 
1.2% - 6.6%) 

Composite: Symptomatic recurrent VTE + 
asymptomatic deterioration on repeat imaging 

5 
(1.5%, 95% CI 
0.6% – 3.4%) 

6 
(3.6%, 95% CI 
1.6% – 7.6%) 

Composite: Symptomatic recurrent VTE + 
asymptomatic deterioration + no change on repeat 
imaging 

21 
(6.3%, 95% CI 
4.0% – 9.2%) 

19 
(11.5%, 95% CI 
7.3% – 17.4%) 

Normalisation on repeat imaging  128 
(38.2%, 95% CI 
33.0% - 43.5%) 

43 
(26.1%, 95% CI 
19.8% - 33.0%) 

Composite: Symptomatic recurrent VTE + major 
bleeding (net clinical benefit) 

4 
(1.2%, 95% CI 
0.4% - 3.0%) 

7 
(4.2%, 95% CI 
2.0% - 8.4%) 

Fatal or non-fatal pulmonary embolism 1 
(0.3%, 95% CI 
0.0% – 1.6%) 

1 
(0.6%, 95% CI 
0.0% – 3.1%) 

*FAS= full analysis set, all children who were randomised 

 
Table 12: Safety results at the end of the main treatment period  

 Rivaroxaban  
N=329* 

Comparator 
N=162* 

Composite: Major bleeding + CRNMB (primary safety 
outcome) 

10 
(3.0%, 95% CI 
1.6% - 5.5%) 

3 
(1.9%, 95% CI 
0.5% - 5.3%) 

Major bleeding 0 
(0.0%, 95% CI 
0.0% - 1.1%) 

2 
(1.2%, 95% CI 
0.2% - 4.3%) 

Any treatment-emergent bleedings 119 (36.2%) 45 (27.8%) 
* SAF= safety analysis set, all children who were randomised and received at least 1 dose of study 

medicinal product.  
 
The efficacy and safety profile of rivaroxaban was largely similar between the paediatric VTE 
population and the DVT/PE adult population, however, the proportion of subjects with any bleeding 
was higher in the paediatric VTE population as compared to the DVT/PE adult population. 
 
Patients with high risk triple positive antiphospholipid syndrome 
In an investigator sponsored, randomised open-label multicentre study with blinded endpoint 
adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, 
diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for 
all 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and 
anti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of 
120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 
569 days. 59 patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinine 
clearance (CrCl) < 50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 
12% of patients randomised to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No 
events were reported in patients randomised to warfarin. Major bleeding occurred in 4 patients (7%) 
of the rivaroxaban group and 2 patients (3%) of the warfarin group. 



76 

 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
The following information is based on the data obtained in adults.  
Rivaroxaban is rapidly absorbed with maximum concentrations (CRmaxR) appearing 2 - 4 hours after 
tablet intake.  
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect 
rivaroxaban AUC or CRmaxR at the 2.5 mg and 10 mg dose.  
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg 
tablet under fasting conditions. When rivaroxaban 20 mg tablets are taken together with food increases 
in mean AUC by 39% were observed when compared to tablet intake under fasting conditions, 
indicating almost complete absorption and high oral bioavailability. Rivaroxaban 15 mg and 20 mg are 
to be taken with food (see section 4.2). 
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state. 
Under fed conditions rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. 
At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and 
decreased absorption rate with increased dose.  
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) 
ranging from 30% to 40%. 
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% 
and 56% decrease in AUC and CRmaxR compared to tablet was reported when rivaroxaban granulate is 
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in 
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the 
stomach should be avoided since this can result in reduced absorption and related rivaroxaban 
exposure. 
Bioavailability (AUC and CRmaxR) was comparable for 20 mg rivaroxaban administered orally as a 
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube 
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional 
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable 
to lower rivaroxaban doses. 
 
Paediatric population 
Children received rivaroxaban tablet or oral suspension during or closely after feeding or food intake 
and with a typical serving of liquid to ensure reliable dosing in children. As in adults, rivaroxaban is 
readily absorbed after oral administration as tablet or granules for oral suspension formulation in 
children. No difference in the absorption rate nor in the extent of absorption between the tablet and 
granules for oral suspension formulation was observed. No PK data following intravenous 
administration to children are available so that the absolute bioavailability of rivaroxaban in children is 
unknown. A decrease in the relative bioavailability for increasing doses (in mg/kg bodyweight) was 
found, suggesting absorption limitations for higher doses, even when taken together with food. 
Rivaroxaban 15 mg tablets should be taken with feeding or with food (see section 4.2).  
 
Distribution 
Plasma protein binding in adults is high at approximately 92% to 95%, with serum albumin being the 
main binding component. The volume of distribution is moderate with VRssR being approximately 
50 litres. 
 



77 

Paediatric population 
No data on rivaroxaban plasma protein binding specific to children is available. No PK data following 
intravenous administration of rivaroxaban to children is available. VRssR estimated via population PK 
modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is 
dependent on body weight and can be described with an allometric function, with an average of 113 L 
for a subject with a body weight of 82.8 kg. 
 
Biotransformation and elimination  
In adults, of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, 
with half then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 
of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, 
mainly via active renal secretion. 
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative 
degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of 
biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter 
proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein). 
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active 
circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be 
classified as a low-clearance substance. After intravenous administration of a 1 mg dose the 
elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption 
rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in 
young individuals, and with terminal half-lives of 11 to 13 hours in the elderly. 
 
Paediatric population 
No metabolism data specific to children is available. No PK data following intravenous administration 
of rivaroxaban to children is available. CL estimated via population PK modelling in children (age 
range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and 
can be described with an allometric function, with an average of 8 L/h for a subject with body weight 
of 82.8 kg. The geometric mean values for disposition half-lives (tR1/2R) estimated via population PK 
modelling decrease with decreasing age and ranged from 4.2 h in adolescents to approximately 3 h in 
children aged 2-12 years down to 1.9 and 1.6 h in children aged 0.5-< 2 years and less than 0.5 years, 
respectively. 
 
Special populations 
Gender 
In adults, there were no clinically relevant differences in pharmacokinetics and pharmacodynamics 
between male and female patients. An exploratory analysis did not reveal relevant differences in 
rivaroxaban exposure between male and female children. 
 
Elderly population 
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values 
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No 
dose adjustment is necessary. 
 
Different weight categories 
In adults, extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban 
plasma concentrations (less than 25%). No dose adjustment is necessary.  
In children, rivaroxaban is dosed based on body weight. An exploratory analysis did not reveal a 
relevant impact of underweight or obesity on rivaroxaban exposure in children. 
 
Inter-ethnic differences 
In adults, no clinically relevant inter-ethnic differences among Caucasian, African-American, 
Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and 
pharmacodynamics.  
An exploratory analysis did not reveal relevant inter-ethnic differences in rivaroxaban exposure among 
Japanese, Chinese or Asian children outside Japan and China compared to the respective overall 
paediatric population. 



78 

 
Hepatic impairment 
Cirrhotic adult patients with mild hepatic impairment (classified as Child Pugh A) exhibited only 
minor changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), 
nearly comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic 
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also 
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. 
There are no data in patients with severe hepatic impairment. 
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic 
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor 
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a 
steeper PK/PD relationship between concentration and PT.  
Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and 
clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see 
section 4.3). 
No clinical data is available in children with hepatic impairment. 
 
Renal impairment 
In adults, there was an increase in rivaroxaban exposure correlated to decrease in renal function, as 
assessed via creatinine clearance measurements. In individuals with mild (creatinine clearance 
50 - 80 ml/min), moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 
15 - 29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 
and 1.6 fold respectively. Corresponding increases in pharmacodynamic effects were more 
pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of 
factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy 
volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. 
There are no data in patients with creatinine clearance < 15 ml/min. 
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. 
Use is not recommended in patients with creatinine clearance < 15 ml/min. Rivaroxaban is to be used 
with caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4). 
No clinical data is available in children 1 year or older with moderate or severe renal impairment 
(glomerular filtration rate < 50 mL/min/1.73 mP

2
P). 

 
Pharmacokinetic data in patients 
In patients receiving rivaroxaban for treatment of acute DVT 20 mg once daily the geometric mean 
concentration (90% prediction interval) 2 - 4 h and about 24 h after dose (roughly representing 
maximum and minimum concentrations during the dose interval) was 215 (22 - 535) and 
32 (6 - 239) mcg/l, respectively. 
 
In paediatric patients with acute VTE receiving body weight-adjusted rivaroxaban leading to an 
exposure similar to that in adult DVT patients receiving a 20 mg once daily dose, the geometric mean 
concentrations (90% interval) at sampling time intervals roughly representing maximum and minimum 
concentrations during the dose interval are summarised in Table 13.  
 



79 

Table 13: Summary statistics (geometric mean (90% interval)) of rivaroxaban steady state 
plasma concentrations (mcg/L) by dosing regimen and age 

Time 
intervals 

        

o.d. N 12 -
< 18 years 

N 6 -< 12 years     

2.5-4h post 171 241.5  
(105-484) 

24 229.7  
(91.5-777) 

    

20-24h post 151 20.6 
(5.69-66.5) 

24 15.9  
(3.42-45.5)  

    

b.i.d. N 6 -< 12 years N 2 -< 6 years N  0.5 -< 2 years   
2.5-4h post 36 145.4  

(46.0-343) 
38 171.8  

(70.7-438) 
2 n.c.   

10-16h post 33 26.0  
(7.99-94.9) 

37 22.2  
(0.25-127) 

3 10.7  
(n.c.-n.c.) 

  

t.i.d. N 2 -< 6 years N Birth -
< 2 years 

N 0.5 -< 2 years N Birth -
< 0.5 years 

0.5-3h post 5 164.7  
(108-283) 

25 111.2  
(22.9-320) 

13 114.3  
(22.9-346) 

12 108.0  
(19.2-320) 

7-8h post 3 33.2  
(18.7-99.7) 

23 18.7  
(10.1-36.5) 

12 21.4  
(10.5-65.6) 

11 16.1  
(1.03-33.6) 

o.d. = once daily, b.i.d. = twice daily, t.i.d. three times daily, n.c. = not calculated 
Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation of 
statistics (LLOQ = 0.5 mcg/L). 

 
Pharmacokinetic/pharmacodynamic relationship 
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma 
concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated 
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between 
rivaroxaban concentration and factor Xa activity was best described by an ERmaxR model. For PT, the 
linear intercept model generally described the data better. Depending on the different PT reagents 
used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and 
the slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses in Phase II and III were 
consistent with the data established in healthy subjects.  
 
Paediatric population 
Safety and efficacy have not been established in the indication prevention of stroke and systemic 
embolism in patients with non-valvular atrial fibrillation for children and adolescents up to 18 years.  
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile 
toxicity. 
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic 
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant 
exposure levels. 
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive 
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic 
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, 
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as 
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams. 
 
Rivaroxaban was tested in juvenile rats up to 3-month treatment duration starting at postnatal day 4 
showing a non dose-related increase in periinsular haemorrhage. No evidence of target organ-specific 
toxicity was seen.  



80 

 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Microcrystalline cellulose 
Croscarmellose sodium 
Lactose monohydrate 
Hypromellose (2910) 
Sodium laurilsulfate 
Magnesium stearate 
 
Film-coat 
Macrogol (3350) 
Hypromellose (2910) 
Titanium dioxide (E 171) 
Iron oxide red (E 172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
Crushed tablets 
Crushed rivaroxaban tablets are stable in water and in apple puree for up to 4 hours. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Cartons containing 10, 14, 28, 42 or 98 film-coated tablets in PP/Alu foil blisters.  
Cartons containing 10 x 1 or 100 x 1 film-coated tablets in PP/Alu foil perforated unit dose blisters.  
Multipacks containing 10 packs of 10 x 1 (100 film-coated tablets) in PP/Alu foil perforated unit dose 
blisters.  
Cartons containing 14 film-coated tablets in PVC/PVDC/Alu foil blisters . 
HDPE bottles with a PP screw cap containing 100 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Crushing of tablets 
Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via a 
nasogastric tube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, the 
tube should be flushed with water. Since rivaroxaban absorption is dependent on the site of active 
substance release, administration of rivaroxaban distal to the stomach should be avoided, as this can 
result in reduced absorption and thereby, reduced active substance exposure. After the administration 



81 

of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should then be immediately followed by 
enteral feeding. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/011-016, EU/1/08/472/023, EU/1/08/472/036, EU/1/08/472/038, EU/1/08/472/048. 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 30 September 2008 
Date of latest renewal: 22 May 2018 
 
 
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. 
 



82 

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 
 
Xarelto 20 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 20 mg rivaroxaban.  
 
Excipient with known effect 
Each film-coated tablet contains 21.76 mg lactose (as monohydrate), see section 4.4. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet)  
Brown-red, round biconvex tablets (6 mm diameter, 9 mm radius of curvature) marked with the 
BAYER-cross on one side and “20” and a triangle on the other side.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Adults 
Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with 
one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes 
mellitus, prior stroke or transient ischaemic attack.  
 
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent 
DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.) 
 
Paediatric population  
Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children and 
adolescents aged less than 18 years and weighing more than 50 kg after at least 5 days of initial 
parenteral anticoagulation treatment. 
 
4.2 Posology and method of administration 
 
Posology 
Prevention of stroke and systemic embolism in adults 
The recommended dose is 20 mg once daily, which is also the recommended maximum dose.  
 
Therapy with Xarelto should be continued long term provided the benefit of prevention of stroke and 
systemic embolism outweighs the risk of bleeding (see section 4.4).  
 
If a dose is missed the patient should take Xarelto immediately and continue on the following day with 
the once daily intake as recommended. The dose should not be doubled within the same day to make 
up for a missed dose.  
 



83 

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE in adults 
The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first 
three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent 
DVT and PE.  
 
Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE 
provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration of 
therapy should be considered in patients with provoked DVT or PE not related to major transient risk 
factors, unprovoked DVT or PE, or a history of recurrent DVT or PE.   
 
When extended prevention of recurrent DVT and PE is indicated (following completion of at least 
6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom 
the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or 
who have developed recurrent DVT or PE on extended prevention with Xarelto 10 mg once daily, a 
dose of Xarelto 20 mg once daily should be considered. 
 
The duration of therapy and dose selection should be individualised after careful assessment of the 
treatment benefit against the risk for bleeding (see section 4.4).  
 

 Time period Dosing schedule Total daily dose 

Treatment and 
prevention of recurrent 
DVT and PE 

Day 1 - 21 15 mg twice daily  30 mg 

Day 22 onwards 20 mg once daily  20 mg 

Prevention of recurrent 
DVT and PE  

Following completion 
of at least 6 months 
therapy for DVT or PE 

10 mg once daily or  
20 mg once daily  

10 mg  
or 20 mg 

 
To support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment initiation pack 
of Xarelto for treatment of DVT/PE is available. 
 
If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take 
Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be 
taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended 
on the following day.  
 
If a dose is missed during the once daily treatment phase, the patient should take Xarelto immediately, 
and continue on the following day with the once daily intake as recommended. The dose should not be 
doubled within the same day to make up for a missed dose.  
 
Treatment of VTE and prevention of VTE recurrence in children and adolescents  
Xarelto treatment in children and adolescents aged less than 18 years should be initiated following at 
least 5 days of initial parenteral anticoagulation treatment (see section 5.1).  
 
The dose for children and adolescent is calculated based on body weight.  
- Body weight of 50 kg or more: 

a once daily dose of 20 mg rivaroxaban is recommended. This is the maximum daily dose.  
- Body weight from 30 to 50 kg: 

a once daily dose of 15 mg rivaroxaban is recommended. This is the maximum daily dose.  
- For patients with body weight less 30 kg refer to the Summary of Product Characteristics of 

Xarelto granules for oral suspension.  
 
The weight of a child should be monitored and the dose reviewed regularly. This is to ensure a 
therapeutic dose is maintained. Dose adjustments should be made based on changes in body weight 
only. 
 



84 

Treatment should be continued for at least 3 months in children and adolescents. Treatment can be 
extended up to 12 months when clinically necessary. There is no data available in children to support a 
dose reduction after 6 months treatment. The benefit-risk of continued therapy after 3 months should 
be assessed on an individual basis taking into account the risk for recurrent thrombosis versus the 
potential bleeding risk.  
 
If a dose is missed, the missed dose should be taken as soon as possible after it is noticed, but only on 
the same day. If this is not possible, the patient should skip the dose and continue with the next dose as 
prescribed. The patient should not take two doses to make up for a missed dose. 
 
Converting from Vitamin K Antagonists (VKA) to Xarelto 
- Prevention of stroke and systemic embolism:  

VKA treatment should be stopped and Xarelto therapy should be initiated when the 
International Normalised Ratio (INR) is ≤ 3.0.  

- Treatment of DVT, PE and prevention of recurrence in adults and treatment of VTE and 
prevention of recurrence in paediatric patients:  
VKA treatment should be stopped and Xarelto therapy should be initiated once the INR is ≤ 2.5.  

When converting patients from VKAs to Xarelto, INR values will be falsely elevated after the intake 
of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and therefore should 
not be used (see section 4.5). 
 
Converting from Xarelto to Vitamin K antagonists (VKA) 
There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. 
Continuous adequate anticoagulation should be ensured during any transition to an alternate 
anticoagulant. It should be noted that Xarelto can contribute to an elevated INR.  
In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is ≥ 2.0. 
For the first two days of the conversion period, standard initial dosing of VKA should be used 
followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the 
INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of 
Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last 
dose (see sections 4.5 and 5.2). 
 
Paediatric patients:  
Children who convert from Xarelto to VKA need to continue Xarelto for 48 hours after the first dose 
of VKA. After 2 days of co-administration an INR should be obtained prior to the next scheduled dose 
of Xarelto. Co-administration of Xarelto and VKA is advised to continue until the INR is ≥ 2.0. Once 
Xarelto is discontinued INR testing may be done reliably 24 hours after the last dose (see above and 
section 4.5). 
 
Converting from parenteral anticoagulants to Xarelto 
For adult and paediatric patients currently receiving a parenteral anticoagulant, discontinue the 
parenteral anticoagulant and start Xarelto 0 to 2 hours before the time that the next scheduled 
administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due 
or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. 
intravenous unfractionated heparin). 
 
Converting from Xarelto to parenteral anticoagulants 
Discontinue Xarelto and give the first dose of parenteral anticoagulant at the time the next Xarelto 
dose would be taken.  
 
Special populations 
Renal impairment 
Adults: 
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) 
indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be 
used with caution in these patients. Use is not recommended in patients with creatinine clearance 
< 15 ml/min (see sections 4.4 and 5.2). 



85 

 
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 
15 - 29 ml/min) renal impairment the following dose recommendations apply: 
 
- For the prevention of stroke and systemic embolism in patients with non-valvular atrial 

fibrillation, the recommended dose is 15 mg once daily (see section 5.2). 
 

- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: patients 
should be treated with 15 mg twice daily for the first 3 weeks. Thereafter, when the 
recommended dose is 20 mg once daily, a reduction of the dose from 20 mg once daily to 15 mg 
once daily should be considered if the patient’s assessed risk for bleeding outweighs the risk for 
recurrent DVT and PE. The recommendation for the use of 15 mg is based on PK modelling and 
has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).  
When the recommended dose is 10 mg once daily, no dose adjustment from the recommended 
dose is necessary.  
 

No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 
50 - 80 ml/min) (see section 5.2).  
 
Paediatric population:  
- Children and adolescents with mild renal impairment (glomerular filtration rate 

50 - 80 mL/min/1.73 mP

2
P): no dose adjustment is required, based on data in adults and limited 

data in paediatric patients (see section 5.2). 
- Children and adolescents with moderate or severe renal impairment (glomerular filtration rate 

< 50 mL/min/1.73 mP

2
P): Xarelto is not recommended as no clinical data is available (see 

section 4.4). 
 
Hepatic impairment 
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically 
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2). 
No clinical data is available in children with hepatic impairment.  
 
Elderly population  
No dose adjustment (see section 5.2) 
 
Body weight 
No dose adjustment for adults (see section 5.2) 
For paediatric patients the dose is determined based on body weight.  
 
Gender 
No dose adjustment (see section 5.2) 
 
Patients undergoing cardioversion 
Xarelto can be initiated or continued in patients who may require cardioversion.  
For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated 
with anticoagulants, Xarelto treatment should be started at least 4 hours before cardioversion to ensure 
adequate anticoagulation (see sections 5.1 and 5.2). For all patients, confirmation should be sought 
prior to cardioversion that the patient has taken Xarelto as prescribed. Decisions on initiation and 
duration of treatment should take established guideline recommendations for anticoagulant treatment 
in patients undergoing cardioversion into account. 
 
Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention) 
with stent placement 
There is limited experience of a reduced dose of 15 mg Xarelto once daily (or 10 mg Xarelto once 
daily for patients with moderate renal impairment [creatinine clearance 30 - 49 ml/min]) in addition to 
a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrial fibrillation who 
require oral anticoagulation and undergo PCI with stent placement (see sections 4.4 and 5.1).  



86 

 
Paediatric population 
The safety and efficacy of Xarelto in children aged 0 to < 18 years have not been established in the 
indication prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. 
No data are available. Therefore, it is not recommended for use in children below 18 years of age in 
indications other than the treatment of VTE and prevention of VTE recurrence.  
 
Method of administration  
Adults 
Xarelto is for oral use.  
The tablets are to be taken with food (see section 5.2). 
 
Crushing of tablets 
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with 
water or apple puree immediately prior to use and administered orally. After the administration of 
crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by 
food. 
The crushed tablet may also be given through gastric tubes (see sections 5.2 and 6.6). 
 
Children and adolescents weighing more than 50 kg 
Xarelto is for oral use.  
49TThe patient should be advised to 49Tswallow the tablet with liquid. It should also be taken with food (see 
section 5.2). The tablets should be taken approximately 24 hours apart.  
 
In case the patient immediately spits up the dose or vomits within 30 minutes after receiving the dose, 
a new dose should be given. However, if the patient vomits more than 30 minutes after the dose, the 
dose should not be re-administered and the next dose should be taken as scheduled. 
 
The tablet must not be split in an attempt to provide a fraction of a tablet dose.  
 
Crushing of tablets 
For patients who are unable to swallow whole tablets, Xarelto granules for oral suspension should be 
used. If the oral suspension is not immediately available, when doses of 15 mg or 20 mg rivaroxaban 
are prescribed, these could be provided by crushing the 15 mg or 20 mg tablet and mixing it with 
water or apple puree immediately prior to use and administering orally.  
The crushed tablet may be given through a nasogastric or gastric feeding tube (see sections 5.2 
and 6.6).  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Active clinically significant bleeding. 
 
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. 
 
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low 
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral 
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of 
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain 
an open central venous or arterial catheter (see section 4.5). 
 



87 

Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic 
patients with Child Pugh B and C (see section 5.2). 
 
Pregnancy and breast-feeding (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment 
period. 
 
Haemorrhagic risk 
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding. 
It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto 
administration should be discontinued if severe haemorrhage occurs (see section 4.9). 
 
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary 
including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently 
during long term rivaroxaban 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 and quantify the clinical relevance of overt 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. 
 
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban 
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional 
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. 
overdose and emergency surgery (see sections 5.1 and 5.2). 
 
Paediatric population 
There is limited data in children with cerebral vein and sinus thrombosis who have a CNS infection 
(see section 5.1). The risk of bleeding should be carefully evaluated before and during therapy with 
rivaroxaban. 
 
Renal impairment 
In adult patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma 
levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding 
risk. Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not 
recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2). 
Xarelto should be used with caution in patients with renal impairment concomitantly receiving other 
medicinal products which increase rivaroxaban plasma concentrations (see section 4.5). 
Xarelto is not recommended in children and adolescents with moderate or severe renal impairment 
(glomerular filtration rate < 50 mL/min/1.73 mP

2
P), as no clinical data is available.  

 
Interaction with other medicinal products 
The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with 
azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV 
protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and 
P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree 
(2.6 fold on average) which may lead to an increased bleeding risk. No clinical data is available in 
children receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp 
(see section 4.5). 
 
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis 
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and 



88 

platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotonin 
norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease 
an appropriate prophylactic treatment may be considered (see section 4.5).  
 
Other haemorrhagic risk factors 
As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding 
risk such as: 
 congenital or acquired bleeding disorders 
 uncontrolled severe arterial hypertension 
 other gastrointestinal disease without active ulceration that can potentially lead to bleeding 

complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal 
reflux disease) 

 vascular retinopathy 
 bronchiectasis or history of pulmonary bleeding 
 
Patients with prosthetic valves 
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone 
transcatheter aortic valve replacement (TAVR). Safety and efficacy of Xarelto have not been studied 
in patients with prosthetic heart valves; therefore, there are no data to support that Xarelto provides 
adequate anticoagulation in this patient population. Treatment with Xarelto is not recommended for 
these patients. 
 
Patients with antiphospholipid syndrome 
Direct acting Oral Anticoagulants (DOACs) including rivaroxaban 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. 
 
Patients with non-valvular atrial fibrillation who undergo PCI with stent placement 
Clinical data are available from an interventional study with the primary objective to assess safety in 
patients with non-valvular atrial fibrillation who undergo PCI with stent placement. Data on efficacy 
in this population are limited (see sections 4.2 and 5.1). No data are available for such patients with a 
history of stroke/transient ischaemic attack (TIA). 
 
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary 
embolectomy 
Xarelto is not recommended as an alternative to unfractionated heparin in patients with pulmonary 
embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary 
embolectomy since the safety and efficacy of Xarelto have not been established in these clinical 
situations.  
 
Spinal/epidural anaesthesia or puncture 
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, 
patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk 
of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. 
The risk of these events may be increased by the post-operative use of indwelling epidural catheters or 
the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by 
traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and 
symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder 
dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior 
to neuraxial intervention the physician should consider the potential benefit versus the risk in 
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical 
experience with the use of 20 mg rivaroxaban in these situations.  
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and 
neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of 
rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when 



89 

the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a 
sufficiently low anticoagulant effect in each patient is not known and should be weighed against the 
urgency of a diagnostic procedure. 
For the removal of an epidural catheter and based on the general PK characteristics at least 2x half-
life, i.e. at least 18 hours in young adult patients and 26 hours in elderly patients should elapse after 
the last administration of rivaroxaban (see section 5.2). Following removal of the catheter, at least 
6 hours should elapse before the next rivaroxaban dose is administered. 
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours. 
No data is available on the timing of the placement or removal of neuraxial catheter in children while 
on Xarelto. In such cases, discontinue rivaroxaban and consider a short acting parenteral 
anticoagulant. 
 
Dosing recommendations before and after invasive procedures and surgical intervention  
If an invasive procedure or surgical intervention is required, Xarelto 20 mg should be stopped at least 
24 hours before the intervention, if possible and based on the clinical judgement of the physician.  
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the 
urgency of the intervention. 
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention 
provided the clinical situation allows and adequate haemostasis has been established as determined by 
the treating physician (see section 5.2). 
 
Elderly population 
Increasing age may increase haemorrhagic risk (see section 5.2). 
 
Dermatological reactions 
Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS 
syndrome, have been reported during post-marketing surveillance in association with the use of 
rivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in the 
course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of 
treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. 
spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal 
lesions. 
 
Information about excipients 
Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose-galactose malabsorption should not take this medicinal product. 
This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially “sodium-free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
The extent of interactions in the paediatric population is not known. The below mentioned interaction 
data was obtained in adults and the warnings in section 4.4 should be taken into account for the 
paediatric population. 
 
CYP3A4 and P-gp inhibitors 
Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a 
day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in 
mean rivaroxaban CRmaxR, with significant increases in pharmacodynamic effects which may lead to an 
increased bleeding risk. Therefore, the use of Xarelto is not recommended in patients receiving 
concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, 
voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong 
inhibitors of both CYP3A4 and P-gp (see section 4.4).  
 
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either 
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. 
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and 



90 

moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in 
CRmaxR. The interaction with clarithromycin is likely not clinically relevant in most patients but can be 
potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). 
 
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 
1.3 fold increase in mean rivaroxaban AUC and CRmaxR. The interaction with erythromycin is likely not 
clinically relevant in most patients but can be potentially significant in high-risk patients. 
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. The effect of erythromycin is additive to that of renal impairment (see 
section 4.4). 
 
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold 
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean CRmaxR. The interaction with 
fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-
risk patients. (For patients with renal impairment: see section 4.4). 
 
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should 
be avoided. 
 
Anticoagulants 
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single 
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on 
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban. 
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any 
other anticoagulants (see sections 4.3 and 4.4).  
 
NSAIDs/platelet aggregation inhibitors 
No clinically relevant prolongation of bleeding time was observed after concomitant administration of 
rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more 
pronounced pharmacodynamic response.  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with 500 mg acetylsalicylic acid. 
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a 
pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was 
observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or 
GPIIb/IIIa receptor levels. 
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) 
and platelet aggregation inhibitors because these medicinal products typically increase the bleeding 
risk (see section 4.4). 
 
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. When 
concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-
major clinically relevant bleeding were observed in all treatment groups. 
 
Warfarin 
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or 
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) 
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, 
inhibition of factor Xa activity and endogenous thrombin potential were additive.  
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the 



91 

fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity 
and ETP) reflected only the effect of rivaroxaban.  
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR 
measurement can be used at the CRtroughR of rivaroxaban (24 hours after the previous intake of 
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point. 
No pharmacokinetic interaction was observed between warfarin and rivaroxaban. 
 
CYP3A4 inducers  
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 
50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The 
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, 
phenobarbital or St. John’s Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban 
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be 
avoided unless the patient is closely observed for signs and symptoms of thrombosis. 
 
Other concomitant therapies  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), 
atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban 
neither inhibits nor induces any major CYP isoforms like CYP3A4. 
 
Laboratory parameters 
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of 
rivaroxaban (see section 5.1).  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
Safety and efficacy of Xarelto 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 rivaroxaban passes the placenta, Xarelto is contraindicated 
during pregnancy (see section 4.3).  
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban. 
 
Breast-feeding 
Safety and efficacy of Xarelto have not been established in breast-feeding women. Data from animals 
indicate that rivaroxaban is secreted into milk. Therefore Xarelto 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 rivaroxaban in humans 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 
 
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope 
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). 
Patients experiencing these adverse reactions should not drive or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety of rivaroxaban has been evaluated in thirteen phase III studies in adults including 
53,103 patients exposed to rivaroxaban and in two phase II and one phase III paediatric studies 
including 412 patients. See phase III studies as listed in table 1. 
 



92 

Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult 
and paediatric phase III studies 

Indication Number of 
patients* 

Total daily dose Maximum 
treatment 
duration 

Prevention of venous 
thromboembolism (VTE) in adult 
patients undergoing elective hip or 
knee replacement surgery 

6,097 10 mg 39 days 

Prevention of VTE in medically ill 
patients 

3,997 10 mg 39 days 

Treatment of DVT, PE and 
prevention of recurrence 

6,790 Day 1 - 21: 30 mg 
Day 22 and 
onwards: 20 mg 
After at least 6 
months: 10 mg or 
20 mg 

21 months 

Treatment of VTE and prevention of 
VTE recurrence in term neonates 
and children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

329 Body weight-
adjusted dose to 
achieve a similar 
exposure as that 
observed in adults 
treated for DVT 
with 20 mg 
rivaroxaban once 
daily 

12 months 

Prevention of stroke and systemic 
embolism in patients with non-
valvular atrial fibrillation 

7,750 20 mg 41 months 

Prevention of atherothrombotic 
events in patients after an acute 
coronary syndrome (ACS) 

10,225 5 mg or 10 mg 
respectively, co-
administered with 
either ASA or ASA 
plus clopidogrel or 
ticlopidine 

31 months 

Prevention of atherothrombotic 
events in patients with CAD/PAD 

18,244 5 mg co-
administered with 
ASA or 10 mg 
alone 

47 months 

* Patients exposed to at least one dose of rivaroxaban 
 
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see 
section 4.4. and ‘Description of selected adverse reactions’ below) (Table 2). The most commonly 
reported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %). 
 



93 

Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the 
completed adult and paediatric phase III studies 
Indication Any bleeding Anaemia 
Prevention of VTE in adult patients 
undergoing elective hip or knee 
replacement surgery 

6.8% of patients 5.9% of patients 

Prevention of VTE in medically ill 
patients 

12.6% of patients 2.1% of patients 

Treatment of DVT, PE and prevention 
of recurrence 

23% of patients 1.6% of patients 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

39.5% of patients 4.6% of patients 

Prevention of stroke and systemic 
embolism in patients with non-
valvular atrial fibrillation 

28 per 100 patient 
years 

2.5 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients after an ACS 

22 per 100 patient 
years 

1.4 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients with CAD/PAD 

6.7 per 100 patient 
years 

0.15 per 100 patient 
years**  

* For all rivaroxaban studies all bleeding events are collected, reported and 
adjudicated.   

**  In the COMPASS study, there is a low anaemia incidence as a selective 
approach to adverse event collection was applied 

 
Tabulated list of adverse reactions 
The frequencies of adverse reactions reported with Xarelto in adult and paediatric patients are 
summarised in Table 3 below by system organ class (in MedDRA) and by frequency.  
 
Frequencies are defined as: 
very common (≥ 1/10) 
common (≥ 1/100 to < 1/10)  
uncommon (≥ 1/1,000 to < 1/100)  
rare (≥ 1/10,000 to < 1/1,000) 
very rare (< 1/10,000) 
not known (cannot be estimated from the available data) 
  



94 

Table 3: All adverse reactions reported in adult patients in phase III clinical studies or through 
post-marketing use* and in two phase II and one phase III studies in paediatric patients   
Common Uncommon Rare Very rare Not known 
Blood and lymphatic system disorders 
Anaemia (incl. 
respective 
laboratory 
parameters) 

Thrombocytosis 
(incl. platelet count 
increased)P

A
P, 

thrombocytopenia 

   

Immune system disorders 
 Allergic reaction, 

dermatitis allergic, 
angioedema and 
allergic oedema 

 Anaphylactic 
reactions including 
anaphylactic shock  

 

Nervous system disorders 
Dizziness, 
headache 

Cerebral and 
intracranial 
haemorrhage, 
syncope 

   

Eye disorders 
Eye haemorrhage 
(incl. conjunctival 
haemorrhage) 

    

Cardiac disorders 
 Tachycardia    
Vascular disorders 
Hypotension, 
haematoma 

    

Respiratory, thoracic and mediastinal disorders 
Epistaxis, 
haemoptysis 

    

Gastrointestinal disorders 
Gingival bleeding, 
gastrointestinal 
tract haemorrhage 
(incl. rectal 
haemorrhage), 
gastrointestinal and 
abdominal pains, 
dyspepsia, nausea, 
constipationP

A
P, 

diarrhoea, 
vomitingP

A 

Dry mouth    

Hepatobiliary disorders 
Increase in 
transaminases 

Hepatic 
impairment, 
increased bilirubin, 
increased blood 
alkaline 
phosphatase P

A
P, 

increased GGTP

A 

Jaundice, bilirubin 
conjugated 
increased (with or 
without 
concomitant 
increase of ALT), 
cholestasis, 
hepatitis (incl. 
hepatocellular 
injury) 

  



95 

Common Uncommon Rare Very rare Not known 
Skin and subcutaneous tissue disorders 
Pruritus (incl. 
uncommon cases of 
generalised 
pruritus), rash, 
ecchymosis, 
cutaneous and 
subcutaneous 
haemorrhage 

Urticaria  Stevens-Johnson 
syndrome/Toxic 
Epidermal 
Necrolysis, DRESS 
syndrome  

 

Musculoskeletal and connective tissue disorders 
Pain in extremity P

A Haemarthrosis Muscle 
haemorrhage 

 Compartment 
syndrome 
secondary to a 
bleeding 

Renal and urinary disorders 
Urogenital tract 
haemorrhage (incl. 
haematuria and 
menorrhagiaP

B
P), 

renal impairment 
(incl. blood 
creatinine 
increased, blood 
urea increased) 

   Renal failure/acute 
renal failure 
secondary to a 
bleeding sufficient 
to cause 
hypoperfusion 

General disorders and administration site conditions 
Fever P

A
P, peripheral 

oedema, decreased 
general strength 
and energy (incl. 
fatigue and 
asthenia) 

Feeling unwell 
(incl. malaise)  

Localised oedemaP

A   

Investigations 
 Increased LDHP

A
P, 

increased lipaseP

A
P, 

increased amylaseP

A 

   

Injury, poisoning and procedural complications 
Postprocedural 
haemorrhage (incl. 
postoperative 
anaemia, and 
wound 
haemorrhage), 
contusion, wound 
secretion P

A 

 Vascular 
pseudoaneurysmP

C 
  

A:  observed in prevention of VTE in adult patients undergoing elective hip or knee replacement 
surgery 

B:  observed in treatment of DVT, PE and prevention of recurrence as very common in women 
< 55 years 

C:  observed as uncommon in prevention of atherothrombotic events in patients after an ACS 
(following percutaneous coronary intervention) 

*   A pre-specified selective approach to adverse event collection was applied. As incidence of 
adverse reactions did not increase and no new adverse reaction was identified, COMPASS 
study data were not included for frequency calculation in this table. 

 



96 

Description of selected adverse reactions 
Due to the pharmacological mode of action, the use of Xarelto 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 “Management of 
bleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito 
urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more 
frequently during long term rivaroxaban 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 and quantify the clinical relevance of overt 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 “Haemorrhagic risk”). Menstrual bleeding may be intensified and/or prolonged. 
Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained 
swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of 
cardiac ischaemia like chest pain or angina pectoris have been observed.  
Known complications secondary to severe bleeding such as compartment syndrome and renal failure 
due to hypoperfusion have been reported for Xarelto. Therefore, the possibility of haemorrhage is to 
be considered in evaluating the condition in any anticoagulated patient. 
 
Paediatric population  
The safety assessment in children and adolescents is based on the safety data from two phase II and 
one phase III open-label active controlled studies in paediatric patients aged birth to less than 18 years. 
The safety findings were generally similar between rivaroxaban and comparator in the various 
paediatric age groups. Overall, the safety profile in the 412 children and adolescents treated with 
rivaroxaban was similar to that observed in the adult population and consistent across age subgroups, 
although assessment is limited by the small number of patients.  
In paediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (very 
common, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increase in bilirubin 
(common, 1.5%) and bilirubin conjugated increased (uncommon, 0.7%) were reported more 
frequently as compared to adults. Consistent with adult population, menorrhagia was observed in 6.6% 
(common) of female adolescents after menarche. Thrombocytopenia as observed in the post-marketing 
experience in adult population was common (4.6%) in paediatric clinical studies. The adverse drug 
reactions in paediatric patients were primarily mild to moderate in severity. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In adults, rare cases of overdose up to 600 mg have been reported without bleeding complications or 
other adverse reactions. There is limited data available in children. Due to limited absorption a ceiling 
effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 
50 mg rivaroxaban or above in adults, however, no data is available at supratherapeutic doses in 
children. 
A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban is 
available for adults, but not established in children (refer to the Summary of Product Characteristics of 
andexanet alfa). 
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.  
 
Management of bleeding 
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban 
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has 
a half-life of approximately 5 to 13 hours in adults. The half life in children estimated using population 



97 

pharmacokinetic (popPK) modelling approaches is shorter (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. 
If bleeding cannot be controlled by the above measures, either the administration of a specific 
factor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of 
rivaroxaban, or a specific procoagulant reversal agent, such as prothrombin complex concentrate 
(PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), 
should be considered. However, there is currently very limited clinical experience with the use of 
these medicinal products in adults and in children receiving rivaroxaban. The recommendation is also 
based on limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and 
titrated depending on improvement of bleeding. Depending on local availability, a consultation with a 
coagulation expert should be considered in case of major bleedings (see section 5.1). 
 
Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. 
There is limited experience with tranexamic acid and no experience with aminocaproic acid and 
aprotinin in adults receiving rivaroxaban. There is no experience on the use of these agents in children 
receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use of 
the systemic haemostatic desmopressin in individuals receiving rivaroxaban. Due to the high plasma 
protein binding rivaroxaban is not expected to be dialysable. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01  
 
Mechanism of action 
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of 
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting 
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin 
(activated factor II) and no effects on platelets have been demonstrated. 
 
Pharmacodynamic effects 
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is 
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations 
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. 
The readout for PT is to be done in seconds, because the INR is only calibrated and validated for 
coumarins and cannot be used for any other anticoagulant.  
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95 
percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for 
15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15 
to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 
14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s. 
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and 
systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at the 
time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in 
patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough 
(16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged 
from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 
to 26 s. 
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult 
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC 
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC 



98 

reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to 
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC 
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation 
than the 4-factor PCC (see section 4.9). 
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently; 
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no 
need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. 
However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-
factor Xa tests (see section 5.2). 
 
Paediatric population 
PT (neoplastin reagent), aPTT, and anti-Xa assay (with a calibrated quantitative test) display a close 
correlation to plasma concentrations in children. The correlation between anti-Xa to plasma 
concentrations is linear with a slope close to 1. Individual discrepancies with higher or lower anti-Xa 
values as compared to the corresponding plasma concentrations may occur. There is no need for 
routine monitoring of coagulation parameters during clinical treatment with rivaroxaban. However, if 
clinically indicated, rivaroxaban concentrations can be measured by calibrated quantitative 
anti-Factor Xa tests in mcg/L (see table 13 in section 5.2 for ranges of observed rivaroxaban plasma 
concentrations in children). The lower limit of quantifications must be considered when the anti-Xa 
test is used to quantify plasma concentrations of rivaroxaban in children. No threshold for efficacy or 
safety events has been established. 
 
Clinical efficacy and safety 
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation 
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for the 
prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.  
In the pivotal double-blind ROCKET AF study, 14,264 patients were assigned either to rivaroxaban 
20 mg once daily (15 mg once daily in patients with creatinine clearance 30 - 49 ml/min) or to 
warfarin titrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0). The median time on treatment 
was 19 months and overall treatment duration was up to 41 months.  
34.9% of patients were treated with acetylsalicylic acid and 11.4% were treated with class III 
antiarrhythmic including amiodarone.  
 
Rivaroxaban was non-inferior to warfarin for the primary composite endpoint of stroke and non-CNS 
systemic embolism. In the per-protocol population on treatment, stroke or systemic embolism occurred 
in 188 patients on rivaroxaban (1.71% per year) and 241 on warfarin (2.16% per year) (HR 0.79; 
95% CI, 0.66 - 0.96; P<0.001 for non-inferiority). Among all randomised patients analysed according 
to ITT, primary events occurred in 269 on rivaroxaban (2.12% per year) and 306 on warfarin (2.42% 
per year) (HR 0.88; 95% CI, 0.74 - 1.03; P<0.001 for non-inferiority; P=0.117 for superiority). Results 
for secondary endpoints as tested in hierarchical order in the ITT analysis are displayed in Table 4. 
Among patients in the warfarin group, INR values were within the therapeutic range (2.0 to 3.0) a 
mean of 55% of the time (median, 58%; interquartile range, 43 to 71). The effect of rivaroxaban did 
not differ across the level of centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized 
quartiles (P=0.74 for interaction). Within the highest quartile according to centre, the Hazard Ratio 
(HR) with rivaroxaban versus warfarin was 0.74 (95% CI, 0.49 - 1.12). 
The incidence rates for the principal safety outcome (major and non-major clinically relevant bleeding 
events) were similar for both treatment groups (see Table 5). 
 



99 

Table 4: Efficacy results from phase III ROCKET AF 

Study population 
ITT analyses of efficacy in patients with non-valvular atrial 
fibrillation 

Treatment dose 

Rivaroxaban 
20 mg once daily  
(15 mg once daily in 
patients with moderate 
renal impairment) 
Event rate (100 pt-yr) 

Warfarin 
titrated to a target 
INR of 2.5 (therapeutic 
range 2.0 to 3.0) 
 
Event rate (100 pt-yr) 

HR (95% CI) 
p-value, test for 
superiority 

Stroke and non-CNS 
systemic embolism 

269 
(2.12) 

306 
(2.42) 

0.88 (0.74 - 1.03) 
0.117 

Stroke, non-CNS systemic 
embolism and vascular 
death 

572 
(4.51) 

609 
(4.81) 

0.94 (0.84 - 1.05) 
0.265 

Stroke, non-CNS systemic 
embolism, vascular death 
and myocardial infarction 

659 
(5.24) 

709 
(5.65) 

0.93 (0.83 - 1.03) 
0.158 

Stroke 
253  
(1.99) 

281 
(2.22) 

0.90 (0.76 - 1.07) 
0.221 

Non-CNS systemic 
embolism 

20  
(0.16) 

27 
(0.21) 

0.74 (0.42 - 1.32) 
0.308 

Myocardial infarction 
130 
 (1.02) 

142 
(1.11) 

0.91 (0.72 - 1.16)  
0.464 

 



100 

Table 5: Safety results from phase III ROCKET AF 
Study population Patients with non-valvular atrial fibrillationP

a) 

Treatment dose  

Rivaroxaban 
20 mg once daily  
(15 mg once daily in 
patients with moderate 
renal impairment) 
Event rate (100 pt-yr) 

Warfarin 
titrated to a target INR 
of 2.5 (therapeutic 
range 2.0 to 3.0) 
 
Event rate (100 pt-yr) 

HR (95% CI) 
p-value  

Major and non-major 
clinically relevant bleeding 
events 

1,475 
(14.91) 

1,449 
(14.52) 

1.03 (0.96 - 1.11) 
0.442 

Major bleeding events 
395 
(3.60) 

386 
(3.45) 

1.04 (0.90 - 1.20) 
0.576 

Death due to 

bleeding* 

27 
(0.24) 

55 
(0.48) 

0.50 (0.31 - 0.79) 
0.003 

Critical organ 

bleeding* 

91 
(0.82) 

133 
(1.18) 

0.69 (0.53 - 0.91) 
0.007 

Intracranial 

haemorrhage* 

55  
(0.49) 

84 
(0.74) 

0.67 (0.47 - 0.93) 
0.019 

Haemoglobin drop* 
305 
(2.77) 

254 
(2.26) 

1.22 (1.03 - 1.44) 
0.019 

Transfusion of 2 or 
more units of packed 
red blood cells or 
whole blood* 

183 
(1.65) 

149 
(1.32) 

1.25 (1.01 - 1.55) 
0.044 

Non-major clinically 
relevant bleeding events 

1,185 
(11.80) 

1,151 
(11.37) 

1.04 (0.96 - 1.13) 
0.345 

All-cause mortality 
208 
(1.87) 

250 
(2.21) 

0.85 (0.70 - 1.02) 
0.073 

a) Safety population, on treatment 
* Nominally significant 

 
In addition to the phase III ROCKET AF study, a prospective, single-arm, post-authorisation, non-
interventional, open-label cohort study (XANTUS) with central outcome adjudication including 
thromboembolic events and major bleeding has been conducted. 6,785 patients with non-valvular 
atrial fibrillation were enrolled for prevention of stroke and non-central nervous system (CNS) 
systemic embolism in clinical practice. The mean CHADSR2R and HAS-BLED scores were both 2.0 in 
XANTUS, compared to a mean CHADSR2R and HAS-BLED score of 3.5 and 2.8 in ROCKET AF, 
respectively. Major bleeding occurred in 2.1 per 100 patient years. Fatal haemorrhage was reported in 
0.2 per 100 patient years and intracranial haemorrhage in 0.4 per 100 patient years. Stroke or non-CNS 
systemic embolism was recorded in 0.8 per 100 patient years.  
These observations in clinical practice are consistent with the established safety profile in this 
indication. 
 
Patients undergoing cardioversion 
A prospective, randomised, open-label, multicentre, exploratory study with blinded endpoint 
evaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naive and pre-treated) with 
non-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted 
VKA (randomised 2:1), for the prevention of cardiovascular events. TEE- guided (1 - 5 days of pre-
treatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies were 
employed. The primary efficacy outcome (all stroke, transient ischaemic attack, non-CNS systemic 
embolism, myocardial infarction (MI) and cardiovascular death) occurred in 5 (0.5%) patients in the 
rivaroxaban group (n = 978) and 5 (1.0%) patients in the VKA group (n = 492; RR 0.50; 95% CI 0.15-
1.73; modified ITT population). The principal safety outcome (major bleeding) occurred in 6 (0.6%) 
and 4 (0.8%) patients in the rivaroxaban (n = 988) and VKA (n = 499) groups, respectively (RR 0.76; 



101 

95 % CI 0.21-2.67; safety population). This exploratory study showed comparable efficacy and safety 
between rivaroxaban and VKA treatment groups in the setting of cardioversion. 
 
Patients with non-valvular atrial fibrillation who undergo PCI with stent placement 
A randomised, open-label, multicentre study (PIONEER AF-PCI) was conducted in 2,124 patients 
with non-valvular atrial fibrillation who underwent PCI with stent placement for primary 
atherosclerotic disease to compare safety of two rivaroxaban regimens and one VKA regimen. Patients 
were randomly assigned in a 1:1:1 fashion for an overall 12-month-therapy. Patients with a history of 
stroke or TIA were excluded.  
Group 1 received rivaroxaban 15 mg once daily (10 mg once daily in patients with creatinine 
clearance 30 - 49 ml/min) plus P2Y12 inhibitor. Group 2 received rivaroxaban 2.5 mg twice daily plus 
DAPT (dual antiplatelet therapy i.e. clopidogrel 75 mg [or alternate P2Y12 inhibitor] plus low-dose 
acetylsalicylic acid [ASA]) for 1, 6 or 12 months followed by rivaroxaban 15 mg (or 10 mg for 
subjects with creatinine clearance 30 - 49 ml/min) once daily plus low-dose ASA. Group 3 received 
dose-adjusted VKA plus DAPT for 1, 6 or 12 months followed by dose-adjusted VKA plus low-dose 
ASA.  
The primary safety endpoint, clinically significant bleeding events, occurred in 109 (15.7%), 117 
(16.6%), and 167 (24.0%) subjects in group 1, group 2 and group 3, respectively (HR 0.59; 95% CI 
0.47-0.76; p<0.001, and HR 0.63; 95% CI 0.50-0.80; p<0.001, respectively). The secondary endpoint 
(composite of cardiovascular events CV death, MI, or stroke) occurred in 41 (5.9%), 36 (5.1%), and 
36 (5.2%) subjects in the group 1, group 2 and group 3, respectively. Each of the rivaroxaban 
regimens showed a significant reduction in clinically significant bleeding events compared to the 
VKA regimen in patients with non-valvular atrial fibrillation who underwent a PCI with stent 
placement. 
The primary objective of PIONEER AF-PCI was to assess safety. Data on efficacy (including 
thromboembolic events) in this population are limited. 
 
Treatment of DVT, PE and prevention of recurrent DVT and PE  
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban in the 
initial and continued treatment of acute DVT and PE and prevention of recurrence. 
Over 12,800 patients were studied in four randomised controlled phase III clinical studies (Einstein 
DVT, Einstein PE, Einstein Extension and Einstein Choice) and additionally a predefined pooled 
analysis of the Einstein DVT and Einstein PE studies was conducted. The overall combined treatment 
duration in all studies was up to 21 months. 
 
In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the 
prevention of recurrent DVT and PE (patients who presented with symptomatic PE were excluded 
from this study). The treatment duration was for 3, 6 or 12 months depending on the clinical 
judgement of the investigator. 
For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. This 
was followed by 20 mg rivaroxaban once daily.  
 
In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention of 
recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinical 
judgement of the investigator. 
For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks. 
This was followed by 20 mg rivaroxaban once daily. 
 
In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted of 
enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until 
the PT/INR was in therapeutic range ( 2.0). Treatment was continued with a vitamin K antagonist 
dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0. 
 
In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent 
DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who had 
completed 6 to 12 months of treatment for venous thromboembolism depending on the clinical 
judgment of the investigator. Rivaroxaban 20 mg once daily was compared with placebo.  



102 

Einstein DVT, PE and Extension used the same pre-defined primary and secondary efficacy outcomes. 
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent 
DVT or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of 
recurrent DVT, non-fatal PE and all-cause mortality.  
In Einstein Choice, 3,396 patients with confirmed symptomatic DVT and/or PE who completed 6-
12 months of anticoagulant treatment were studied for the prevention of fatal PE or non-fatal 
symptomatic recurrent DVT or PE. Patients with an indication for continued therapeutic-dosed 
anticoagulation were excluded from the study. The treatment duration was up to 12 months depending 
on the individual randomisation date (median: 351 days). Rivaroxaban 20 mg once daily and 
Rivaroxaban 10 mg once daily were compared with 100 mg acetylsalicylic acid once daily.  
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent 
DVT or fatal or non-fatal PE.  
 
In the Einstein DVT study (see Table 6) rivaroxaban was demonstrated to be non-inferior to 
enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); HR: 0.680 
(0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primary efficacy 
outcome plus major bleeding events) was reported with a HR of 0.67 ((95% CI: 0.47 - 0.95), nominal 
p value p=0.027) in favour of rivaroxaban. INR values were within the therapeutic range a mean of 
60.3% of the time for the mean treatment duration of 189 days, and 55.4%, 60.1%, and 62.8% of the 
time in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In the 
enoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in 
Target INR Range of 2.0 - 3.0) in the equally sized tertiles and the incidence of the recurrent VTE 
(P=0.932 for interaction). Within the highest tertile according to centre, the HR with rivaroxaban 
versus warfarin was 0.69 (95% CI: 0.35 - 1.35). 
 
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding 
events) as well as the secondary safety outcome (major bleeding events) were similar for both 
treatment groups. 
 
Table 6: Efficacy and safety results from phase III Einstein DVT 

Study population 
3,449 patients with symptomatic acute deep vein 
thrombosis 

Treatment dose and duration 
Rivaroxaban P

a) 

3, 6 or 12 months 
N=1,731 

Enoxaparin/VKAP

b) 
3, 6 or 12 months 
N=1,718 

Symptomatic recurrent VTE* 
36 
(2.1%) 

51 
(3.0%) 

Symptomatic recurrent PE 
20 
(1.2%) 

18 
(1.0%) 

Symptomatic recurrent 
DVT 

14 
(0.8%) 

28 
(1.6%) 

Symptomatic PE and DVT 
1 
(0.1%) 

0 

Fatal PE/death where PE 
cannot be ruled out 

4 
(0.2%) 

6 
(0.3%) 

Major or clinically relevant non-
major bleeding 

139 
(8.1%) 

138 
(8.1%) 

Major bleeding events 
14 
(0.8%) 

20 
(1.2%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 

* p < 0.0001 (non-inferiority to a prespecified HR of 2.0); HR: 0.680 (0.443 - 1.042), p=0.076 
(superiority) 

 



103 

In the Einstein PE study (see Table 7) rivaroxaban was demonstrated to be non-inferior to 
enoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority); HR: 1.123 
(0.749 - 1.684)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding 
events) was reported with a HR of 0.849 ((95% CI: 0.633 - 1.139), nominal p value p= 0.275). INR 
values were within the therapeutic range a mean of 63% of the time for the mean treatment duration of 
215 days, and 57%, 62%, and 65% of the time in the 3-, 6-, and 12-month intended treatment duration 
groups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level of 
mean centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized tertiles and the 
incidence of the recurrent VTE (p=0.082 for interaction). Within the highest tertile according to 
centre, the HR with rivaroxaban versus warfarin was 0.642 (95% CI: 0.277 - 1.484). 
 
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding 
events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the 
enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome 
(major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the 
enoxaparin/VKA group (2.2% (52/2405)) with a HR 0.493 (95% CI: 0.308 - 0.789). 
 
Table 7: Efficacy and safety results from phase III Einstein PE 
Study population 4,832 patients with an acute symptomatic PE 

Treatment dose and duration 
Rivaroxaban P

a) 
3, 6 or 12 months 
N=2,419 

Enoxaparin/VKA P

b) 
3, 6 or 12 months 
N=2,413 

Symptomatic recurrent VTE* 
50 
(2.1%) 

44 
(1.8%) 

Symptomatic recurrent PE 
23 
(1.0%) 

20 
(0.8%) 

Symptomatic recurrent 
DVT 

18 
(0.7%) 

17 
(0.7%) 

Symptomatic PE and DVT 0 
2 
(<0.1%) 

Fatal PE/death where PE 
cannot be ruled out 

11 
(0.5%) 

7 
(0.3%) 

Major or clinically relevant non-
major bleeding 

249 
(10.3%) 

274 
(11.4%) 

Major bleeding events 
26 
(1.1%) 

52 
(2.2%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 
* p < 0.0026 (non-inferiority to a prespecified HR of 2.0); HR: 1.123 (0.749 - 1.684)  

 
A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see 
Table 8). 
 



104 

Table 8: Efficacy and safety results from pooled analysis of phase III Einstein DVT and Einstein 
PE 
Study population 8,281 patients with an acute symptomatic DVT or PE 

Treatment dose and duration 
Rivaroxaban P

a) 

3, 6 or 12 months 
N=4,150 

Enoxaparin/VKAP

b) 
3, 6 or 12 months 
N=4,131 

Symptomatic recurrent VTE* 
86 
(2.1%) 

95 
(2.3%) 

Symptomatic recurrent PE 
43 
(1.0%) 

38 
(0.9%) 

Symptomatic recurrent 
DVT 

32 
(0.8%) 

45 
(1.1%) 

Symptomatic PE and DVT 
1 
(<0.1%) 

2 
(<0.1%) 

Fatal PE/death where PE 
cannot be ruled out 

15 
(0.4%) 

13 
(0.3%) 

Major or clinically relevant non-
major bleeding 

388 
(9.4%) 

412 
(10.0%) 

Major bleeding events 
40 
(1.0%) 

72 
(1.7%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 

* p < 0.0001 (non-inferiority to a prespecified HR of 1.75); HR: 0.886 (0.661 - 1.186) 
 
The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the 
pooled analysis was reported with a HR of 0.771 ((95% CI: 0.614 - 0.967), nominal p value 
p = 0.0244). 
 
In the Einstein Extension study (see Table 9) rivaroxaban was superior to placebo for the primary and 
secondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was a 
non-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once 
daily compared to placebo. The secondary safety outcome (major or clinically relevant non-major 
bleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared 
to placebo.  
 
Table 9: Efficacy and safety results from phase III Einstein Extension 

Study population 
1,197 patients continued treatment and prevention 
of recurrent venous thromboembolism 

Treatment dose and duration 
Rivaroxaban P

a)
P  

6 or 12 months 
N=602 

Placebo 
6 or 12 months 
N=594 

Symptomatic recurrent VTE* 
8 
(1.3%) 

42 
(7.1%) 

Symptomatic recurrent PE 
2 
(0.3%) 

13 
(2.2%) 

Symptomatic recurrent DVT 
5 
(0.8%) 

31 
(5.2%) 

Fatal PE/death where PE 
cannot be ruled out 

1 
(0.2%) 

1 
(0.2%) 

Major bleeding events 
4 
(0.7%) 

0 
(0.0%) 

Clinically relevant non-major 
bleeding 

32 
(5.4%) 

7 
(1.2%) 

a) Rivaroxaban 20 mg once daily 

* p < 0.0001 (superiority), HR: 0.185 (0.087 - 0.393) 
 



105 

In the Einstein Choice study (see Table 10) rivaroxaban 20 mg and 10 mg were both superior to 100 
mg acetylsalicylic acid for the primary efficacy outcome. The principal safety outcome (major 
bleeding events) was similar for patients treated with rivaroxaban 20 mg and 10 mg once daily 
compared to 100 mg acetylsalicylic acid.  
 
Table 10: Efficacy and safety results from phase III Einstein Choice 

Study population 
3,396 patients continued prevention of 
recurrent venous thromboembolism 

Treatment dose  
Rivaroxaban 20 mg 
once daily 
N=1,107 

Rivaroxaban 10 
mg once daily 
N=1,127 

ASA 100 mg once 
daily 
N=1,131 

Treatment duration median 
[interquartile range] 

349 [189-362] days 353 [190-362] days 350 [186-362] days 

Symptomatic recurrent VTE 
17 
(1.5%)* 

13 
(1.2%)** 

50 
(4.4%) 

Symptomatic recurrent 
PE 

6 
(0.5%) 

6 
(0.5%) 

19 
(1.7%) 

Symptomatic recurrent 
DVT 

9 
(0.8%) 

8 
(0.7%) 

30 
(2.7%) 

Fatal PE/death where PE 
cannot be ruled out 

2 
(0.2%) 

0 
(0.0%) 

2 
(0.2%) 

Symptomatic recurrent VTE, 
MI, stroke, or non-CNS 
systemic embolism 

19 
(1.7%) 

18 
(1.6%) 

56 
(5.0%) 

Major bleeding events 
6 
(0.5%) 

5 
(0.4%) 

3 
(0.3%) 

Clinically relevant non-major 
bleeding 

30  
(2.7) 

22  
(2.0) 

20  
(1.8) 

Symptomatic recurrent VTE 
or major bleeding (net 
clinical benefit) 

23  
(2.1%) P

+ 
17  
(1.5%) P

++ 
53  
(4.7%) 

*  p<0.001(superiority) rivaroxaban 20 mg od vs ASA 100 mg od; HR=0.34 (0.20-0.59) 
** p<0.001 (superiority) rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.26 (0.14-0.47) 
P

+  
PRivaroxaban 20 mg od vs ASA 100 mg od; HR=0.44 (0.27-0.71), p=0.0009 (nominal)  

P

++
P  Rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.32 (0.18-0.55), p<0.0001 (nominal) 

 
In addition to the phase III EINSTEIN programme, a prospective, non-interventional, open-label 
cohort study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and 
death has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-term 
safety of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice. 
Rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 
0.5%, respectively. There were differences in patient baseline characteristics including age, cancer and 
renal impairment. A pre-specified propensity score stratified analysis was used to adjust for measured 
baseline differences but residual confounding may, in spite of this, influence the results. Adjusted HRs 
comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-cause mortality 
were 0.77 (95% CI 0.40 - 1.50), 0.91 (95% CI 0.54 - 1.54) and 0.51 (95% CI 0.24 - 1.07), respectively.  
These results in clinical practice are consistent with the established safety profile in this indication. 
 
Paediatric population 
Treatment of VTE and prevention of VTE recurrence in paediatric patients  
A total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in 
6 open-label, multicentre paediatric studies. Body weight-adjusted dosing in patients from birth to less 
than 18 years resulted in rivaroxaban exposure similar to that observed in adult DVT patients treated 
with rivaroxaban 20 mg once daily as confirmed in the phase III study (see section 5.2).  
 
The EINSTEIN Junior phase III study was a randomised, active-controlled, open-label multicentre 
clinical study in 500 paediatric patients (aged from birth to < 18 years) with confirmed acute VTE. 



106 

There were 276 children aged 12 to < 18 years, 101 children aged 6 to < 12 years, 69 children aged 2 
to < 6 years, and 54 children aged < 2 years.  
 
Index VTE was classified as either central venous catheter-related VTE (CVC-VTE; 90/335 patients 
in the rivaroxaban group, 37/165 patients in the comparator group), cerebral vein and sinus thrombosis 
(CVST; 74/335 patients in the rivaroxaban group, 43/165 patients in the comparator group), and all 
others including DVT and PE (non-CVC-VTE; 171/335 patients in the rivaroxaban group, 
84/165 patients in the comparator group). The most common presentation of index thrombosis in 
children aged 12 to < 18 years was non-CVC-VTE in 211 (76.4%); in children aged 6 to < 12 years 
and aged 2 to < 6 years was CVST in 48 (47.5%) and 35 (50.7%), respectively; and in children aged 
< 2 years was CVC-VTE in 37 (68.5%). There were no children < 6 months with CVST in the 
rivaroxaban group. 22 of the patients with CVST had a CNS infection (13 patients in the rivaroxaban 
group and 9 patients in comparator group). 
 
VTE was provoked by persistent, transient, or both persistent and transient risk factors in 438 (87.6%) 
children.  
 
Patients received initial treatment with therapeutic doses of UFH, LMWH, or fondaparinux for at least 
5 days, and were randomised 2:1 to receive either body weight-adjusted doses of rivaroxaban or 
comparator group (heparins, VKA) for a main study treatment period of 3 months (1 month for 
children < 2 years with CVC-VTE). At the end of the main study treatment period, the diagnostic 
imaging test, which was obtained at baseline, was repeated, if clinically feasible. The study treatment 
could be stopped at this point, or at the discretion of the Investigator continued for up to 12 months 
(for children <2 years with CVC-VTE up to 3 months) in total. 
 
The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was the 
composite of major bleeding and clinically relevant non-major bleeding (CRNMB). All efficacy and 
safety outcomes were centrally adjudicated by an independent committee blinded for treatment 
allocation. The efficacy and safety results are shown in Tables 11 and 12 below. 
 
Recurrent VTEs occurred in the rivaroxaban group in 4 of 335 patients and in the comparator group in 
5 of 165 patients. The composite of major bleeding and CRNMB was reported in 10 of 329 patients 
(3%) treated with rivaroxaban and in 3 of 162 patients (1.9%) treated with comparator. Net clinical 
benefit (symptomatic recurrent VTE plus major bleeding events) was reported in the rivaroxaban 
group in 4 of 335 patients and in the comparator group in 7 of 165 patients. Normalisation of the 
thrombus burden on repeat imaging occurred in 128 of 335 patients with rivaroxaban treatment and in 
43 of 165 patients in the comparator group. These findings were generally similar among age groups. 
There were 119 (36.2%) children with any treatment-emergent bleeding in the rivaroxaban group and 
45 (27.8%) children in the comparator group. 
 
 



107 

Table 11: Efficacy results at the end of the main treatment period  
Event Rivaroxaban  

N=335* 
Comparator 
N=165* 

Recurrent VTE (primary efficacy outcome) 4 
(1.2%, 95% CI 
0.4% – 3.0%) 

5 
(3.0%, 95% CI 
1.2% - 6.6%) 

Composite: Symptomatic recurrent VTE + 
asymptomatic deterioration on repeat imaging 

5 
(1.5%, 95% CI 
0.6% – 3.4%) 

6 
(3.6%, 95% CI 
1.6% – 7.6%) 

Composite: Symptomatic recurrent VTE + 
asymptomatic deterioration + no change on repeat 
imaging 

21 
(6.3%, 95% CI 
4.0% – 9.2%) 

19 
(11.5%, 95% CI 
7.3% – 17.4%) 

Normalisation on repeat imaging  128 
(38.2%, 95% CI 
33.0% - 43.5%) 

43 
(26.1%, 95% CI 
19.8% - 33.0%) 

Composite: Symptomatic recurrent VTE + major 
bleeding (net clinical benefit) 

4 
(1.2%, 95% CI 
0.4% - 3.0%) 

7 
(4.2%, 95% CI 
2.0% - 8.4%) 

Fatal or non-fatal pulmonary embolism 1 
(0.3%, 95% CI 
0.0% – 1.6%) 

1 
(0.6%, 95% CI 
0.0% – 3.1%) 

* FAS= full analysis set, all children who were randomised 

 
Table 12: Safety results at the end of the main treatment period  

 Rivaroxaban  
N=329* 

Comparator 
N=162* 

Composite: Major bleeding + CRNMB (primary safety 
outcome) 

10 
(3.0%, 95% CI 
1.6% - 5.5%) 

3 
(1.9%, 95% CI 
0.5% - 5.3%) 

Major bleeding 0 
(0.0%, 95% CI 
0.0% - 1.1%) 

2 
(1.2%, 95% CI 
0.2% - 4.3%) 

Any treatment-emergent bleedings 119 (36.2%) 45 (27.8%) 
* SAF = safety analysis set, all children who were randomised and received at least 1 dose of study 
medicinal product 

 
The efficacy and safety profile of rivaroxaban was largely similar between the paediatric VTE 
population and the DVT/PE adult population, however, the proportion of subjects with any bleeding 
was higher in the paediatric VTE population as compared to the DVT/PE adult population. 
 
Patients with high risk triple positive antiphospholipid syndrome 
In an investigator sponsored, randomised open-label multicentre study with blinded endpoint 
adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, 
diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for 
all 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and 
anti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of 
120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 
569 days. 59 patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinine 
clearance (CrCl) < 50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 
12% of patients randomised to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No 
events were reported in patients randomised to warfarin. Major bleeding occurred in 4 patients (7%) 
of the rivaroxaban group and 2 patients (3%) of the warfarin group. 



108 

 
Paediatric population 
The European Medicines Agency has waived the obligation to submit the results of studies with 
Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
The following information is based on the data obtained in adults.  
Rivaroxaban is rapidly absorbed with maximum concentrations (CRmaxR) appearing 2 - 4 hours after 
tablet intake.  
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect 
rivaroxaban AUC or CRmaxR at the 2.5 mg and 10 mg dose.  
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg 
tablet under fasting conditions. When rivaroxaban 20 mg tablets are taken together with food increases 
in mean AUC by 39% were observed when compared to tablet intake under fasting conditions, 
indicating almost complete absorption and high oral bioavailability. Rivaroxaban 15 mg and 20 mg are 
to be taken with food (see section 4.2). 
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state. 
Under fed conditions rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. 
At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and 
decreased absorption rate with increased dose.  
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) 
ranging from 30% to 40%. 
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% 
and 56% decrease in AUC and CRmaxR compared to tablet was reported when rivaroxaban granulate is 
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in 
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the 
stomach should be avoided since this can result in reduced absorption and related rivaroxaban 
exposure. 
Bioavailability (AUC and CRmaxR) was comparable for 20 mg rivaroxaban administered orally as a 
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube 
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional 
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable 
to lower rivaroxaban doses. 
 
Paediatric population 
Children received rivaroxaban tablet or oral suspension during or closely after feeding or food intake 
and with a typical serving of liquid to ensure reliable dosing in children. As in adults, rivaroxaban is 
readily absorbed after oral administration as tablet or granules for oral suspension formulation in 
children. No difference in the absorption rate nor in the extent of absorption between the tablet and 
granules for oral suspension formulation was observed. No PK data following intravenous 
administration to children are available so that the absolute bioavailability of rivaroxaban in children is 
unknown. A decrease in the relative bioavailability for increasing doses (in mg/kg bodyweight) was 
found, suggesting absorption limitations for higher doses, even when taken together with food. 
Rivaroxaban 20 mg tablets should be taken with feeding or with food (see section 4.2).  
 
Distribution 
Plasma protein binding in adults is high at approximately 92% to 95%, with serum albumin being the 
main binding component. The volume of distribution is moderate with VRssR being approximately 
50 litres. 
 



109 

Paediatric population 
No data on rivaroxaban plasma protein binding specific to children is available. No PK data following 
intravenous administration of rivaroxaban to children is available. VRssR estimated via population PK 
modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is 
dependent on body weight and can be described with an allometric function, with an average of 113 L 
for a subject with a body weight of 82.8 kg. 
 
Biotransformation and elimination  
In adults, of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, 
with half then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 
of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, 
mainly via active renal secretion. 
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative 
degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of 
biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter 
proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein). 
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active 
circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be 
classified as a low-clearance substance. After intravenous administration of a 1 mg dose the 
elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption 
rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in 
young individuals, and with terminal half-lives of 11 to 13 hours in the elderly. 
 
Paediatric population 
No metabolism data specific to children is available. No PK data following intravenous administration 
of rivaroxaban to children is available. CL estimated via population PK modelling in children (age 
range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and 
can be described with an allometric function, with an average of 8 L/h for a subject with body weight 
of 82.8 kg. The geometric mean values for disposition half-lives (tR1/2R) estimated via population PK 
modelling decrease with decreasing age and ranged from 4.2 h in adolescents to approximately 3 h in 
children aged 2-12 years down to 1.9 and 1.6 h in children aged 0.5-< 2 years and less than 0.5 years, 
respectively. 
 
Special populations 
Gender 
In adults, there were no clinically relevant differences in pharmacokinetics and pharmacodynamics 
between male and female patients. An exploratory analysis did not reveal relevant differences in 
rivaroxaban exposure between male and female children. 
 
Elderly population 
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values 
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No 
dose adjustment is necessary. 
 
Different weight categories 
In adults, extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban 
plasma concentrations (less than 25%). No dose adjustment is necessary.  
In children, rivaroxaban is dosed based on body weight. An exploratory analysis did not reveal a 
relevant impact of underweight or obesity on rivaroxaban exposure in children. 
 
Inter-ethnic differences 
In adults, no clinically relevant inter-ethnic differences among Caucasian, African-American, 
Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and 
pharmacodynamics.  
An exploratory analysis did not reveal relevant inter-ethnic differences in rivaroxaban exposure among 
Japanese, Chinese or Asian children outside Japan and China compared to the respective overall 
paediatric population. 



110 

 
Hepatic impairment 
Cirrhotic adult patients with mild hepatic impairment (classified as Child Pugh A) exhibited only 
minor changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), 
nearly comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic 
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also 
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. 
There are no data in patients with severe hepatic impairment. 
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic 
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor 
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a 
steeper PK/PD relationship between concentration and PT.  
Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and 
clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see 
section 4.3). 
No clinical data is available in children with hepatic impairment. 
 
Renal impairment 
In adults, there was an increase in rivaroxaban exposure correlated to decrease in renal function, as 
assessed via creatinine clearance measurements. In individuals with mild (creatinine clearance 
50 - 80 ml/min), moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 
15 - 29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 
and 1.6 fold respectively. Corresponding increases in pharmacodynamic effects were more 
pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of 
factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy 
volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. 
There are no data in patients with creatinine clearance < 15 ml/min. 
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. 
Use is not recommended in patients with creatinine clearance < 15 ml/min. Rivaroxaban is to be used 
with caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4). 
No clinical data is available in children 1 year or older with moderate or severe renal impairment 
(glomerular filtration rate < 50 mL/min/1.73 mP

2
P). 

 
Pharmacokinetic data in patients 
In patients receiving rivaroxaban for treatment of acute DVT 20 mg once daily the geometric mean 
concentration (90% prediction interval) 2 - 4 h and about 24 h after dose (roughly representing 
maximum and minimum concentrations during the dose interval) was 215 (22 - 535) and 
32 (6 - 239) mcg/l, respectively. 
 
In paediatric patients with acute VTE receiving body weight-adjusted rivaroxaban leading to an 
exposure similar to that in adult DVT patients receiving a 20 mg once daily dose, the geometric mean 
concentrations (90% interval) at sampling time intervals roughly representing maximum and minimum 
concentrations during the dose interval are summarised in Table 13.  
 



111 

Table 13: Summary statistics (geometric mean (90% interval)) of rivaroxaban steady state 
plasma concentrations (mcg/L) by dosing regimen and age 

Time 
intervals 

        

o.d. N 12 -
< 18 years 

N 6 -< 12 years     

2.5-4h post 171 241.5  
(105-484) 

24 229.7  
(91.5-777) 

    

20-24h post 151 20.6 
(5.69-66.5) 

24 15.9  
(3.42-45.5)  

    

b.i.d. N 6 -< 12 years N 2 -< 6 years N  0.5 -< 2 years   
2.5-4h post 36 145.4  

(46.0-343) 
38 171.8  

(70.7-438) 
2 n.c.   

10-16h post 33 26.0  
(7.99-94.9) 

37 22.2  
(0.25-127) 

3 10.7  
(n.c.-n.c.) 

  

t.i.d. N 2 -< 6 years N Birth -
< 2 years 

N 0.5 -< 2 years N Birth -
< 0.5 years 

0.5-3h post 5 164.7  
(108-283) 

25 111.2  
(22.9-320) 

13 114.3  
(22.9-346) 

12 108.0  
(19.2-320) 

7-8h post 3 33.2  
(18.7-99.7) 

23 18.7  
(10.1-36.5) 

12 21.4  
(10.5-65.6) 

11 16.1  
(1.03-33.6) 

o.d. = once daily, b.i.d. = twice daily, t.i.d. three times daily, n.c. = not calculated 
Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculation of 
statistics (LLOQ = 0.5 mcg/L). 

 
Pharmacokinetic/pharmacodynamic relationship 
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma 
concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated 
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between 
rivaroxaban concentration and factor Xa activity was best described by an ERmaxR model. For PT, the 
linear intercept model generally described the data better. Depending on the different PT reagents 
used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and 
the slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses in Phase II and III were 
consistent with the data established in healthy subjects.  
 
Paediatric population 
Safety and efficacy have not been established in the indication prevention of stroke and systemic 
embolism in patients with non-valvular atrial fibrillation for children and adolescents up to 18 years.  
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile 
toxicity. 
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic 
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant 
exposure levels. 
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive 
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic 
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, 
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as 
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams. 
 
Rivaroxaban was tested in juvenile rats up to 3-month treatment duration starting at postnatal day 4 
showing a non dose-related increase in periinsular haemorrhage. No evidence of target organ-specific 
toxicity was seen.  



112 

 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Microcrystalline cellulose 
Croscarmellose sodium 
Lactose monohydrate 
Hypromellose (2910) 
Sodium laurilsulfate 
Magnesium stearate 
 
Film-coat 
Macrogol (3350) 
Hypromellose (2910) 
Titanium dioxide (E 171) 
Iron oxide red (E 172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
Crushed tablets 
Crushed rivaroxaban tablets are stable in water and in apple puree for up to 4 hours. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Cartons containing 10, 14, 28 or 98 film-coated tablets in PP/Alu foil blisters.  
Cartons containing 10 x 1 or 100 x 1 film-coated tablets in PP/Alu foil perforated unit dose blisters.  
Multipacks containing 10 packs of 10 x 1 (100 film-coated tablets) in PP/Alu foil perforated unit dose 
blisters.  
Cartons containing 14 film-coated tablets in PVC/PVDC/Alu foil blisters . 
HDPE bottles with a PP screw cap containing 100 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Crushing of tablets 
Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via a 
nasogastric tube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, the 
tube should be flushed with water. Since rivaroxaban absorption is dependent on the site of active 
substance release, administration of rivaroxaban distal to the stomach should be avoided, as this can 
result in reduced absorption and thereby, reduced active substance exposure. After the administration 



113 

of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should then be immediately followed by 
enteral feeding. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/017-021, EU/1/08/472/024, EU/1/08/472/037, EU/1/08/472/039, EU/1/08/472/049. 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 30 September 2008 
Date of latest renewal: 22 May 2018 
 
 
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. 
 



114 

Treatment Initiation Pack 
 

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 
 
Xarelto 15 mg film-coated tablets 
Xarelto 20 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each 15 mg film-coated tablet contains 15 mg rivaroxaban.  
Each 20 mg film-coated tablet contains 20 mg rivaroxaban.  
 
Excipient with known effect 
Each 15 mg film-coated tablet contains 24.13 mg lactose (as monohydrate), see section 4.4. 
Each 20 mg film-coated tablet contains 21.76 mg lactose (as monohydrate), see section 4.4. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet)  
 
15 mg film-coated tablet: red, round biconvex tablets (6 mm diameter, 9 mm radius of curvature) 
marked with the BAYER-cross on one side and “15” and a triangle on the other side.  
20 mg film-coated tablet: brown-red, round biconvex tablets (6 mm diameter, 9 mm radius of 
curvature) marked with the BAYER-cross on one side and “20” and a triangle on the other side. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent 
DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.) 
 
4.2 Posology and method of administration 
 
Posology 
Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE 
The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first 
three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent 
DVT and PE.  
 
Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE 
provoked by major transient risk factors (i.e. recent major surgery or trauma). Longer duration of 
therapy should be considered in patients with provoked DVT or PE not related to major transient risk 
factors, unprovoked DVT or PE, or a history of recurrent DVT or PE.   
 
When extended prevention of recurrent DVT and PE is indicated (following completion of at least 
6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom 



115 

the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or 
who have developed recurrent DVT or PE on extended prevention with Xarelto 10 mg once daily, a 
dose of Xarelto 20 mg once daily should be considered. 
 
The duration of therapy and dose selection should be individualised after careful assessment of the 
treatment benefit against the risk for bleeding (see section 4.4).  
 

 Time period Dosing schedule Total daily dose 

Treatment and 
prevention of recurrent 
DVT and PE 

Day 1 - 21 15 mg twice daily  30 mg 

Day 22 onwards 20 mg once daily  20 mg 

Prevention of recurrent 
DVT and PE  

Following completion 
of at least 6 months 
therapy for DVT or PE 

10 mg once daily or  
20 mg once daily  

10 mg  
or 20 mg 

 
The 4-week treatment initiation pack of Xarelto is dedicated to patients who will transition from 
15 mg twice daily to 20 mg once daily from Day 22 onwards (see section 6.5). 
For patients with moderate or severe renal impairment where the decision has been taken for 15 mg 
once daily from Day 22 onwards, other pack sizes only containing 15 mg film-coated tablets are 
available (see dosing instructions in section “Special populations” below). 
 
If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take 
Xarelto immediately to ensure intake of 30 mg Xarelto per day. In this case two 15 mg tablets may be 
taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended 
on the following day.  
 
If a dose is missed during the once daily treatment phase, the patient should take Xarelto immediately, 
and continue on the following day with the once daily intake as recommended. The dose should not be 
doubled within the same day to make up for a missed dose.  
 
Converting from Vitamin K Antagonists (VKA) to Xarelto 
For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be stopped and 
Xarelto therapy should be initiated once the International Normalised Ratio (INR) is ≤ 2.5.  
When converting patients from VKAs to Xarelto, INR values will be falsely elevated after the intake 
of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and therefore should 
not be used (see section 4.5). 
 
Converting from Xarelto to Vitamin K antagonists (VKA) 
There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. 
Continuous adequate anticoagulation should be ensured during any transition to an alternate 
anticoagulant. It should be noted that Xarelto can contribute to an elevated INR.  
In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is ≥ 2.0. 
For the first two days of the conversion period, standard initial dosing of VKA should be used 
followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the 
INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of 
Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last 
dose (see sections 4.5 and 5.2). 
 
Converting from parenteral anticoagulants to Xarelto 
For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant 
and start Xarelto 0 to 2 hours before the time that the next scheduled administration of the parenteral 
medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation 
of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin). 
 
Converting from Xarelto to parenteral anticoagulants 
Give the first dose of parenteral anticoagulant at the time the next Xarelto dose would be taken.  



116 

 
Special populations 
Renal impairment 
Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) 
indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be 
used with caution in these patients. Use is not recommended in patients with creatinine clearance 
< 15 ml/min (see sections 4.4 and 5.2). 
 
In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 
15 - 29 ml/min) renal impairment the following dose recommendations apply: 
 
- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE, patients 

should be treated with 15 mg twice daily for the first 3 weeks.  
Thereafter, when the recommended dose is 20 mg once daily, a reduction of the dose from 
20 mg once daily to 15 mg once daily should be considered if the patient’s assessed risk for 
bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 
15 mg is based on PK modelling and has not been studied in this clinical setting (see 
sections 4.4, 5.1 and 5.2).  
When the recommended dose is 10 mg once daily, no dose adjustment from the recommended 
dose is necessary. 
 

No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 
50 - 80 ml/min) (see section 5.2).  
 
Hepatic impairment 
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically 
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2). 
 
Elderly population  
No dose adjustment (see section 5.2) 
 
Body weight 
No dose adjustment (see section 5.2) 
 
Gender 
No dose adjustment (see section 5.2) 
 
Paediatric population 
Xarelto treatment initiation pack should not be used in children aged 0 to 18 years because it is 
specifically designed for treatment of adult patients and is not appropriate for use in paediatric 
patients.  
 
Method of administration  
Xarelto is for oral use.  
The tablets are to be taken with food (see section 5.2). 
 
Crushing of tablets 
For patients who are unable to swallow whole tablets, Xarelto tablet may be crushed and mixed with 
water or apple puree immediately prior to use and administered orally. After the administration of 
crushed Xarelto 15 mg or 20 mg film-coated tablets, the dose should be immediately followed by 
food. 
The crushed tablet may also be given through gastric tubes (see sections 5.2 and 6.6). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 



117 

Active clinically significant bleeding. 
 
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. 
 
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low 
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral 
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of 
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain 
an open central venous or arterial catheter (see section 4.5). 
 
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic 
patients with Child Pugh B and C (see section 5.2). 
 
Pregnancy and breast-feeding (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment 
period. 
 
Haemorrhagic risk 
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding. 
It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto 
administration should be discontinued if severe haemorrhage occurs (see section 4.9). 
 
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary 
including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently 
during long term rivaroxaban 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 and quantify the clinical relevance of overt 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. 
 
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban 
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional 
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. 
overdose and emergency surgery (see sections 5.1 and 5.2). 
 
Renal impairment 
In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels 
may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. 
Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not 
recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2). 
Xarelto should be used with caution in patients with renal impairment concomitantly receiving other 
medicinal products which increase rivaroxaban plasma concentrations (see section 4.5). 
 
Interaction with other medicinal products 
The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with 
azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV 
protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and 



118 

P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree 
(2.6 fold on average) which may lead to an increased bleeding risk (see section 4.5). 
 
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis 
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and 
platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotonin 
norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease 
an appropriate prophylactic treatment may be considered (see section 4.5).  
 
Other haemorrhagic risk factors 
As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding 
risk such as: 
 congenital or acquired bleeding disorders 
 uncontrolled severe arterial hypertension 
 other gastrointestinal disease without active ulceration that can potentially lead to bleeding 

complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal 
reflux disease) 

 vascular retinopathy 
 bronchiectasis or history of pulmonary bleeding 
 
Patients with prosthetic valves 
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone 
transcatheter aortic valve replacement (TAVR). Safety and efficacy of Xarelto have not been studied 
in patients with prosthetic heart valves; therefore, there are no data to support that Xarelto provides 
adequate anticoagulation in this patient population. Treatment with Xarelto is not recommended for 
these patients. 
 
Patients with antiphospholipid syndrome 
Direct acting Oral Anticoagulants (DOACs) including rivaroxaban 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. 
 
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary 
embolectomy 
Xarelto is not recommended as an alternative to unfractionated heparin in patients with pulmonary 
embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary 
embolectomy since the safety and efficacy of Xarelto have not been established in these clinical 
situations.  
 
Spinal/epidural anaesthesia or puncture 
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, 
patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk 
of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. 
The risk of these events may be increased by the post-operative use of indwelling epidural catheters or 
the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by 
traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and 
symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder 
dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior 
to neuraxial intervention the physician should consider the potential benefit versus the risk in 
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical 
experience with the use of 15 mg or 20 mg rivaroxaban in these situations. 
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and 
neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of 
rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when 



119 

the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a 
sufficiently low anticoagulant effect in each patient is not known. 
For the removal of an epidural catheter and based on the general PK characteristics at least 2x half-
life, i.e. at least 18 hours in young patients and 26 hours in elderly patients should elapse after the last 
administration of rivaroxaban (see section 5.2). Following removal of the catheter, at least 6 hours 
should elapse before the next rivaroxaban dose is administered. 
If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours. 
 
Dosing recommendations before and after invasive procedures and surgical intervention  
If an invasive procedure or surgical intervention is required, Xarelto 15 mg/ Xarelto 20 mg should be 
stopped at least 24 hours before the intervention, if possible and based on the clinical judgement of the 
physician.  
If the procedure cannot be delayed the increased risk of bleeding should be assessed against the 
urgency of the intervention. 
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention 
provided the clinical situation allows and adequate haemostasis has been established as determined by 
the treating physician (see section 5.2). 
 
Elderly population 
Increasing age may increase haemorrhagic risk (see section 5.2). 
 
Dermatological reactions 
Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS 
syndrome, have been reported during post-marketing surveillance in association with the use of 
rivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in the 
course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of 
treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. 
spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal 
lesions. 
 
Information about excipients 
Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose-galactose malabsorption should not take this medicinal product. 
This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say 
essentially “sodium-free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
CYP3A4 and P-gp inhibitors 
Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a 
day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in 
mean rivaroxaban CRmaxR, with significant increases in pharmacodynamic effects which may lead to an 
increased bleeding risk. Therefore, the use of Xarelto is not recommended in patients receiving 
concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, 
voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong 
inhibitors of both CYP3A4 and P-gp (see section 4.4).  
 
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either 
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. 
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and 
moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in 
CRmaxR. The interaction with clarithromycin is likely not clinically relevant in most patients but can be 
potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). 
 
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 
1.3 fold increase in mean rivaroxaban AUC and CRmaxR. The interaction with erythromycin is likely not 
clinically relevant in most patients but can be potentially significant in high-risk patients. 



120 

In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. The effect of erythromycin is additive to that of renal impairment (see 
section 4.4). 
 
Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold 
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean CRmaxR. The interaction with 
fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-
risk patients. (For patients with renal impairment: see section 4.4). 
 
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should 
be avoided. 
 
Anticoagulants 
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single 
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on 
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban. 
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any 
other anticoagulants (see sections 4.3 and 4.4).  
 
NSAIDs/platelet aggregation inhibitors 
No clinically relevant prolongation of bleeding time was observed after concomitant administration of 
rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more 
pronounced pharmacodynamic response.  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with 500 mg acetylsalicylic acid. 
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a 
pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was 
observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or 
GPIIb/IIIa receptor levels. 
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) 
and platelet aggregation inhibitors because these medicinal products typically increase the bleeding 
risk (see section 4.4). 
 
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. When 
concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-
major clinically relevant bleeding were observed in all treatment groups. 
 
Warfarin 
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or 
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) 
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, 
inhibition of factor Xa activity and endogenous thrombin potential were additive.  
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the 
fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity 
and ETP) reflected only the effect of rivaroxaban.  
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR 
measurement can be used at the CRtroughR of rivaroxaban (24 hours after the previous intake of 
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point. 
No pharmacokinetic interaction was observed between warfarin and rivaroxaban. 
 



121 

CYP3A4 inducers  
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 
50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The 
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, 
phenobarbital or St. John’s Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban 
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be 
avoided unless the patient is closely observed for signs and symptoms of thrombosis. 
 
Other concomitant therapies  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), 
atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban 
neither inhibits nor induces any major CYP isoforms like CYP3A4. 
 
Laboratory parameters 
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of 
rivaroxaban (see section 5.1).  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
Safety and efficacy of Xarelto 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 rivaroxaban passes the placenta, Xarelto is contraindicated 
during pregnancy (see section 4.3).  
Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban. 
 
Breast-feeding 
Safety and efficacy of Xarelto have not been established in breast-feeding women. Data from animals 
indicate that rivaroxaban is secreted into milk. Therefore Xarelto 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 rivaroxaban in humans 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 
 
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope 
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). 
Patients experiencing these adverse reactions should not drive or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety of rivaroxaban has been evaluated in thirteen phase III studies in adults including 
53,103 patients exposed to rivaroxaban and in two phase II and one phase III paediatric studies 
including 412 patients. See phase III studies as listed in Table 1. 
 



122 

Table 1: Number of patients studied, total daily dose and maximum treatment duration in adult 
and paediatric phase III studies 

Indication Number of 
patients* 

Total daily dose Maximum 
treatment duration 

Prevention of venous thromboembolism 
(VTE) in adult patients undergoing 
elective hip or knee replacement surgery 

6,097 10 mg 39 days 

Prevention of VTE in medically ill 
patients 

3,997 10 mg 39 days 

Treatment of DVT, PE and prevention 
of recurrence 

6,790 Day 1 - 21: 30 mg 
Day 22 and onwards: 
20 mg 
After at least 6 
months: 10 mg or 
20 mg 

21 months 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

329 Body weight-adjusted 
dose to achieve a 
similar exposure as 
that observed in adults 
treated for DVT with 
20 mg rivaroxaban 
once daily 

12 months 

Prevention of stroke and systemic 
embolism in patients with non-valvular 
atrial fibrillation 

7,750 20 mg 41 months 

Prevention of atherothrombotic events 
in patients after an acute coronary 
syndrome (ACS) 

10,225 5 mg or 10 mg 
respectively, co-
administered with 
either ASA or ASA 
plus clopidogrel or 
ticlopidine 

31 months 

Prevention of atherothrombotic events 
in patients with CAD/PAD 

18,244 5 mg co-administered 
with ASA or 10 mg 
alone 

47 months 

* Patients exposed to at least one dose of rivaroxaban 
 
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see 
section 4.4. and ‘Description of selected adverse reactions’ below) (Table 2). The most commonly 
reported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %). 
 



123 

Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the 
completed adult and paediatric phase III studies 
Indication Any bleeding Anaemia 
Prevention of VTE in adult patients 
undergoing elective hip or knee 
replacement surgery 

6.8% of patients 5.9% of patients 

Prevention of VTE in medically ill 
patients 

12.6% of patients 2.1% of patients 

Treatment of DVT, PE and prevention 
of recurrence 

23% of patients 1.6% of patients 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

39.5% of patients 4.6% of patients 

Prevention of stroke and systemic 
embolism in patients with non-
valvular atrial fibrillation 

28 per 100 patient 
years 

2.5 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients after an ACS 

22 per 100 patient 
years 

1.4 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients with CAD/PAD 

6.7 per 100 patient 
years 

0.15 per 100 patient 
years**  

* For all rivaroxaban studies all bleeding events are collected, reported and 
adjudicated.   

**  In the COMPASS study, there is a low anaemia incidence as a selective 
approach to adverse event collection was applied 

 
Tabulated list of adverse reactions 
The frequencies of adverse reactions reported with Xarelto in adult and paediatric patients are 
summarised in Table 3 below by system organ class (in MedDRA) and by frequency.  
 
Frequencies are defined as: 
very common (≥ 1/10) 
common (≥ 1/100 to < 1/10)  
uncommon (≥ 1/1,000 to < 1/100)  
rare (≥ 1/10,000 to < 1/1,000)  
very rare (< 1/10,000) 
not known (cannot be estimated from the available data) 
  



124 

Table 3: All adverse reactions reported in adult patients in phase III clinical studies or through 
post-marketing use* and in two phase II and one phase III studies in paediatric patients 
Common Uncommon Rare Very rare Not known 
Blood and lymphatic system disorders 
Anaemia (incl. 
respective 
laboratory 
parameters) 

Thrombocytosis 
(incl. platelet count 
increased)P

A
P, 

thrombocytopenia 

   

Immune system disorders 
 Allergic reaction, 

dermatitis allergic, 
angioedema and 
allergic oedema 

 Anaphylactic 
reactions including 
anaphylactic shock  

 

Nervous system disorders 
Dizziness, 
headache 

Cerebral and 
intracranial 
haemorrhage, 
syncope 

   

Eye disorders 
Eye haemorrhage 
(incl. conjunctival 
haemorrhage) 

    

Cardiac disorders 
 Tachycardia    
Vascular disorders 
Hypotension, 
haematoma 

    

Respiratory, thoracic and mediastinal disorders 
Epistaxis, 
haemoptysis 

    

Gastrointestinal disorders 
Gingival bleeding, 
gastrointestinal 
tract haemorrhage 
(incl. rectal 
haemorrhage), 
gastrointestinal and 
abdominal pains, 
dyspepsia, nausea, 
constipationP

A
P, 

diarrhoea, 
vomitingP

A 

Dry mouth    

Hepatobiliary disorders 
Increase in 
transaminases 

Hepatic 
impairment, 
increased bilirubin, 
increased blood 
alkaline 
phosphatase P

A
P, 

increased GGTP

A 

Jaundice, bilirubin 
conjugated 
increased (with or 
without 
concomitant 
increase of ALT), 
cholestasis, 
hepatitis (incl. 
hepatocellular 
injury) 

  



125 

Common Uncommon Rare Very rare Not known 
Skin and subcutaneous tissue disorders 
Pruritus (incl. 
uncommon cases of 
generalised 
pruritus), rash, 
ecchymosis, 
cutaneous and 
subcutaneous 
haemorrhage 

Urticaria  Stevens-Johnson 
syndrome/Toxic 
Epidermal 
Necrolysis, DRESS 
syndrome  

 

Musculoskeletal and connective tissue disorders 
Pain in extremity P

A Haemarthrosis Muscle 
haemorrhage 

 Compartment 
syndrome 
secondary to a 
bleeding 

Renal and urinary disorders 
Urogenital tract 
haemorrhage (incl. 
haematuria and 
menorrhagiaP

B
P), 

renal impairment 
(incl. blood 
creatinine 
increased, blood 
urea increased) 

   Renal failure/acute 
renal failure 
secondary to a 
bleeding sufficient 
to cause 
hypoperfusion 

General disorders and administration site conditions 
Fever P

A
P, peripheral 

oedema, decreased 
general strength 
and energy (incl. 
fatigue and 
asthenia) 

Feeling unwell 
(incl. malaise)  

Localised oedemaP

A   

Investigations 
 Increased LDHP

A
P, 

increased lipaseP

A
P, 

increased amylaseP

A 

   

Injury, poisoning and procedural complications 
Postprocedural 
haemorrhage (incl. 
postoperative 
anaemia, and 
wound 
haemorrhage), 
contusion, wound 
secretion P

A 

 Vascular 
pseudoaneurysmP

C 
  

A:  observed in prevention of VTE in adult patients undergoing elective hip or knee replacement 
surgery 

B:  observed in treatment of DVT, PE and prevention of recurrence as very common in women 
< 55 years 

C:  observed as uncommon in prevention of atherothrombotic events in patients after an ACS 
(following percutaneous coronary intervention) 

*   A pre-specified selective approach to adverse event collection was applied. As incidence of 
adverse reactions did not increase and no new adverse reaction was identified, COMPASS 
study data were not included for frequency calculation in this table. 

 



126 

Description of selected adverse reactions 
Due to the pharmacological mode of action, the use of Xarelto 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 “Management of 
bleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito 
urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more 
frequently during long term rivaroxaban 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 and quantify the clinical relevance of overt 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 “Haemorrhagic risk”). Menstrual bleeding may be intensified and/or prolonged. 
Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained 
swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of 
cardiac ischaemia like chest pain or angina pectoris have been observed.  
Known complications secondary to severe bleeding such as compartment syndrome and renal failure 
due to hypoperfusion have been reported for Xarelto. 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. 
 
4.9 Overdose 
 
Rare cases of overdose up to 600 mg have been reported without bleeding complications or other 
adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma 
exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.  
A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban is 
available (refer to the Summary of Product Characteristics of andexanet alfa). 
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.  
 
Management of bleeding 
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban 
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has 
a half-life of approximately 5 to 13 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. 
If bleeding cannot be controlled by the above measures, either the administration of a specific 
factor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of 
rivaroxaban, or a specific procoagulant reversal agent, such as prothrombin complex concentrate 
(PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), 
should be considered. However, there is currently very limited clinical experience with the use of 
these medicinal products in individuals receiving rivaroxaban. The recommendation is also based on 
limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated 
depending on improvement of bleeding. Depending on local availability, a consultation with a 
coagulation expert should be considered in case of major bleedings (see section 5.1). 
 
Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. 
There is limited experience with tranexamic acid and no experience with aminocaproic acid and 
aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor 



127 

experience with the use of the systemic haemostatic desmopressin in individuals receiving 
rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01  
 
Mechanism of action 
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of 
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting 
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin 
(activated factor II) and no effects on platelets have been demonstrated. 
 
Pharmacodynamic effects 
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is 
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations 
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. 
The readout for PT is to be done in seconds, because the INR is only calibrated and validated for 
coumarins and cannot be used for any other anticoagulant.  
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95 
percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for 
15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15 
to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 
14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s. 
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and 
systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at the 
time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in 
patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough 
(16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged 
from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 
to 26 s. 
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult 
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC 
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC 
reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to 
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC 
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation 
than the 4-factor PCC (see section 4.9). 
The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently; 
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no 
need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. 
However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-
factor Xa tests (see section 5.2). 
 
Clinical efficacy and safety 
Treatment of DVT, PE and prevention of recurrent DVT and PE  
The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban in the 
initial and continued treatment of acute DVT and PE and prevention of recurrence. 
Over 12,800 patients were studied in four randomised controlled phase III clinical studies (Einstein 
DVT, Einstein PE, Einstein Extension and Einstein Choice) and additionally a predefined pooled 
analysis of the Einstein DVT and Einstein PE studies was conducted. The overall combined treatment 
duration in all studies was up to 21 months. 
 



128 

In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the 
prevention of recurrent DVT and PE (patients who presented with symptomatic PE were excluded 
from this study). The treatment duration was for 3, 6 or 12 months depending on the clinical 
judgement of the investigator. 
For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. This 
was followed by 20 mg rivaroxaban once daily.  
 
In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention of 
recurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinical 
judgement of the investigator. 
For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks. 
This was followed by 20 mg rivaroxaban once daily.  
 
In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted of 
enoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until 
the PT/INR was in therapeutic range ( 2.0). Treatment was continued with a vitamin K antagonist 
dose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0. 
 
In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent 
DVT and PE. The treatment duration was for an additional 6 or 12 months in patients who had 
completed 6 to 12 months of treatment for venous thromboembolism depending on the clinical 
judgment of the investigator. Rivaroxaban 20 mg once daily was compared with placebo.  
 
Einstein DVT, PE and Extension used the same pre-defined primary and secondary efficacy outcomes. 
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent 
DVT or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of 
recurrent DVT, non-fatal PE and all-cause mortality.  
 
In Einstein Choice, 3,396 patients with confirmed symptomatic DVT and/or PE who completed 6-12 
months of anticoagulant treatment were studied for the prevention of fatal PE or non-fatal 
symptomatic recurrent DVT or PE. Patients with an indication for continued therapeutic-dosed 
anticoagulation were excluded from the study. The treatment duration was up to 12 months depending 
on the individual randomisation date (median: 351 days). Rivaroxaban 20 mg once daily and 
rivaroxaban 10 mg once daily were compared with 100 mg acetylsalicylic acid once daily. 
The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent 
DVT or fatal or non-fatal PE.  
In the Einstein DVT study (see Table 4) rivaroxaban was demonstrated to be non-inferior to 
enoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); Hazard Ratio 
(HR): 0.680 (0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit 
(primary efficacy outcome plus major bleeding events) was reported with a HR of 0.67 
((95% CI: 0.47 - 0.95), nominal p value p=0.027) in favour of rivaroxaban. INR values were within 
the therapeutic range a mean of 60.3% of the time for the mean treatment duration of 189 days, and 
55.4%, 60.1%, and 62.8% of the time in the 3-, 6-, and 12-month intended treatment duration groups, 
respectively. In the enoxaparin/VKA group, there was no clear relation between the level of mean 
centre TTR (Time in Target INR Range of 2.0 - 3.0) in the equally sized tertiles and the incidence of 
the recurrent VTE (P=0.932 for interaction). Within the highest tertile according to centre, the HR 
with rivaroxaban versus warfarin was 0.69 (95% CI: 0.35 - 1.35). 
 
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding 
events) as well as the secondary safety outcome (major bleeding events) were similar for both 
treatment groups. 
 



129 

Table 4: Efficacy and safety results from phase III Einstein DVT 
Study population 3,449 patients with symptomatic acute deep vein thrombosis 

Treatment dose and duration 
Rivaroxaban P

a) 

3, 6 or 12 months 
N=1,731 

Enoxaparin/VKAP

b) 
3, 6 or 12 months 
N=1,718 

Symptomatic recurrent VTE* 
36 
(2.1%) 

51 
(3.0%) 

Symptomatic recurrent PE 
20 
(1.2%) 

18 
(1.0%) 

Symptomatic recurrent 
DVT 

14 
(0.8%) 

28 
(1.6%) 

Symptomatic PE and 
DVT 

1 
(0.1%) 

0 

Fatal PE/death where PE 
cannot be ruled out 

4 
(0.2%) 

6 
(0.3%) 

Major or clinically relevant non-
major bleeding 

139 
(8.1%) 

138 
(8.1%) 

Major bleeding events 
14 
(0.8%) 

20 
(1.2%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 

* p < 0.0001 (non-inferiority to a prespecified HR of 2.0); HR: 0.680 (0.443 - 1.042), p=0.076 
(superiority) 

 
In the Einstein PE study (see Table 5) rivaroxaban was demonstrated to be non-inferior to 
enoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority); HR: 1.123 
(0.749 - 1.684)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding 
events) was reported with a HR of 0.849 ((95% CI: 0.633 - 1.139), nominal p value p= 0.275). INR 
values were within the therapeutic range a mean of 63% of the time for the mean treatment duration of 
215 days, and 57%, 62%, and 65% of the time in the 3-, 6-, and 12-month intended treatment duration 
groups, respectively. In the enoxaparin/VKA group, there was no clear relation between the level of 
mean centre TTR (Time in Target INR Range of 2.0 – 3.0) in the equally sized tertiles and the 
incidence of the recurrent VTE (p=0.082 for interaction). Within the highest tertile according to 
centre, the HR with rivaroxaban versus warfarin was 0.642 (95% CI: 0.277 - 1.484). 
 
The incidence rates for the primary safety outcome (major or clinically relevant non-major bleeding 
events) were slightly lower in the rivaroxaban treatment group (10.3% (249/2412)) than in the 
enoxaparin/VKA treatment group (11.4% (274/2405)). The incidence of the secondary safety outcome 
(major bleeding events) was lower in the rivaroxaban group (1.1% (26/2412)) than in the 
enoxaparin/VKA group (2.2% (52/2405)) with a HR 0.493 (95% CI: 0.308 - 0.789). 
 



130 

Table 5: Efficacy and safety results from phase III Einstein PE 
Study population 4,832 patients with an acute symptomatic PE 

Treatment dose and duration 
Rivaroxaban P

a) 
3, 6 or 12 months 
N=2,419 

Enoxaparin/VKAP

b) 
3, 6 or 12 months 
N=2,413 

Symptomatic recurrent VTE* 
50 
(2.1%) 

44 
(1.8%) 

Symptomatic recurrent PE 
23 
(1.0%) 

20 
(0.8%) 

Symptomatic recurrent 
DVT 

18 
(0.7%) 

17 
(0.7%) 

Symptomatic PE and 
DVT 

0 
2 
(<0.1%) 

Fatal PE/death where PE 
cannot be ruled out 

11 
(0.5%) 

7 
(0.3%) 

Major or clinically relevant non-
major bleeding 

249 
(10.3%) 

274 
(11.4%) 

Major bleeding events 
26 
(1.1%) 

52 
(2.2%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 
* p < 0.0026 (non-inferiority to a prespecified HR of 2.0); HR: 1.123 (0.749 - 1.684)  

 
A prespecified pooled analysis of the outcome of the Einstein DVT and PE studies was conducted (see 
Table 6). 
 
Table 6: Efficacy and safety results from pooled analysis of phase III Einstein DVT and 
Einstein PE 
Study population 8,281 patients with an acute symptomatic DVT or PE 

Treatment dose and duration 
Rivaroxaban P

a) 

3, 6 or 12 months 
N=4,150 

Enoxaparin/VKAP

b) 
3, 6 or 12 months 
N=4,131 

Symptomatic recurrent VTE* 
86 
(2.1%) 

95 
(2.3%) 

Symptomatic recurrent PE 
43 
(1.0%) 

38 
(0.9%) 

Symptomatic recurrent 
DVT 

32 
(0.8%) 

45 
(1.1%) 

Symptomatic PE and 
DVT 

1 
(<0.1%) 

2 
(<0.1%) 

Fatal PE/death where PE 
cannot be ruled out 

15 
(0.4%) 

13 
(0.3%) 

Major or clinically relevant non-
major bleeding 

388 
(9.4%) 

412 
(10.0%) 

Major bleeding events 
40 
(1.0%) 

72 
(1.7%) 

a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once daily 
b) Enoxaparin for at least 5 days, overlapped with and followed by VKA 

* p < 0.0001 (non-inferiority to a prespecified HR of 1.75); HR: 0.886 (0.661 - 1.186) 
 
The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the 
pooled analysis was reported with a HR of 0.771 ((95% CI: 0.614 - 0.967), nominal p value 
p = 0.0244). 
 



131 

In the Einstein Extension study (see Table 7) rivaroxaban was superior to placebo for the primary and 
secondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was a 
non-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once 
daily compared to placebo. The secondary safety outcome (major or clinically relevant non-major 
bleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared 
to placebo.  
 
Table 7: Efficacy and safety results from phase III Einstein Extension 

Study population 
1,197 patients continued treatment and prevention 
of recurrent venous thromboembolism 

Treatment dose and duration 
Rivaroxaban P

a)
P  

6 or 12 months 
N=602 

Placebo 
6 or 12 months 
N=594 

Symptomatic recurrent VTE* 
8 
(1.3%) 

42 
(7.1%) 

Symptomatic recurrent PE 
2 
(0.3%) 

13 
(2.2%) 

Symptomatic recurrent 
DVT 

5 
(0.8%) 

31 
(5.2%) 

Fatal PE/death where PE 
cannot be ruled out 

1 
(0.2%) 

1 
(0.2%) 

Major bleeding events 
4 
(0.7%) 

0 
(0.0%) 

Clinically relevant non-major 
bleeding 

32 
(5.4%) 

7 
(1.2%) 

a) Rivaroxaban 20 mg once daily 

* p < 0.0001 (superiority), HR: 0.185 (0.087 - 0.393) 
 
In the Einstein Choice study (see Table 8) rivaroxaban 20 mg and 10 mg were both superior to 100 mg 
acetylsalicylic acid for the primary efficacy outcome. The principal safety outcome (major bleeding 
events) was similar for patients treated with rivaroxaban 20 mg and 10 mg once daily compared to 100 
mg acetylsalicylic acid.  
 



132 

Table 8: Efficacy and safety results from phase III Einstein Choice 

Study population 
3,396 patients continued prevention of 
recurrent venous thromboembolism 

Treatment dose  
Rivaroxaban 20 mg 
once daily 
N=1,107 

Rivaroxaban 10 
mg once daily 
N=1,127 

ASA 100 mg once 
daily 
N=1,131 

Treatment duration median 
[interquartile range] 

349 [189-362] days 353 [190-362] days 350 [186-362] days 

Symptomatic recurrent VTE 
17 
(1.5%)* 

13 
(1.2%)** 

50 
(4.4%) 

Symptomatic recurrent 
PE 

6 
(0.5%) 

6 
(0.5%) 

19 
(1.7%) 

Symptomatic recurrent 
DVT 

9 
(0.8%) 

8 
(0.7%) 

30 
(2.7%) 

Fatal PE/death where PE 
cannot be ruled out 

2 
(0.2%) 

0 
(0.0%) 

2 
(0.2%) 

Symptomatic recurrent VTE, 
MI, stroke, or non-CNS 
systemic embolism 

19 
(1.7%) 

18 
(1.6%) 

56 
(5.0%) 

Major bleeding events 
6 
(0.5%) 

5 
(0.4%) 

3 
(0.3%) 

Clinically relevant non-major 
bleeding 

30  
(2.7) 

22  
(2.0) 

20  
(1.8) 

Symptomatic recurrent VTE 
or major bleeding (net 
clinical benefit) 

23  
(2.1%) P

+ 
17  
(1.5%) P

++ 
53  
(4.7%) 

*  p<0.001(superiority) rivaroxaban 20 mg od vs ASA 100 mg od; HR=0.34 (0.20-0.59) 
**  p<0.001 (superiority) rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.26 (0.14-0.47) 
P

+  
PRivaroxaban 20 mg od vs ASA 100 mg od; HR=0.44 (0.27-0.71), p=0.0009 (nominal)  

P

++
P  Rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.32 (0.18-0.55), p<0.0001 (nominal) 

 
In addition to the phase III EINSTEIN programme, a prospective, non-interventional, open-label 
cohort study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and 
death has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-term 
safety of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice. 
Rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7%, 1.4% and 
0.5%, respectively. There were differences in patient baseline characteristics including age, cancer and 
renal impairment. A pre-specified propensity score stratified analysis was used to adjust for measured 
baseline differences but residual confounding may, in spite of this, influence the results. Adjusted HRs 
comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-cause mortality 
were 0.77 (95% CI 0.40 - 1.50), 0.91 (95% CI 0.54 - 1.54) and 0.51 (95% CI 0.24 - 1.07), respectively.  
These results in clinical practice are consistent with the established safety profile in this indication. 
 
Patients with high risk triple positive antiphospholipid syndrome 
In an investigator sponsored, randomised open-label multicentre study with blinded endpoint 
adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, 
diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for 
all 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and 
anti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of 
120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 
569 days. 59 patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinine 
clearance (CrCl) < 50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 
12% of patients randomised to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No 
events were reported in patients randomised to warfarin. Major bleeding occurred in 4 patients (7%) 
of the rivaroxaban group and 2 patients (3%) of the warfarin group. 



133 

 
Paediatric population 
Xarelto treatment initiation pack is specifically designed for treatment of adult patients and is not 
appropriate for use in paediatric patients. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
Rivaroxaban is rapidly absorbed with maximum concentrations (CRmaxR) appearing 2 - 4 hours after 
tablet intake.  
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect 
rivaroxaban AUC or CRmaxR at the 2.5 mg and 10 mg dose.  
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg 
tablet under fasting conditions. When rivaroxaban 20 mg tablets are taken together with food increases 
in mean AUC by 39% were observed when compared to tablet intake under fasting conditions, 
indicating almost complete absorption and high oral bioavailability. Rivaroxaban 15 mg and 20 mg are 
to be taken with food (see section 4.2). 
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state. 
Under fed conditions rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. 
At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and 
decreased absorption rate with increased dose.  
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) 
ranging from 30% to 40%. 
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% 
and 56% decrease in AUC and CRmaxR compared to tablet was reported when rivaroxaban granulate is 
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in 
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the 
stomach should be avoided since this can result in reduced absorption and related rivaroxaban 
exposure. 
Bioavailability (AUC and CRmaxR) was comparable for 20 mg rivaroxaban administered orally as a 
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube 
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional 
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable 
to lower rivaroxaban doses. 
 
Distribution 
Plasma protein binding in humans is high at approximately 92% to 95%, with serum albumin being 
the main binding component. The volume of distribution is moderate with VRssR being approximately 
50 litres. 
 
Biotransformation and elimination  
Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half 
then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the 
administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly 
via active renal secretion. 
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative 
degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of 
biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter 
proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein). 
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active 
circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be 
classified as a low-clearance substance. After intravenous administration of a 1 mg dose the 
elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption 
rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in 
young individuals, and with terminal half-lives of 11 to 13 hours in the elderly. 
 



134 

Special populations 
Gender 
There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between 
male and female patients. 
 
Elderly population 
Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values 
being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No 
dose adjustment is necessary. 
 
Different weight categories 
Extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasma 
concentrations (less than 25%). No dose adjustment is necessary. 
 
Inter-ethnic differences 
No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, 
Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and 
pharmacodynamics. 
 
Hepatic impairment 
Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor 
changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly 
comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic 
impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 
2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also 
had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. 
There are no data in patients with severe hepatic impairment. 
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic 
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor 
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a 
steeper PK/PD relationship between concentration and PT.  
Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and 
clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see 
section 4.3). 
 
Renal impairment 
There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via 
creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min), 
moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal 
impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold 
respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In 
individuals with mild, moderate and severe renal impairment the overall inhibition of factor Xa 
activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; 
prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no 
data in patients with creatinine clearance < 15 ml/min. 
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. 
Use is not recommended in patients with creatinine clearance < 15 ml/min. Rivaroxaban is to be used 
with caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4). 
 
Pharmacokinetic data in patients 
In patients receiving rivaroxaban for treatment of acute DVT 20 mg once daily the geometric mean 
concentration (90% prediction interval) 2 - 4 h and about 24 h after dose (roughly representing 
maximum and minimum concentrations during the dose interval) was 215 (22 - 535) and 
32 (6 - 239) mcg/l, respectively. 
 



135 

Pharmacokinetic/pharmacodynamic relationship 
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma 
concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated 
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between 
rivaroxaban concentration and factor Xa activity was best described by an ERmaxR model. For PT, the 
linear intercept model generally described the data better. Depending on the different PT reagents 
used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and 
the slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses in Phase II and III were 
consistent with the data established in healthy subjects.  
 
Paediatric population 
Xarelto treatment initiation pack is specifically designed for treatment of adult patients and is not 
appropriate for use in paediatric patients. 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile 
toxicity. 
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic 
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant 
exposure levels. 
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive 
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic 
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, 
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as 
placental changes were observed at clinically relevant plasma concentrations. In the pre- and post-
natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
Microcrystalline cellulose 
Croscarmellose sodium 
Lactose monohydrate 
Hypromellose (2910) 
Sodium laurilsulfate 
Magnesium stearate 
 
Film-coat 
Macrogol (3350) 
Hypromellose (2910) 
Titanium dioxide (E 171) 
Iron oxide red (E 172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
 
Crushed tablets 



136 

Crushed rivaroxaban tablets are stable in water and in apple puree for up to 4 hours. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Treatment initiation pack for the first 4 weeks of treatment:  
Wallet containing 49 film-coated tablets in PP/Aluminium foil blisters:  
42 film-coated tablets of 15 mg and 7 film-coated tablets of 20 mg.  
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Crushing of tablets 
Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via a 
nasogastric tube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, the 
tube should be flushed with water. Since rivaroxaban absorption is dependent on the site of active 
substance release, administration of rivaroxaban distal to the stomach should be avoided, as this can 
result in reduced absorption and thereby, reduced active substance exposure. After the administration 
of a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should then be immediately followed by 
enteral feeding. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/040 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 30 September 2008 
Date of latest renewal: 22 May 2018 
 
 
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. 
 



137 

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 
 
Xarelto 1 mg/mL granules for oral suspension  
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
The granules contain 19.7 mg rivaroxaban per gram. 
Each bottle contains 51.7 mg rivaroxaban or 103.4 mg rivaroxaban. 
Following reconstitution the oral suspension contains 1 mg rivaroxaban per mL. 
 
Excipient with known effect 
Each mL of the reconstituted oral suspension contains 1.8 mg sodium benzoate (E 211), see 
section 4.4. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Granules for oral suspension 
White granules 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in term neonates, 
infants and toddlers, children, and adolescents aged less than 18 years after at least 5 days of initial 
parenteral anticoagulation treatment. 
 
4.2 Posology and method of administration 
 
Posology 
The dose and frequency of administration are determined based on body weight (see Table 1).  
 



138 

Table 1: Recommended dose for Xarelto in paediatric patients from full-term neonates 
(following at least 10 days of oral feeding and weighing at least 2.6 kg) to children less than 
18 years of age 
Bodyweight 
[kg] 

Regimen  
Dose rivaroxaban 

Total daily dose Suitable blue 
syringe  

 (1 mg rivaroxaban corresponds to 1 mL of the suspension)  
Min Max once a day 2 times a day 3 times a day   
2.6 < 3   0.8 mg 2.4 mg 1 mL 
3 < 4   0.9 mg 2.7 mg 1 mL 
4 < 5   1.4 mg 4.2 mg 5 mL 
5 < 7   1.6 mg 4.8 mg 5 mL 
7 < 8   1.8 mg 5.4 mg 5 mL 
8 < 9   2.4 mg 7.2 mg 5 mL 
9 < 10   2.8 mg 8.4 mg 5 mL 
10 < 12   3.0 mg 9.0 mg 5 mL 
12 < 30  5 mg  10 mg 5 mL or 10 mL 
30 < 50 15 mg   15 mg 10 mL 
≥ 50  20 mg   20 mg 10 mL 
 
The weight of the child should be monitored and the dose reviewed regularly, especially for children 
below 12 kg. This is to ensure that a therapeutic dose is maintained. Dose adjustments should be made 
based on changes in body weight only. 
 
Frequency of dosing:  
 For a once a day regimen 

The doses should be taken approximately 24 hours apart. 
 For a two times a day regimen 

The doses should be taken approximately 12 hours apart. 
 For a three times a day regimen 

The doses should be taken approximately 8 hours apart. 
 
For patients with body weight of at least 2.6 kg to less than 30 kg only the oral suspension should be 
used. Do not split Xarelto tablets or use Xarelto tablets of lower strength in an attempt to provide 
doses for children with body weight below 30 kg.  
For patients with body weight of at least 30 kg, Xarelto oral suspension or tablets of 15 mg or 20 mg 
strength can be administered once a day.  
 
Xarelto oral suspension is provided with either 1 mL or 5 mL and 10 mL blue syringes (oral dosing 
syringe) with their adapter. To ensure accurate dosing it is recommended to use the blue syringes as 
follows (see Table 1): 
 1 mL blue syringe (with 0.1 mL graduations) must be used in patients weighing less than 4 kg 
 5 mL blue syringe (with 0.2 mL graduations) may be used in patients weighing 4 kg up to less 

than 30 kg 
 10 mL blue syringe (with 0.5 mL graduations) is only recommended for use in patients 

weighing 12 kg or more 
For patients weighing 12 kg up to less than 30 kg, either 5 mL or 10 mL blue syringes can be used. 
It is recommended that the healthcare professional advises the patient or caregiver which blue syringe 
to use to ensure that the correct volume is administered. 
Instructions for Use booklet is provided with the medicinal product. 
 
Initiation of treatment  
 Paediatric patients from term neonates to less than 6 months 

Treatment for paediatric patients from term neonates to less than 6 months of age, who at birth 
had at least 37 weeks of gestation, weigh at least 2.6 kg, and have had at least 10 days of oral 
feeding should be initiated following at least 5 days of initial parenteral anticoagulation 



139 

treatment (see sections 4.4 and 5.1). Xarelto is dosed based on body weight using the oral 
suspension formulation (see Table 1).  
 

 Paediatric patients from 6 months of age to less than 18 years 
Treatment for paediatric patients from 6 months to less than 18 years of age should be initiated 
following at least 5 days of initial parenteral anticoagulation treatment (see section 5.1). Xarelto 
is dosed based on body weight (see Table 1).  

 
Duration of treatment  
 All children, except those aged less than 2 years with catheter-related thrombosis 

Therapy should be continued for at least 3 months. Treatment can be extended up to 12 months 
when clinically necessary. There is no data available in children to support a dose reduction 
after 6 months treatment. The benefit-risk of continued therapy after 3 months should be 
assessed on an individual basis taking into account the risk for recurrent thrombosis versus the 
potential bleeding risk. 

 
 Children aged less than 2 years with catheter-related thrombosis 

Therapy should be continued for at least 1 month. Treatment can be extended up to 3 months 
when clinically necessary. The benefit-risk of continued therapy after 1 month should be 
assessed on an individual basis taking into account the risk for recurrent thrombosis versus the 
potential bleeding risk. 

 
Missed doses 
 Once a day regimen 

If taken once a day, a missed dose should be taken as soon as possible after it is noticed, but 
only on the same day. If this is not possible, the patient should skip the dose and continue with 
the next dose as prescribed. The patient should not take two doses to make up for a missed dose. 

 
 Two times a day regimen 

If taken twice a day, a missed morning dose should be taken immediately when it is noticed, and 
it may be taken together with the evening dose. A missed evening dose can only be taken during 
the same evening, the patient should not take two doses the next morning. 

 
 Three times a day regimen  

If taken three times a day, the three times daily administration schedule with approximately 
8-hour intervals should simply be resumed at the next scheduled dose without compensating for 
the missed dose. 

 
On the following day, the child should continue with the regular once, twice or three times daily 
regimen. 
 
Converting from parenteral anticoagulants to Xarelto  
For patients currently receiving a parenteral anticoagulant, start Xarelto 0 to 2 hours before the time of 
the next scheduled administration of the parenteral medicinal product (e.g. LMWH) or at the time of 
discontinuation of a continuously administered parenteral medicinal product (e.g. intravenous 
unfractionated heparin). 
 
Converting from Xarelto to parenteral anticoagulants  
Discontinue Xarelto and give the first dose of parenteral anticoagulant at the time that the next Xarelto 
dose would be taken.  
 
Converting from Vitamin K antagonists (VKA) to Xarelto  
VKA treatment should be stopped and Xarelto therapy should be initiated once the International 
Normalised Ratio (INR) is ≤ 2.5.  
When converting patients from VKAs to Xarelto, INR values will be falsely elevated after the intake 
of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and therefore should 
not be used (see section 4.5). 



140 

 
Converting from Xarelto to Vitamin K antagonists (VKA)  
There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. 
Continuous adequate anticoagulation should be ensured during any transition to an alternate 
anticoagulant. It should be noted that Xarelto can contribute to an elevated INR. 
Children who convert from Xarelto to VKA need to continue Xarelto for 48 hours after the first dose 
of VKA. After 2 days of co-administration an INR should be obtained prior to the next scheduled dose 
of Xarelto. Co-administration of Xarelto and VKA is advised to continue until the INR is ≥ 2.0. Once 
Xarelto is discontinued INR testing may be done reliably 24 hours after the last dose (see above and 
section 4.5). 
 
Special populations 
Renal impairment 
 Children 1 year or older with mild renal impairment (glomerular filtration rate 

50 - 80 mL/min/1.73 mP

2
P): no dose adjustment is required, based on data in adults and limited 

data in paediatric patients (see section 5.2).  
 Children 1 year or older with moderate or severe renal impairment (glomerular filtration rate 

< 50 mL/min/1.73 mP

2
P): Xarelto is not recommended as no clinical data is available (see 

section 4.4).  
 Children below 1 year: the renal function should only be determined using serum creatinine. 

Xarelto is not recommended in children younger than 1 year with serum creatinine results above 
97.5th percentile (see Table 2), as no data are available (see section 4.4). 

 
Table 2: Reference values of serum creatinine in children younger than 1 year of age (Boer et al, 
2010) 
Age 97.5P

th
P percentile of 

creatinine (µmol/L ) 
97.5P

th
P percentile of 

creatinine (mg/dL ) 
Day 1 81 0.92 
Day 2 69 0.78 
Day 3 62 0.70 
Day 4 58 0.66 
Day 5 55 0.62 
Day 6 53 0.60 
Day 7 51 0.58 
Week 2 46 0.52 
Week 3 41 0.46 
Week 4 37 0.42 
Month 2 33 0.37 
Month 3 30 0.34 
Month 4–6 30 0.34 
Month 7–9 30 0.34 
Month 10–12 32 0.36 

 
Hepatic impairment 
No clinical data is available in children with hepatic impairment. 
Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically 
relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 4.3 and 5.2). 
 
Body weight  
For children the dose is determined based on body weight (see Posology above). 
 
Gender 
No dose adjustment (see section 5.2) 
 



141 

Paediatric population 
The safety and efficacy of Xarelto in children aged 0 to < 18 years have not been established in 
indications other than treatment of venous thromboembolism (VTE) and prevention of VTE 
recurrence. No data are available for other indications. Therefore, Xarelto is not recommended for use 
in children below 18 years of age in indications other than the treatment of VTE and prevention of 
VTE recurrence. 
 
Method of administration  
Xarelto is for oral use. 
The oral suspension should be taken with feeding or with food (see section 5.2). 
 
For details on preparation and administration of the oral suspension see section 6.6.  
The oral suspension may be given through a nasogastric or gastric feeding tube (see sections 5.2 and 
6.6). 
 
Each dose should be immediately followed by the intake of one typical serving of liquid. This typical 
serving may include liquid volume used for feeding. 
In case the patient immediately spits up the dose or vomits within 30 minutes after receiving the dose, 
a new dose should be given. However, if the patient vomits more than 30 minutes after the dose, the 
dose should not be re-administered and the next dose should be taken as scheduled.  
 
If the oral suspension is not immediately available, when doses of 15 mg or 20 mg rivaroxaban are 
prescribed, these could be provided by crushing the 15 mg or 20 mg tablet and mixing it with water or 
apple puree immediately prior to use and administering it orally (see sections 5.2 and 6.6).  
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
Active clinically significant bleeding. 
 
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. 
 
Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low 
molecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral 
anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of 
switching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain 
an open central venous or arterial catheter (see section 4.5). 
 
Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic 
patients with Child Pugh B and C (see section 5.2). 
 
Pregnancy and breast-feeding (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 
Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment 
period. 
 
Dosing of rivaroxaban cannot be reliably determined in the following patient populations and was not 
studied. It is therefore not recommended in children less than 6 months of age who: 



142 

 at birth had less than 37 weeks of gestation, or 
 have a body weight of less than 2.6 kg, or 
 had less than 10 days of oral feeding. 
 
Haemorrhagic risk 
As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding. 
It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto 
administration should be discontinued if severe haemorrhage occurs (see section 4.9). 
 
In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary 
including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequent 
during long term rivaroxaban 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 and quantify the clinical relevance of overt bleeding, as judged to be appropriate. 
 
Several sub-groups of patients, as detailed below, are at an 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. 
 
Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban 
levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional 
situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. 
overdose and emergency surgery (see sections 5.1 and 5.2). 
 
There is limited data in children with cerebral vein and sinus thrombosis who have a CNS infection 
(see section 5.1). The risk of bleeding should be carefully evaluated before and during therapy with 
rivaroxaban. 
 
Renal impairment 
Xarelto is not recommended in children 1 year or older with moderate or severe renal impairment 
(glomerular filtration rate < 50 mL/min/1.73 mP

2
P), as no clinical data is available.  

Xarelto is not recommended in children younger than 1 year with serum creatinine results above 
97.5th percentile, as no clinical data are available.  
 
Interaction with other medicinal products 
No clinical data is available in children receiving concomitant systemic treatment with strong 
inhibitors of both CYP3A4 and P-gp.  
Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-
antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease 
inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and P-gp and 
therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree (2.6 fold on 
average) which may lead to an increased bleeding risk (see section 4.5). 
 
Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis 
such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid and 
platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotonin 
norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease 
an appropriate prophylactic treatment may be considered (see section 4.5).  
 



143 

Other haemorrhagic risk factors 
As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding 
risk such as: 
 congenital or acquired bleeding disorders 
 uncontrolled arterial hypertension  
 other gastrointestinal disease without active ulceration that can potentially lead to bleeding 

complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal 
reflux disease) 

 vascular retinopathy 
 bronchiectasis or history of pulmonary bleeding 
 
Patients with prosthetic valves 
Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergone 
transcatheter aortic valve replacement (TAVR). Safety and efficacy of Xarelto have not been studied 
in patients with prosthetic heart valves; therefore, there are no data to support that this medicinal 
product provides adequate anticoagulation in this patient population. Treatment with Xarelto is not 
recommended for these patients. 
 
Patients with antiphospholipid syndrome 
Direct acting oral anticoagulants (DOACs) including rivaroxaban 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. 
 
Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary 
embolectomy 
Xarelto is not recommended as an alternative to unfractionated heparin in patients with pulmonary 
embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary 
embolectomy since the safety and efficacy of Xarelto have not been established in these clinical 
situations.  
 
Spinal/epidural anaesthesia or lumbar puncture 
When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, 
patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk 
of developing an epidural or spinal haematoma which can result in long-term or permanent paralysis. 
The risk of these events may be increased by the post-operative use of indwelling epidural catheters or 
the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by 
traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and 
symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder 
dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior 
to neuraxial intervention the physician should consider the potential benefit versus the risk in 
anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical 
experience with the use of rivaroxaban in these situations. 
To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and 
neuraxial (epidural/spinal) anaesthesia or lumbar puncture, consider the pharmacokinetic profile of 
rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when 
the anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach a 
sufficiently low anticoagulant effect in each patient is not known and should be weighed against the 
urgency of a diagnostic procedure. 
No data is available on the timing of the placement or removal of neuraxial catheter in children while 
on Xarelto. In such cases, discontinue rivaroxaban and consider a short acting parenteral 
anticoagulant. 
 
Dosing recommendations before and after invasive procedures and surgical intervention  
If an invasive procedure or surgical intervention is required, Xarelto should be stopped at least 
24 hours before the intervention, if possible and based on the clinical judgement of the physician.  



144 

If the procedure cannot be delayed the increased risk of bleeding should be assessed against the 
urgency of the intervention. 
Xarelto should be restarted as soon as possible after the invasive procedure or surgical intervention 
provided the clinical situation allows and adequate haemostasis has been established as determined by 
the treating physician (see section 5.2). 
 
Dermatological reactions 
Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS 
syndrome, have been reported during post-marketing surveillance in association with the use of 
rivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in the 
course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of 
treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. 
spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal 
lesions. 
 
Information about excipients 
Xarelto granules for oral suspension contains 1.8 mg sodium benzoate (E 211) in each mL oral 
suspension. Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn 
infants (up to 4 weeks old). Increase in bilirubinaemia following its displacement from albumin may 
increase neonatal jaundice which may develop into kernicterus (non-conjugated bilirubin deposits in 
the brain tissue). 
 
This medicinal product contains less than 1 mmol sodium (23 mg) per millilitre, that is to say 
essentially “sodium-free”. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
The extent of interactions in the paediatric population is not known. The below mentioned interaction 
data was obtained in adults and the warnings in section 4.4 should be taken into account for the 
paediatric population. 
 
CYP3A4 and P-gp inhibitors 
Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a 
day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in 
mean rivaroxaban CRmaxR, with significant increases in pharmacodynamic effects which may lead to an 
increased bleeding risk. Therefore, the use of Xarelto is not recommended in patients receiving 
concomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole, 
voriconazole and posaconazole or HIV protease inhibitors. These active substances are strong 
inhibitors of both CYP3A4 and P-gp (see section 4.4).  
 
Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either 
CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. 
Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and 
moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in 
CRmaxR. The interaction with clarithromycin is likely not clinically relevant in most patients but can be 
potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4). 
 
Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a 
1.3 fold increase in mean rivaroxaban AUC and CRmaxR. The interaction with erythromycin is likely not 
clinically relevant in most patients but can be potentially significant in high-risk patients. 
In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold 
increase in mean rivaroxaban AUC and 1.6 fold increase in CRRmaxR when compared to subjects with 
normal renal function. The effect of erythromycin is additive to that of renal impairment (see 
section 4.4). 
 



145 

Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold 
increase in mean rivaroxaban AUC and a 1.3 fold increase in mean CRmaxR. The interaction with 
fluconazole is likely not clinically relevant in most patients but can be potentially significant in high-
risk patients. (For patients with renal impairment: see section 4.4). 
 
Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should 
be avoided. 
 
Anticoagulants 
After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single 
dose) an additive effect on anti-factor Xa activity was observed without any additional effects on 
clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban. 
Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any 
other anticoagulants (see sections 4.3 and 4.4).  
 
NSAIDs/platelet aggregation inhibitors 
No clinically relevant prolongation of bleeding time was observed after concomitant administration of 
rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more 
pronounced pharmacodynamic response.  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with 500 mg acetylsalicylic acid. 
Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a 
pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was 
observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or 
GPIIb/IIIa receptor levels. 
Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) 
and platelet aggregation inhibitors because these medicinal products typically increase the bleeding 
risk (see section 4.4). 
 
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. When 
concomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-
major clinically relevant bleeding were observed in all treatment groups. 
 
Warfarin 
Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or 
from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) 
more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, 
inhibition of factor Xa activity and endogenous thrombin potential were additive.  
If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti-
factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the 
fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity 
and ETP) reflected only the effect of rivaroxaban.  
If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR 
measurement can be used at the CRtroughR of rivaroxaban (24 hours after the previous intake of 
rivaroxaban) as this test is minimally affected by rivaroxaban at this time point. 
No pharmacokinetic interaction was observed between warfarin and rivaroxaban. 
 
CYP3A4 inducers  
Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 
50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The 
concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, 
phenobarbital or St. John’s Wort (Hypericum perforatum)) may also lead to reduced rivaroxaban 
plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be 
avoided unless the patient is closely observed for signs and symptoms of thrombosis.  
 



146 

Other concomitant therapies  
No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when 
rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), 
atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban 
neither inhibits nor induces any major CYP isoforms like CYP3A4. 
 
Laboratory parameters 
Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action of 
rivaroxaban (see section 5.1).  
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
Safety and efficacy of Xarelto 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 rivaroxaban passes the placenta, Xarelto is contraindicated 
during pregnancy (see section 4.3).  
Female adolescents of child-bearing potential should avoid becoming pregnant during treatment with 
rivaroxaban. 
 
Breast-feeding 
Safety and efficacy of Xarelto have not been established in breast-feeding women. Data from animals 
indicate that rivaroxaban is secreted into milk. Therefore Xarelto 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 rivaroxaban in humans 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 
 
Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope 
(frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). 
Patients experiencing these adverse reactions should not drive or use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety of rivaroxaban has been evaluated in thirteen phase III studies in adults including 
53,103 patients exposed to rivaroxaban and in two phase II and one phase III paediatric studies 
including 412 patients. See phase III studies as listed in table 3. 
 



147 

Table 3: Number of patients studied, total daily dose and maximum treatment duration in adult 
and paediatric phase III studies 

Indication Number of 
patients* 

Total daily dose Maximum 
treatment duration 

Prevention of venous thromboembolism 
(VTE) in adult patients undergoing 
elective hip or knee replacement surgery 

6,097 10 mg 39 days 

Prevention of VTE in medically ill 
patients 

3,997 10 mg 39 days 

Treatment of DVT, PE and prevention 
of recurrence 

6,790 Day 1 - 21: 30 mg 
Day 22 and onwards: 
20 mg 
After at least 6 
months: 10 mg or 
20 mg 

21 months 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

329 Body weight-adjusted 
dose to achieve a 
similar exposure as 
that observed in adults 
treated for DVT with 
20 mg rivaroxaban 
once daily 

12 months 

Prevention of stroke and systemic 
embolism in patients with non-valvular 
atrial fibrillation 

7,750 20 mg 41 months 

Prevention of atherothrombotic events in 
patients after an acute coronary 
syndrome (ACS) 

10,225 5 mg or 10 mg 
respectively, co-
administered with 
either ASA or ASA 
plus clopidogrel or 
ticlopidine 

31 months 

Prevention of atherothrombotic events in 
patients with CAD/PAD 

18,244 5 mg co-administered 
with ASA or 10 mg 
alone 

47 months 

* Patients exposed to at least one dose of rivaroxaban 
 
The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (see 
section 4.4. and ‘Description of selected adverse reactions’ below) (Table 4). The most commonly 
reported bleedings were epistaxis (4.5%) and gastrointestinal tract haemorrhage (3.8%). 
 



148 

Table 4: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the 
completed adult and paediatric phase III studies 
Indication Any bleeding Anaemia 
Prevention of VTE in adult patients 
undergoing elective hip or knee 
replacement surgery 

6.8% of patients 5.9% of patients 

Prevention of VTE in medically ill 
patients 

12.6% of patients 2.1% of patients 

Treatment of DVT, PE and prevention 
of recurrence 

23% of patients 1.6% of patients 

Treatment of VTE and prevention of 
VTE recurrence in term neonates and 
children aged less than 18 years 
following initiation of standard 
anticoagulation treatment 

39.5% of patients 4.6% of patients 

Prevention of stroke and systemic 
embolism in patients with non-
valvular atrial fibrillation 

28 per 100 patient 
years 

2.5 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients after an ACS 

22 per 100 patient 
years 

1.4 per 100 patient 
years 

Prevention of atherothrombotic events 
in patients with CAD/PAD 

6.7 per 100 patient 
years 

0.15 per 100 patient 
years**  

* For all rivaroxaban studies all bleeding events are collected, reported and 
adjudicated. 

** In the COMPASS study, there is a low anaemia incidence as a selective 
approach to adverse event collection was applied. 

 
Tabulated list of adverse reactions 
The frequencies of adverse reactions reported with Xarelto in adult and paediatric patients are 
summarised in Table 5 below by system organ class (in MedDRA) and by frequency.  
 
Frequencies are defined as: 
very common (≥ 1/10) 
common (≥ 1/100 to < 1/10)  
uncommon (≥ 1/1,000 to < 1/100)  
rare (≥ 1/10,000 to < 1/1,000)  
very rare (< 1/10,000) 
not known (cannot be estimated from the available data) 
 



149 

Table 5: All adverse reactions reported in adult patients in phase III clinical studies or through 
post-marketing use* and in two phase II and one phase III studies in paediatric patients 
Common Uncommon Rare Very rare Not known 
Blood and lymphatic system disorders 
Anaemia (incl. 
respective 
laboratory 
parameters) 

Thrombocytosis 
(incl. platelet count 
increased)P

A
P, 

thrombocytopenia 

   

Immune system disorders 
 Allergic reaction, 

dermatitis allergic, 
angioedema and 
allergic oedema 

 Anaphylactic 
reactions including 
anaphylactic shock  

 

Nervous system disorders 
Dizziness, 
headache 

Cerebral and 
intracranial 
haemorrhage, 
syncope 

   

Eye disorders 
Eye haemorrhage 
(incl. conjunctival 
haemorrhage) 

    

Cardiac disorders 
 Tachycardia    
Vascular disorders 
Hypotension, 
haematoma 

    

Respiratory, thoracic and mediastinal disorders 
Epistaxis, 
haemoptysis 

    

Gastrointestinal disorders 
Gingival bleeding, 
gastrointestinal 
tract haemorrhage 
(incl. rectal 
haemorrhage), 
gastrointestinal and 
abdominal pains, 
dyspepsia, nausea, 
constipationP

A
P, 

diarrhoea, 
vomitingP

A 

Dry mouth    

Hepatobiliary disorders 
Increase in 
transaminases 

Hepatic 
impairment, 
increased bilirubin, 
increased blood 
alkaline 
phosphatase P

A
P, 

increased GGTP

A 

Jaundice, bilirubin 
conjugated 
increased (with or 
without 
concomitant 
increase of ALT), 
cholestasis, 
hepatitis (incl. 
hepatocellular 
injury) 

  



150 

Common Uncommon Rare Very rare Not known 
Skin and subcutaneous tissue disorders 
Pruritus (incl. 
uncommon cases of 
generalised 
pruritus), rash, 
ecchymosis, 
cutaneous and 
subcutaneous 
haemorrhage 

Urticaria  Stevens-Johnson 
syndrome/ Toxic 
Epidermal 
NecrolysisP

 
P, 

DRESS syndrome  

 

Musculoskeletal and connective tissue disorders 
Pain in extremity P

A Haemarthrosis Muscle 
haemorrhage 

 Compartment 
syndrome 
secondary to a 
bleeding 

Renal and urinary disorders 
Urogenital tract 
haemorrhage (incl. 
haematuria and 
menorrhagiaP

B
P), 

renal impairment 
(incl. blood 
creatinine 
increased, blood 
urea increased) 

   Renal failure/acute 
renal failure 
secondary to a 
bleeding sufficient 
to cause 
hypoperfusion 

General disorders and administration site conditions 
Fever P

A
P, peripheral 

oedema, decreased 
general strength 
and energy (incl. 
fatigue and 
asthenia) 

Feeling unwell 
(incl. malaise)  

Localised oedemaP

A   

Investigations 
 Increased LDHP

A
P, 

increased lipaseP

A
P, 

increased amylaseP

A 

   

Injury, poisoning and procedural complications 
Postprocedural 
haemorrhage (incl. 
postoperative 
anaemia, and 
wound 
haemorrhage), 
contusion, wound 
secretion P

A 

 Vascular 
pseudoaneurysmP

C 
  

A:  observed in prevention of VTE in adult patients undergoing elective hip or knee replacement 
surgery 

B:  observed in treatment of DVT, PE and prevention of recurrence as very common in women 
< 55 years 

C:  observed as uncommon in prevention of atherothrombotic events in patients after an ACS 
(following percutaneous coronary intervention) 

*   A pre-specified selective approach to adverse event collection was applied. As incidence of 
adverse reactions did not increase and no new adverse reaction was identified, COMPASS 
study data were not included for frequency calculation in this table. 

 



151 

Description of selected adverse reactions 
Due to the pharmacological mode of action, the use of Xarelto 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 “Management of 
bleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito 
urinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen more 
frequently during long term rivaroxaban 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 and quantify the clinical relevance of overt 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 “Haemorrhagic risk”). Menstrual bleeding may be intensified and/or prolonged. 
Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained 
swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of 
cardiac ischaemia like chest pain or angina pectoris have been observed.  
Known complications secondary to severe bleeding such as compartment syndrome and renal failure 
due to hypoperfusion have been reported for Xarelto. Therefore, the possibility of haemorrhage is to 
be considered in evaluating the condition in any anticoagulated patient. 
 
Paediatric patients 
The safety assessment in children and adolescents is based on the safety data from two phase II and 
one phase III open-label active controlled studies in paediatric patients aged birth to less than 18 years. 
The safety findings were generally similar between rivaroxaban and comparator in the various 
paediatric age groups. Overall, the safety profile in the 412 children and adolescents treated with 
rivaroxaban was similar to that observed in the adult population and consistent across age subgroups, 
although assessment is limited by the small number of patients.  
In paediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (very 
common, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increase in bilirubin 
(common, 1.5%) and bilirubin conjugated increased (uncommon, 0.7%) were reported more 
frequently as compared to adults. Consistent with adult population, menorrhagia was observed in 6.6% 
(common) of female adolescents after menarche. Thrombocytopenia as observed in the post-marketing 
experience in adult population was common (4.6%) in paediatric clinical studies. The adverse drug 
reactions in paediatric patients were primarily mild to moderate in severity. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose  
 
In adults, rare cases of overdose up to 600 mg have been reported without bleeding complications or 
other adverse reactions. There is limited data available in children. Due to limited absorption a ceiling 
effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 
50 mg rivaroxaban or above in adults, however no data is available at supratherapeutic doses in 
children. 
A specific reversal agent antagonising the pharmacodynamic effect of rivaroxaban is not established in 
children. 
The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered. 
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. 
 
Management of bleeding 
Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban 
administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has 
a half-life of approximately 5 to 13 hours in adults. The half-life in children estimated using 



152 

population pharmacokinetic (popPK) modelling approaches is shorter (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. 
If bleeding cannot be controlled by the above measures, administration of a specific procoagulant 
reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated 
prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is 
currently very limited clinical experience with the use of these medicinal products in adults and in 
children receiving rivaroxaban (see section 5.1). 
 
Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. 
There is limited experience with tranexamic acid and no experience with aminocaproic acid and 
aprotinin in adults receiving rivaroxaban. There is no experience on the use of these agents in children 
receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use of 
the systemic haemostatic desmopressin in individuals receiving rivaroxaban.  
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01  
 
Mechanism of action 
Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition of 
factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting 
both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin 
(activated factor II) and no effects on platelets have been demonstrated. 
 
Pharmacodynamic effects 
Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) is 
influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations 
(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. 
The readout for PT is to be done in seconds, because the INR is only calibrated and validated for 
coumarins and cannot be used for any other anticoagulant.  
In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95 
percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximum effect) for 
15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15 
to 30 s. At trough (8 - 16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 
14 to 24 s and for 20 mg once daily (18 - 30 h after tablet intake) from 13 to 20 s. 
In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke and 
systemic embolism, the 5/95 percentiles for PT (Neoplastin) 1 - 4 hours after tablet intake (i.e. at the 
time of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and in 
patients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough 
(16 - 36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged 
from 12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 
to 26 s. 
In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adult 
subjects (n=22), the effects of single doses (50 IU/kg) of two different types of PCCs, a 3-factor PCC 
(Factors II, IX and X) and a 4-factor PCC (Factors II, VII, IX and X) were assessed. The 3-factor PCC 
reduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared to 
reductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCC 
had a greater and more rapid overall effect on reversing changes in endogenous thrombin generation 
than the 4-factor PCC (see section 4.9). 



153 

The activated partial thromboplastin time (aPTT) and HepTest are also prolonged dose-dependently; 
however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no 
need for monitoring of coagulation parameters during treatment with rivaroxaban in routine clinical 
practice. However, if clinically indicated rivaroxaban levels can be measured by calibrated 
quantitative anti-factor Xa tests (see section 5.2). 
 
Paediatric population 
PT (neoplastin reagent), aPTT, and anti-Xa assay (with a calibrated quantitative test) display a close 
correlation to plasma concentrations in children. The correlation between anti-Xa to plasma 
concentrations is linear with a slope close to 1. Individual discrepancies with higher or lower anti-Xa 
values as compared to the corresponding plasma concentrations may occur. There is no need for 
routine monitoring of coagulation parameters during clinical treatment with rivaroxaban. However, if 
clinically indicated, rivaroxaban concentrations can be measured by calibrated quantitative 
anti-Factor Xa tests in mcg/L (see Table 8 in section 5.2 for ranges of observed rivaroxaban plasma 
concentrations in children). The lower limit of quantifications must be considered when the anti-Xa 
test is used to quantify plasma concentrations of rivaroxaban in children. No threshold for efficacy or 
safety events has been established. 
 
Clinical efficacy and safety 
Treatment of VTE and prevention of VTE recurrence in paediatric patients  
A total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in 
6 open-label, multicentre paediatric studies. Body weight-adjusted dosing in patients from birth to less 
than 18 years resulted in rivaroxaban exposure similar to that observed in adult DVT patients treated 
with rivaroxaban 20 mg once daily as confirmed in the phase III study (see section 5.2).  
 
The EINSTEIN Junior phase III study was a randomised, active-controlled, open-label multicentre 
clinical study in 500 paediatric patients (aged from birth to < 18 years) with confirmed acute VTE. 
There were 276 children aged 12 to < 18 years, 101 children aged 6 to < 12 years, 69 children aged 2 
to < 6 years, and 54 children aged < 2 years.  
 
Index VTE was classified as either central venous catheter-related VTE (CVC-VTE; 90/335 patients 
in the rivaroxaban group, 37/165 patients in the comparator group), cerebral vein and sinus thrombosis 
(CVST; 74/335 patients in the rivaroxaban group, 43/165 patients in the comparator group), and all 
others including DVT and PE (non-CVC-VTE; 171/335 patients in the rivaroxaban group, 
84/165 patients in the comparator group). The most common presentation of index thrombosis in 
children aged 12 to < 18 years was non-CVC-VTE in 211 (76.4%); in children aged 6 to < 12 years 
and aged 2 to < 6 years was CVST in 48 (47.5%) and 35 (50.7%), respectively; and in children aged 
< 2 years was CVC-VTE in 37 (68.5%). There were no children < 6 months with CVST in the 
rivaroxaban group. 22 of the patients with CVST had a CNS infection (13 patients in the rivaroxaban 
group and 9 patients in comparator group). 
 
VTE was provoked by persistent, transient, or both persistent and transient risk factors in 438 (87.6%) 
children.  
 
Patients received initial treatment with therapeutic doses of UFH, LMWH, or fondaparinux for at least 
5 days, and were randomised 2:1 to receive either body weight-adjusted doses of rivaroxaban or 
comparator group (heparins, VKA) for a main study treatment period of 3 months (1 month for 
children < 2 years with CVC-VTE). At the end of the main study treatment period, the diagnostic 
imaging test, which was obtained at baseline, was repeated, if clinically feasible. The study treatment 
could be stopped at this point, or at the discretion of the Investigator continued for up to 12 months 
(for children < 2 years with CVC-VTE up to 3 months) in total. 
 
The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was the 
composite of major bleeding and clinically relevant non-major bleeding (CRNMB). All efficacy and 
safety outcomes were centrally adjudicated by an independent committee blinded for treatment 
allocation. The efficacy and safety results are shown in Tables 6 and 7 below. 
 



154 

Recurrent VTEs occurred in the rivaroxaban group in 4 of 335 patients and in the comparator group in 
5 of 165 patients. The composite of major bleeding and CRNMB was reported in 10 of 329 patients 
(3%) treated with rivaroxaban and in 3 of 162 patients (1.9%) treated with comparator. Net clinical 
benefit (symptomatic recurrent VTE plus major bleeding events) was reported in the rivaroxaban 
group in 4 of 335 patients and in the comparator group in 7 of 165 patients. Normalisation of the 
thrombus burden on repeat imaging occurred in 128 of 335 patients with rivaroxaban treatment and in 
43 of 165patients in the comparator group. These findings were generally similar among age groups. 
There were 119 (36.2%) children with any treatment-emergent bleeding in the rivaroxaban group and 
45 (27.8%) children in the comparator group. 
 
Table 6: Efficacy results at the end of the main treatment period  

Event Rivaroxaban  
N=335* 

Comparator 
N=165* 

Recurrent VTE (primary efficacy outcome) 4 
(1.2%, 95% CI 
0.4% – 3.0%) 

5 
(3.0%, 95% CI 
1.2% - 6.6%) 

Composite: Symptomatic recurrent VTE + 
asymptomatic deterioration on repeat imaging 

5 
(1.5%, 95% CI 
0.6% – 3.4%) 

6 
(3.6%, 95% CI 
1.6% – 7.6%) 

Composite: Symptomatic recurrent VTE + 
asymptomatic deterioration + no change on repeat 
imaging 

21 
(6.3%, 95% CI 
4.0% – 9.2%) 

19 
(11.5%, 95% CI 
7.3% – 17.4%) 

Normalisation on repeat imaging  128 
(38.2%, 95% CI 
33.0% - 43.5%) 

43 
(26.1%, 95% CI 
19.8% - 33.0%) 

Composite: Symptomatic recurrent VTE + major 
bleeding (net clinical benefit) 

4 
(1.2%, 95% CI 
0.4% - 3.0%) 

7 
(4.2%, 95% CI 
2.0% - 8.4%) 

Fatal or non-fatal pulmonary embolism 1 
(0.3%, 95% CI 
0.0% – 1.6%) 

1 
(0.6%, 95% CI 
0.0% – 3.1%) 

* FAS = full analysis set, all children who were randomised 

 
Table 7: Safety results at the end of the main treatment period  

 Rivaroxaban  
N=329* 

Comparator 
N=162* 

Composite: Major bleeding + CRNMB (primary safety 
outcome) 

10 
(3.0%, 95% CI 
1.6% - 5.5%) 

3 
(1.9%, 95% CI 
0.5% - 5.3%) 

Major bleeding 0 
(0.0%, 95% CI 
0.0% - 1.1%) 

2 
(1.2%, 95% CI 
0.2% - 4.3%) 

Any treatment-emergent bleedings 119 (36.2%) 45 (27.8%) 
* SAF = safety analysis set, all children who were randomised and received at least 1 dose of study 

medicinal product  
 
The efficacy and safety profile of rivaroxaban was largely similar between the paediatric VTE 
population and the DVT/PE adult population, however, the proportion of subjects with any bleeding 
was higher in the paediatric VTE population as compared to the DVT/PE adult population. 
 
Patients with high risk triple positive antiphospholipid syndrome 
In an investigator sponsored, randomised open-label multicentre study with blinded endpoint 
adjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis, 
diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for all 



155 

3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and 
anti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of 
120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was 
569 days. 59 patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinine 
clearance (CrCl) < 50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in 
12% of patients randomised to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No 
events were reported in patients randomised to warfarin. Major bleeding occurred in 4 patients (7%) of 
the rivaroxaban group and 2 patients (3%) of the warfarin group. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
The following information is based on the data obtained in adults.  
Rivaroxaban is rapidly absorbed with maximum concentrations (CRmaxR) appearing 2 - 4 hours after 
tablet intake.  
Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the 
2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions.  
Due to a reduced extent of absorption an oral bioavailability of 66% was determined for the 20 mg 
tablet under fasting conditions. When rivaroxaban 20 mg tablets are taken together with food increases 
in mean AUC by 39% were observed when compared to tablet intake under fasting conditions, 
indicating almost complete absorption and high oral bioavailability.  
Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state. 
Under fed conditions rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality. 
At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and 
decreased absorption rate with increased dose.  
Bioequivalence was demonstrated for the granules for oral suspension formulation compared to the 
marketed tablet at the 10 mg dose in fasted state as well as for the 20 mg dose in fed state. 
Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) 
ranging from 30% to 40%. 
Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% 
and 56% decrease in AUC and CRmaxR compared to tablet was reported when rivaroxaban granulate is 
released in the proximal small intestine. Exposure is further reduced when rivaroxaban is released in 
the distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to the 
stomach should be avoided since this can result in reduced absorption and related rivaroxaban 
exposure. 
Bioavailability (AUC and CRmaxR) was comparable for 20 mg rivaroxaban administered orally as a 
crushed tablet mixed in apple puree, or suspended in water and administered via a gastric tube 
followed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportional 
pharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicable 
to lower rivaroxaban doses. 
 
Paediatric population 
Children received a rivaroxaban tablet or oral suspension during or closely after feeding or food intake 
and with a typical serving of liquid to ensure reliable dosing in children. As in adults, rivaroxaban is 
readily absorbed after oral administration as a tablet or granules for oral suspension formulation in 
children. No difference in the absorption rate nor in the extent of absorption between the tablet and 
granules for oral suspension formulation was observed. No PK data following intravenous 
administration to children is available so the absolute bioavailability of rivaroxaban in children is 
unknown. A decrease in the relative bioavailability for increasing doses (in mg/kg bodyweight) was 
found, suggesting absorption limitations for higher doses, even when taken together with food. 
Rivaroxaban oral suspension should be taken with feeding or with food (see section 4.2).  
 
Distribution 
Plasma protein binding in adults is high at approximately 92% to 95%, with serum albumin being the 
main binding component. The volume of distribution is moderate with VRssR being approximately 
50 litres. 
 



156 

Paediatric population 
No data on rivaroxaban plasma protein binding specific to children is available. No PK data following 
intravenous administration of rivaroxaban to children is available. VRssR estimated via population PK 
modelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban is 
dependent on body weight and can be described with an allometric function, with an average of 113 L 
for a subject with a body weight of 82.8 kg. 
 
Biotransformation and elimination  
In adults, of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, 
with half then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 
of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, 
mainly via active renal secretion. 
Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative 
degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of 
biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter 
proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein). 
Unchanged rivaroxaban is the most important compound in human plasma, with no major or active 
circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be 
classified as a low-clearance substance. After intravenous administration of a 1 mg dose the 
elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption 
rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in 
young individuals, and with terminal half-lives of 11 to 13 hours in the elderly. 
 
Paediatric population 
No metabolism data specific to children is available. No PK data following intravenous administration 
of rivaroxaban to children is available. CL estimated via population PK modelling in children (age 
range 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight and 
can be described with an allometric function, with an average of 8 L/h for a subject with body weight 
of 82.8 kg. The geometric mean values for disposition half-lives (tR1/2R) estimated via population PK 
modelling decrease with decreasing age and ranged from 4.2 h in adolescents to approximately 3 h in 
children aged 2-12 years down to 1.9 and 1.6 h in children aged 0.5-< 2 years and less than 0.5 years, 
respectively. 
 
Special populations 
Hepatic impairment 
No clinical data is available in children with hepatic impairment. In adults, cirrhotic patients with mild 
hepatic impairment (classified as Child Pugh A) exhibited only minor changes in rivaroxaban 
pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly comparable to their 
matched healthy control group. In cirrhotic patients with moderate hepatic impairment (classified as 
Child Pugh B), rivaroxaban mean AUC was significantly increased by 2.3 fold compared to healthy 
volunteers. Unbound AUC was increased 2.6 fold. These patients also had reduced renal elimination 
of rivaroxaban, similar to patients with moderate renal impairment. There are no data in patients with 
severe hepatic impairment. 
The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic 
impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor 
of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a 
steeper PK/PD relationship between concentration and PT.  
Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and 
clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see 
section 4.3). 
 
Renal impairment 
No clinical data is available in children 1 year or older with moderate or severe renal impairment 
(glomerular filtration rate < 50 mL/min/1.73 mP

2
P) or in children younger than 1 year with serum 

creatinine results above 97.5th percentile (see section 4.4). 
In adults, there was an increase in rivaroxaban exposure correlated to decrease in renal function, as 
assessed via creatinine clearance measurements. In individuals with mild (creatinine clearance 



157 

50 - 80 mL/min), moderate (creatinine clearance 30 - 49 mL/min) and severe (creatinine clearance 
15 - 29 mL/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 
and 1.6 fold respectively. Corresponding increases in pharmacodynamic effects were more 
pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of 
factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy 
volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. 
There are no data in patients with creatinine clearance < 15 mL/min. 
Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. 
 
Gender 
In adults, there were no clinically relevant differences in pharmacokinetics and pharmacodynamics 
between male and female patients. An exploratory analysis did not reveal relevant differences in 
rivaroxaban exposure between male and female children.  
 
Different weight categories 
In adults, extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban 
plasma concentrations (less than 25%). In children, rivaroxaban is dosed based on body weight. An 
exploratory analysis in children did not reveal a relevant impact of underweight or obesity on 
rivaroxaban exposure.  
 
Inter-ethnic differences 
In adults, no clinically relevant inter-ethnic differences among Caucasian, African-American, 
Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and 
pharmacodynamics.  
An exploratory analysis did not reveal relevant inter-ethnic differences in rivaroxaban exposure among 
Japanese, Chinese or Asian children outside Japan and China compared to the respective overall 
paediatric population.  
 
Pharmacokinetic data in patients 
In paediatric patients with acute VTE receiving body weight-adjusted rivaroxaban leading to an 
exposure similar to that in adult DVT patients receiving a 20 mg once daily dose, the geometric mean 
concentrations (90% interval) at sampling time intervals roughly representing maximum and minimum 
concentrations during the dose interval are summarised in Table 8.  
 



158 

Table 8: Summary statistics (geometric mean (90% interval)) of rivaroxaban steady state 
plasma concentrations (mcg/L) by dosing regimen and age 

Time 
intervals 

        

o.d. N 12 -
< 18 years 

N 6 -< 12 years     

2.5-4h post 171 241.5  
(105-484) 

24 229.7  
(91.5-777) 

    

20-24h post 151 20.6 
 (5.69-66.5) 

24 15.9  
(3.42-45.5)  

    

b.i.d. N 6 -< 12 years N 2 -< 6 years N  0.5 -< 2 years   
2.5-4h post 36 145.4  

(46.0-343) 
38 171.8  

(70.7-438) 
2 n.c.   

10-16h post 33 26.0  
(7.99-94.9) 

37 22.2  
(0.25-127) 

3 10.7  
(n.c.-n.c.) 

  

t.i.d. N 2 -< 6 years N Birth -
< 2 years 

N 0.5 -< 2 years N Birth -
< 0.5 years 

0.5-3h post 5 164.7  
(108-283) 

25 111.2  
(22.9-320) 

13 114.3  
(22.9-346) 

12 108.0  
(19.2-320) 

7-8h post 3 33.2  
(18.7-99.7) 

23 18.7  
(10.1-36.5) 

12 21.4  
(10.5-65.6) 

11 16.1  
(1.03-33.6) 

o.d. = once daily, b.i.d. = twice daily, t.i.d. three times daily, n.c. = not calculated 
Values below lower limit of quantification (LLOQ) were substituted by ½ LLOQ for the calculation of 
statistics (LLOQ = 0.5 mcg/L). 

 
Pharmacokinetic/pharmacodynamic relationship 
The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma 
concentration and several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated 
after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between 
rivaroxaban concentration and factor Xa activity was best described by an ERmaxR model. For PT, the 
linear intercept model generally described the data better. Depending on the different PT reagents 
used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and 
the slope was around 3 to 4 s/(100 mcg/L). The results of the PK/PD analyses in Phase II and III were 
consistent with the data established in healthy subjects.  
 
5.3 Preclinical safety data 
 
Non-clinical data reveal no special hazard for humans based on conventional studies of safety 
pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile 
toxicity. 
Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic 
activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant 
exposure levels. 
In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive 
toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic 
complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, 
hepatic multiple light coloured spots) and an increased incidence of common malformations as well as 
placental changes were observed at clinically relevant plasma concentrations. In the pre- and 
post-natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the 
dams. 
 
Rivaroxaban was tested in juvenile rats up to 3-month treatment duration starting at postnatal day 4 
showing a non dose-related increase in periinsular haemorrhage. No evidence of target organ-specific 
toxicity was seen.  
 
 



159 

6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Citric acid, anhydrous (E 330) 
Hypromellose (2910)  
Mannitol (E 421) 
Microcrystalline cellulose and carmellose sodium 
Sodium benzoate (E 211) 
Sucralose (E 955) 
Xanthan gum (E 415) 
Flavour sweet and creamy: flavouring substances, maltodextrin (maize), propylene glycol (E 1520) 
and acacia gum (E 414). 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years 
After reconstitution the suspension is stable for 14 days. 
 
6.4 Special precautions for storage 
 
Do not store above 30 °C. 
Do not freeze.  
Store the prepared suspension upright. 
 
6.5 Nature and contents of container 
 
Xarelto 1 mg/mL granules for oral suspension is packed in a folding box containing:  
 For children weighing less than 4 kg: 

- 2.625 g granules, corresponding to 51.7 mg rivaroxaban, in 1 brown glass bottle 100 mL, 
closed with a child resistant screw cap  

- 2 blue syringes 1 mL with 0.1 mL marked graduations 
- 1 adapter for bottles and blue syringes  
- 1 water syringe 50 mL with 1 mL marked graduations 

 
51Tor 
 For children weighing 4 kg and more:  

- 5.25 g granules, corresponding to 103.4 mg rivaroxaban, in 1 brown glass bottle 250 mL, 
closed with a child resistant screw cap  

- 2 blue syringes 5 mL with 0.2 mL marked graduations 
- 2 blue syringes 10 mL with 0.5 mL marked graduations 
- 1 adapter for bottles and blue syringes  
- 1 water syringe 100 mL with 2 mL marked graduations 

 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal and other handling  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 



160 

Suspension 
Before administration the granules must be suspended into a homogenous suspension with non-
carbonated water giving a final concentration of 1 mg per mL. 
The amount of water to be used is:  
- 50 mL for the 100 mL bottle containing 2.625 g granules  
- 100 mL for the 250 mL bottle containing 5.25 g granules  
The bottle has to be shaken after reconstitution for 60 seconds and before each dose for 10 seconds.  
After reconstitution the medicinal product is a white to off-white suspension.  
For dose administration after reconstitution, the blue syringes (1 mL, 5 mL or 10 mL) are provided 
(see section 4.2, Table 1).  
Complete details on preparation and administration of the oral suspension can be found in the 
Instructions for Use that is provided with the medicinal product or in an educational video which can 
be accessed via QR code displayed on the Patient Alert Card that is also provided with the medicinal 
product.  
 
The suspension may be given through a nasogastric or gastric feeding tube. Gastric placement of the 
tube should be confirmed before administering Xarelto. Since rivaroxaban absorption is dependent on 
the site of active substance release, administration of rivaroxaban distal to the stomach should be 
avoided, as this can result in reduced absorption and thereby, reduced active substance exposure. After 
the administration, the feeding tube should be flushed with water. This should then be immediately 
followed by nasogastric or gastric feeding. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/050-051 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 30 September 2008 
Date of latest renewal: 22 May 2018 
 
 
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. 

 
  



161 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 

  



162 

3BA. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Bayer AG 
Kaiser-Wilhelm-Allee 
51368 Leverkusen 
Germany 
 
Bayer HealthCare Manufacturing Srl. 
Via delle Groane, 126 
20024 Garbagnate Milanese 
Italy 
 
Bayer Bitterfeld GmbH 
Ortsteil Greppin, Salegaster Chaussee 1 
06803 Bitterfeld-Wolfen 
Germany  
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
4BB. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
5BC.  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. 
 
 
6BD.  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. 

  



163 

 Additional risk minimisation measures 
 
The MAH shall provide an educational pack prior to launch, targeting all physicians who are expected 
to prescribe/use Xarelto. The educational pack is aimed at increasing awareness about the potential 
risk of bleeding during treatment with Xarelto and providing guidance on how to manage that risk. 
The physician educational pack should contain: 
• The Summary of Product Characteristics 
• Prescriber Guide 
• Patient Alert Cards [Text included in Annex III] 
• Patient Alert Cards (Xarelto granules for oral suspension) [Text included in Annex III] 
 
The MAH must agree the content and format of the Prescriber Guide together with a communication 
plan, with the national competent authority in each Member State prior to distribution of the 
educational pack in their territory. The Prescriber Guide should contain the following key safety 
messages: 

 Details of populations potentially at higher risk of bleeding 
 Recommendations for dose reduction in at risk populations 
 Guidance regarding switching from or to rivaroxaban treatment  
 The need for intake of the 15 mg and 20 mg tablets with food 
 Management of overdose situations 
 The use of coagulation tests and their interpretation 
 That all patients should be counselled about: 

 Signs or symptoms of bleeding and when to seek attention from a health care 
provider. 

 Importance of treatment compliance 
 The need for intake of the 15 mg and 20 mg tablets with food 
 Necessity to carry the Patient Alert Card that is included in each pack, with them at all 

times 
 The need to inform Health Care Professionals that they are taking Xarelto if they need 

to have any surgery or invasive procedure. 
 That all parents/caregivers of pediatric patients and all pediatric patients administered Xarelto 

granules for oral suspension should be counselled about: 
 reconstitution and dosing of the oral suspension 

 
The MAH shall also provide a Patient Alert Card in each medicine pack, the text of which is included 
in Annex III.  
 
To ensure correct reconstitution and handling of Xarelto granules for oral suspension, a training video 
for healthcare providers and caregivers will be made available by the MAH electronically on company 
webpages (as per local country requirements). The MAH shall send notifications to potential 
prescribers in line with the communication plan agreed with the national competent authority detailing 
the location of the training video, the necessity of training and the documentation of training.  
 



164 

 Obligation to conduct post-authorisation measures 
 
The MAH shall complete, within the stated timeframe, the below measures: 
 

Description Due dates 

A post-authorisation study programme that addresses the 
safety of rivaroxaban in the secondary prevention of Acute 
Coronary Syndrome (ACS) outside the clinical trial setting, 
especially with regard to incidence, severity, management and 
outcome of bleeding events in all population and particularly 
in patients at increased risk of bleeding consisting of the 
following remaining studies: 
 Drug Utilisation and Outcome Studies in the UK, 

Germany, The Netherlands and Sweden 
 Specialist Cohort Event Monitoring (SCEM) ACS Study 

With the submission of the last final study report from the 
programme, the MAH should provide an overview and 
discussion of the results from all studies of the programme in 
view of ACS patients. 

 Interim analyses reports 
provided annually 
beginning Q4 2015 until 
completion of the study 
programme.  

 Final Study Reports 
submitted by Q4 2020 

 
  



165 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



166 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1BA. LABELLING 



167 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR 2.5 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 2.5 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 2.5 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
14 film-coated tablets 
20 film-coated tablets 
28 film-coated tablets 
30 film-coated tablets 
56 film-coated tablets 
60 film-coated tablets 
98 film-coated tablets 
168 film-coated tablets 
196 film-coated tablets 
10 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 
 



168 

 
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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/025 14 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/026 28 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/027 56 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/028 60 film-coated tablets  (PP/Aluminium foil blisters) 
EU/1/08/472/029 98 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/030 168 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/031 196 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/032 10 x 1 film-coated tablets  (PP/Aluminium foil blisters) 
EU/1/08/472/033 100 x 1 film-coated tablets  (PP/Aluminium foil blisters) 
EU/1/08/472/035 30 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/041 20 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/047 14 film-coated tablets   (PVC/PVDC/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 2.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  



169 

SN  
NN  
 



170 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) FOR 2.5 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 2.5 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 2.5 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 100 (10 packs of 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 

 
 



171 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/034 100 film-coated tablets (10 x 10 x 1) (multipack) (PP/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 2.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
  



172 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) FOR 2.5 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 2.5 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 2.5 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 x 1 film-coated tablets. 
Component of a multipack, can’t be sold separately. 
 
 
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 

 



173 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/034 100 film-coated tablets (10 x 10 x 1) (multipack) (PP/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 2.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



174 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE BLISTER (10 x 1 TABLETS) FOR 2.5 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 2.5 mg tablets 
rivaroxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
  



175 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 10 TABLETS FOR 2.5 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 2.5 mg tablets 
rivaroxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



176 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 14 TABLETS FOR 2.5 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 2.5 mg tablets 
rivaroxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 
 
sun as symbol 
moon as symbol 

 



177 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR HDPE BOTTLE FOR 2.5 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 2.5 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 2.5 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 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 

 



178 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/046  100 film-coated tablets   (HDPE Bottle) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. (only applicable for bottle label, not applicable for 
outer carton) 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 2.5 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) 
 
  



179 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR 10 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 10 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 10 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
5 film-coated tablets 
10 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets  
30 film-coated tablets 
98 film-coated tablets 
10 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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 



180 

 
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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/001 5 film-coated tablets   (PVC/PVDC/Aluminium foil blisters) 
EU/1/08/472/002 10 film-coated tablets   (PVC/PVDC/Aluminium foil blisters) 
EU/1/08/472/003 30 film-coated tablets   (PVC/PVDC/Aluminium foil blisters) 
EU/1/08/472/004 100 x 1 film-coated tablets (PVC/PVDC/Aluminium foil blisters) 
EU/1/08/472/005 5 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/006 10 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/007 30 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/008 100 x 1 film-coated tablets  (PP/Aluminium foil blisters) 
EU/1/08/472/009 10 x 1 film-coated tablets  (PVC/PVDC/Aluminium foil blisters) 
EU/1/08/472/010 10 x 1 film-coated tablets  (PP/Aluminium foil blisters) 
EU/1/08/472/042 14 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/043 28 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/044 98 film-coated tablets   (PP/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 10 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  



181 

 



182 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) FOR 10 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 10 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 10 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 100 (10 packs of 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 

 
 



183 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/022 100 film-coated tablets (10 x 10 x 1) (multipack) (PP/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 10 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
  



184 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) FOR 10 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 10 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 10 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 x 1 film-coated tablets.  
Component of a multipack, can’t be sold separately. 
 
 
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 
 
 



185 

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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/022 100 film-coated tablets (10 x 10 x 1) (multipack) (PP/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 10 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



186 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 10 TABLETS FOR 10 MG 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 10 mg tablets 
rivaroxaban 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 

3. EXPIRY DATE 
 
EXP 
 
 

4. BATCH NUMBER 
 
Lot 
 
 

5. OTHER 
 
  



187 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 14 TABLETS FOR 10 MG 

 
 

1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 10 mg tablets 
rivaroxaban 
 
 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 

3. EXPIRY DATE 
 
EXP 
 
 

4. BATCH NUMBER 
 
Lot 
 
 

5. OTHER 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 
 



188 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR HDPE BOTTLE FOR 10 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 10 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 10 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 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 

 



189 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/045  100 film-coated tablets   (HDPE Bottle) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. (only applicable for bottle label, not applicable for 
outer carton) 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 10 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) 
 
  



190 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR UNIT PACK FOR 15 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 15 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 15 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets 
42 film-coated tablets 
98 film-coated tablets 
10 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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



191 

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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/011 14 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/012 28 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/013 42 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/014 98 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/015 10 x 1 film-coated tablets  (PP/Aluminium foil blisters) 
EU/1/08/472/016 100 x 1 film-coated tablets  (PP/Aluminium foil blisters) 
EU/1/08/472/038 10 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/048 14 film-coated tablets   (PVC/PVDC/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 15 mg 
  
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
  



192 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) FOR 15 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 15 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 15 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 100 (10 packs of 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 

 
 



193 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/023 100 film-coated tablets (10 x 10 x 1) (multipack) (PP/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 15 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
  



194 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) FOR 15 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 15 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 15 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 x 1 film-coated tablets. 
Component of a multipack, can’t be sold separately. 
 
 
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 
 
 



195 

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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/023 100 film-coated tablets (10 x 10 x 1) (multipack) (PP/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 15 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



196 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE BLISTER (10 X 1 TABLETS) FOR 15 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 15 mg tablets 
rivaroxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



197 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 14 TABLETS FOR 15 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 15 mg tablets 
rivaroxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 
 



198 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 10 TABLETS FOR 15 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 15 mg tablets 
rivaroxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



199 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR HDPE BOTTLE FOR 15 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 15 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 15 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 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 

 



200 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/036  100 film-coated tablets   (HDPE Bottle) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. (only applicable for bottle label, not applicable for 
outer carton) 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 15 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) 
 
  



201 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON FOR UNIT PACK FOR 20 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 20 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 20 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
14 film-coated tablets 
28 film-coated tablets 
98 film-coated tablets 
10 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 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



202 

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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/017 14 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/018 28 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/019 98 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/020 10 x 1 film-coated tablets  (PP/Aluminium foil blisters) 
EU/1/08/472/021 100 x 1 film-coated tablets  (PP/Aluminium foil blisters) 
EU/1/08/472/039 10 film-coated tablets   (PP/Aluminium foil blisters) 
EU/1/08/472/049 14 film-coated tablets   (PVC/PVDC/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 20 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
  



203 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) FOR 20 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 20 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 20 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 100 (10 packs of 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 

 
 



204 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/024 100 film-coated tablets (10 x 10 x 1) (multipack) (PP/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 20 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
  



205 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) FOR 20 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 20 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 20 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 x 1 film-coated tablets.  
Component of a multipack, can’t be sold separately. 
 
 
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 
 
 



206 

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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/024 100 film-coated tablets (10 x 10 x 1) (multipack) (PP/Aluminium foil blisters) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 20 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
  



207 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
UNIT DOSE BLISTER (10 X 1 TABLETS) FOR 20 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 20 mg tablets 
rivaroxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



208 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 14 TABLETS FOR 20 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 20 mg tablets 
rivaroxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Mon. 
Tue. 
Wed. 
Thu. 
Fri. 
Sat. 
Sun. 
 
 



209 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF 10 TABLETS FOR 20 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 20 mg tablets 
rivaroxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



210 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON AND LABEL FOR HDPE BOTTLE FOR 20 MG 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 20 mg film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 20 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 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 

 



211 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/037  100 film-coated tablets   (HDPE Bottle) 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. (only applicable for bottle label, not applicable for 
outer carton) 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 20 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) 
 



212 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON OF TREATMENT INITIATION PACK (42 FILM-COATED TABLETS OF 
15 MG AND 7 FILM-COATED TABLETS OF 20 MG) (INCLUDING BLUE BOX) 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 15 mg  
Xarelto 20 mg  
film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each red film-coated tablet for week 1, 2 and 3 contains 15 mg rivaroxaban. 
Each brown-red film-coated tablet for week 4 contains 20 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Each pack of 49 film-coated tablets contains:  
42 film-coated tablets of 15 mg rivaroxaban 
7 film-coated tablets of 20 mg rivaroxaban 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
Treatment Initiation Pack  
 
This treatment initiation pack is only for the first 4 weeks of treatment.  
 
DOSE 
Day 1 to 21: One 15 mg tablet twice a day (one 15 mg tablet in the morning and one in the evening) 
together with food.  
From Day 22: One 20 mg tablet once a day (taken at same time each day) together with food.  
 
 
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 
 
 



213 

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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/040 42 film-coated tablets of 15 mg rivaroxaban and 

7 film-coated tablets of 20 mg rivaroxaban  
(treatment initiation pack) 

 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 15 mg  
Xarelto 20 mg  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC  
SN  
NN  
 



214 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
WALLET OF TREATMENT INITIATION PACK (42 FILM-COATED TABLETS OF 15 MG 
AND 7 FILM-COATED TABLETS OF 20 MG) (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 15 mg  
Xarelto 20 mg  
film-coated tablets 
rivaroxaban 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each red film-coated tablet for week 1, 2 and 3 contains 15 mg rivaroxaban. 
Each brown-red film-coated tablet for week 4 contains 20 mg rivaroxaban. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Each pack of 49 film-coated tablets contains:  
42 film-coated tablets of 15 mg rivaroxaban 
7 film-coated tablets of 20 mg rivaroxaban 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
Treatment Initiation Pack  
 
This treatment initiation pack is only for the first 4 weeks of treatment.  
 
Back and front side 
DOSE and DOSING SCHEME 
Day 1 to 21: One 15 mg tablet twice a day (one 15 mg tablet in the morning and one in the evening) 
with food.  
From Day 22: One 20 mg tablet once a day (taken at same time each day) with food.  
 
Initial treatment  Xarelto 15 mg twice a day  First 3 weeks 
Continuous treatment  Xarelto 20 mg once a day  Week 4 onwards Visit your doctor to 
ensure continued treatment. 
To be taken with food.  
 
 



215 

Xarelto 15 mg 
Start of therapy  
15 mg 
twice a day  
Start date  
WEEK 1, WEEK 2, WEEK 3  
DAY 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21  
 
sun as symbol 
moon as symbol 
 
 
Dose change  
Xarelto 20 mg 
20 mg  
once a day  
taken at same time each day 
Date of dose change  
WEEK 4 
DAY 22 DAY 23 DAY 24 DAY 25 DAY 26 DAY 27 DAY 28  
 
 
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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 



216 

12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/040 42 film-coated tablets of 15 mg rivaroxaban and 

7 film-coated tablets of 20 mg rivaroxaban  
(treatment initiation pack) 

 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted.  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
 



217 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER OF TREATMENT INITIATION PACK IN WALLET (42 FILM-COATED 
TABLETS OF 15 MG AND 7 FILM-COATED TABLETS OF 20 MG) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 15 mg tablets 
Xarelto 20 mg tablets 
rivaroxaban 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Bayer (logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



218 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON FOR GLASS BOTTLE 100 ML (GRANULES) (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 1 mg/mL granules for oral suspension 
rivaroxaban 
For children weighing less than 4 kg 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
The granules contain 19.69 mg rivaroxaban per gram. 
The glass bottle contains 51.7 mg rivaroxaban. 
Following reconstitution the oral suspension contains 1 mg rivaroxaban per mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sodium benzoate (E 211). See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules for oral suspension  
The bottle contains 2.625 g granules to be resuspended in 50 mL water. 
 
1 bottle 100 mL 
1 water syringe 50 mL  
2 blue syringes 1 mL 
1 adapter 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Please ask your pharmacist or doctor to fill in the prescription information:  
Body weight of the child:  kg 
Dose for the child:   mL 
This dose is to be given to the child three times a day  
 
Shake after preparation at least 60 seconds.  
Shake before each use at least 10 seconds.  

 
Oral use only after reconstitution.  
Read the package leaflet and the Instructions for Use before use.  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 



219 

 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
After reconstitution the suspension is stable for 14 days. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 °C. Do not freeze. Store the prepared suspension upright. 
 
 
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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/050 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Xarelto 1 mg/mL 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included.  



220 

 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN  
NN 
 



221 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
LABEL FOR GLASS BOTTLE 100 ML (GRANULES) (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 1 mg/mL granules for oral suspension 
rivaroxaban 
 
For children weighing less than 4 kg.  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
The granules contain 19.69 mg rivaroxaban per gram. 
The bottle contains 51.7 mg rivaroxaban. 
Following reconstitution the oral suspension contains 1 mg rivaroxaban per mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sodium benzoate (E 211). See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules for oral suspension 
2.625 g granules to be resuspended in 50 mL water.  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Shake after preparation at least 60 seconds.  
Shake before each use at least 10 seconds.  

 
Oral use only after reconstitution.  
Read the package leaflet and the Instructions for Use before 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. 
 
 



222 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
Expiry date (= date of preparation + 14 days):  
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 °C. Do not freeze. Store the prepared suspension upright. 
 
 
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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/050 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 



223 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
OUTER CARTON FOR GLASS BOTTLE 250 ML (GRANULES) (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 1 mg/mL granules for oral suspension 
rivaroxaban 
For children weighing 4 kg and more. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
The granules contain 19.69 mg rivaroxaban per gram. 
The glass bottle contains 103.4 mg rivaroxaban. 
Following reconstitution the oral suspension contains 1 mg rivaroxaban per mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sodium benzoate (E 211). See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules for oral suspension  
The bottle contains 5.25 g granules to be resuspended in 100 mL water.  
 
1 bottle 250 mL 
1 water syringe 100 mL  
2 blue syringes 5 mL  
2 blue syringes 10 mL 
1 adapter 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Please ask your pharmacist or doctor to fill in the prescription information:  
Body weight of the child:  kg 
Dose for the child:   mL 
This dose is to be given to the child (tick the box): 
□ Once daily 
□ Twice daily 
□ Three times a day  
 
Shake after preparation at least 60 seconds. 
Shake before each use at least 10 seconds. 

 
Oral use only after reconstitution.  
Read the package leaflet and the Instructions for Use before use.  



224 

 
 
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 
 
After reconstitution the suspension is stable for 14 days. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 °C. Do not freeze. Store the prepared suspension upright. 
 
 
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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/051 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 



225 

16. INFORMATION IN BRAILLE 
 
Xarelto 1 mg/mL 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 
 
 



226 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
LABEL FOR GLASS BOTTLE 250 ML (GRANULES) (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Xarelto 1 mg/mL granules for oral suspension 
rivaroxaban 
 
For children weighing 4 kg and more. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
The granules contain 19.69 mg rivaroxaban per gram. 
The bottle contains 103.4 mg rivaroxaban. 
Following reconstitution the oral suspension contains 1 mg rivaroxaban per mL. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sodium benzoate (E 211). See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Granules for oral suspension 
5.25 g granules to be resuspended in 100 mL water.  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Shake after preparation at least 60 seconds.  
Shake before each use at least 10 seconds.  

 
Oral use only after reconstitution.  
Read the package leaflet and the Instructions for Use before 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. 
 
 



227 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
Expiry date (= date of preparation + 14 days):  
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 30 °C. Do not freeze. Store upright after reconstitution. 
 
 
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 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/472/051 
 
 
13. BATCH NUMBER 
 
Batch 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
  



228 

PATIENT ALERT CARD 
[Xarelto tablets 2.5 mg / 10 mg / 15 mg / 20 mg / treatment initiation pack] 
 
Patient Alert Card 
Bayer (logo) 
 
Xarelto 2.5 mg (tick box to tick the prescribed dose) 
Xarelto 10 mg (tick box to tick the prescribed dose) 
Xarelto 15 mg (tick box to tick the prescribed dose) 
Xarelto 20 mg (tick box to tick the prescribed dose) 
 
♦ Keep this card with you at all times 
♦ Present this card to every physician or dentist prior to treatment 
 
I am under anticoagulation treatment with Xarelto (rivaroxaban) 
Name: 
Address: 
Birth date: 
Weight: 
Other medicines / conditions: 
 
In case of emergency, please notify: 
Doctor’s name: 
Doctor’s phone: 
Doctor’s stamp: 
 
Please also notify: 
Name: 
Phone: 
Relationship: 
 
Information for health care providers: 
♦ INR values should not be used as they are not a dependable measure of the anticoagulant activity of 
Xarelto. 
 
What should I know about Xarelto? 
♦ Xarelto thins the blood, which prevents you from getting dangerous blood clots. 
♦ Xarelto must be taken exactly as prescribed by your doctor. To ensure optimal protection from blood 
clots, never skip a dose. 
♦ You must not stop taking Xarelto without first talking to your doctor as your risk of blood clots may 
increase. 
♦ Tell your health care provider about any other medicines you are currently taking, took recently or 
intend to start taking, before you start Xarelto. 
♦ Tell your health care provider that you are taking Xarelto before any surgery or invasive procedure. 
 
When should I seek advice from my health care provider? 
When taking a blood thinner such as Xarelto it is important to be aware of its possible side effects. 
Bleeding is the most common side effect. Do not start taking Xarelto if you know you are at risk of 
bleeding, without first discussing this with your doctor. Tell your health care provider straight away if 
you have any signs or symptoms of bleeding such as the following: 
♦ pain 
♦ swelling or discomfort 
♦ headache, dizziness or weakness 
♦ unusual bruising, nosebleeds, bleeding of gums, cuts that take a long time to stop bleeding 
♦ menstrual flow or vaginal bleeding that is heavier than normal 
♦ blood in your urine which may be pink or brown, red or black stools 
♦ coughing up blood, or vomiting blood or material that looks like coffee grounds 



229 

 
How do I take Xarelto? 
♦ To ensure optimal protection, Xarelto 

- 2.5 mg can be taken with or without food 
- 10 mg can be taken with or without food 
- 15 mg must be taken with food 
- 20 mg must be taken with food 

 
 

  



230 

PATIENT ALERT CARD 
[Xarelto 1 mg/mL granules for oral suspension] 
 
Patient Alert Card 
Bayer (logo) 
 
Xarelto 1 mg/mL granules for oral suspension 
 
Information to caregivers/patients: 
♦ Keep this card with you at all times. 
♦ Present this card to every physician or dentist prior to treatment of the patient. 
 
The patient who is under anticoagulation treatment with Xarelto (rivaroxaban): 
Name: 
Address: 
Birth date: 
Weight: 
Other medicines / conditions: 
 
In case of emergency, please notify: 
Doctor’s name: 
Doctor’s phone: 
Doctor’s stamp: 
 
Please also notify: 
Name: 
Phone: 
Relationship: 
 
Information for health care providers: 
♦ INR values should not be used as they are not a dependable measure of the anticoagulant activity of 
Xarelto. 
 
What should I know about Xarelto? 
♦ Xarelto thins the blood, which prevents from getting dangerous blood clots. 
♦ Xarelto must be taken exactly as prescribed by the doctor. To ensure optimal protection from blood 
clots, never skip a dose. 
♦ You must not stop giving/taking Xarelto without first talking to the doctor as the risk of blood clots 
may increase. 
♦ Tell the health care provider about any other medicines the child is/you are currently taking, took 
recently or intend to start taking, before starting Xarelto. 
♦ Tell the health care provider that the child is/you are taking Xarelto before any surgery or invasive 
procedure. 
 
When should I seek advice from a health care provider? 
When taking a blood thinner such as Xarelto it is important to be aware of its possible side effects. 
Bleeding is the most common side effect. Do not start giving Xarelto to the child/taking Xarelto if you 
know the child is/you are at risk of bleeding, without first discussing this with the doctor. Tell the 
health care provider straight away if the child has/you have any signs or symptoms of bleeding such as 
the following: 
♦ pain 
♦ swelling or discomfort 
♦ headache, dizziness or weakness 
♦ unusual bruising, nosebleeds, bleeding of gums, cuts that take a long time to stop bleeding 
♦ menstrual flow or vaginal bleeding that is heavier than normal 
♦ blood in the urine which may be pink or brown, red or black stools 
♦ coughing up blood, or vomiting blood or material that looks like coffee grounds 



231 

 
How do I give Xarelto to the child?/ How do I take Xarelto? 
♦ To ensure optimal protection, Xarelto 1 mg/mL must be given/taken with feeding (breast milk or 
formula feeding) or with a meal.  
It can be administered through a nasogastric or gastric feeding tube.  
 
 

  



232 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2BB. PACKAGE LEAFLET 
 
 



233 

Package leaflet: Information for the user 
 

Xarelto 2.5 mg film-coated tablets 
rivaroxaban 

 

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 Xarelto is and what it is used for 
2. What you need to know before you take Xarelto 
3. How to take Xarelto 
4. Possible side effects 
5. How to store Xarelto 
6. Contents of the pack and other information 
 
 
1. What Xarelto is and what it is used for 
 
You have been given Xarelto because  

- you have been diagnosed with an acute coronary syndrome (a group of conditions that 
includes heart attack and unstable angina, a severe type of chest pain) and have been 
shown to have had an increase in certain cardiac blood tests. 
Xarelto reduces the risk in adults of having another heart attack or reduces the risk of 
dying from a disease related to your heart or your blood vessels. 
Xarelto will not be given to you on its own. Your doctor will also tell you to take either: 
 acetylsalicylic acid or 
 acetylsalicylic acid plus clopidogrel or ticlopidine. 
 
or  

 
- you have been diagnosed with a high risk of getting a blood clot due to a coronary artery 

disease or peripheral artery disease which causes symptoms.  
Xarelto reduces the risk in adults of getting blot clots (atherothrombotic events).  
Xarelto will not be given to you on its own. Your doctor will also tell you to take 
acetylsalicylic acid. 

 
Xarelto contains the active substance rivaroxaban and belongs to a group of medicines called 
antithrombotic agents. It works by blocking a blood clotting factor (factor Xa) and thus reducing the 
tendency of the blood to form clots.  
 
 



234 

2. What you need to know before you take Xarelto 
 
Do not take Xarelto 
 16Tif you are allergic16T to rivaroxaban or any of the other ingredients of this medicine (listed in 

section 6) 
 16Tif you are bleeding excessively 
 16Tif you have a disease or condition in an organ of the body that increases the risk of serious 

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

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

 16Tif you have an acute coronary syndrome and previously had a bleeding or a blood clot in your 
brain (stroke)  

 16Tif you have 16Tcoronary artery disease or peripheral artery disease and previously had a bleeding in 
your brain (stroke) or where there was a blockage of the small arteries providing blood to the 
brain’s deep tissues (lacunar stroke) or if you had a blood clot in your brain (ischaemic, non-
lacunar stroke) in the previous month  

 16Tif you have a liver disease16T which leads to an increased risk of bleeding 
 16Tif you are pregnant or breast-feeding 
16TDo not take Xarelto 16T 16Tand tell your doctor16T if any of these apply to you. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Xarelto. 
Xarelto should not be used in combination with certain other medicines which reduce blood clotting 
such as prasugrel or ticagrelor other than acetylsalicylic acid and clopidogrel/ticlopidine. 
 
Take special care with Xarelto 
 if you have 16Tan increased risk of bleeding, as could be the case in situations16T such as: 

 16T▪ severe kidney disease, since your kidney function may affect the amount of 
medicine that works in your body 

 16T▪ if you are taking other medicines to prevent blood clotting (e.g. warfarin, 
dabigatran, apixaban or heparin), when changing anticoagulant treatment or while getting 
heparin through a venous or arterial line to keep it open (see section “Other medicines 
and Xarelto”) 

 16T▪ bleeding disorders  
 16T▪ very high blood pressure, not controlled by medical treatment 
 16T▪ diseases of your stomach or bowel that might result in bleeding, e.g. inflammation 

of the bowels or stomach, or inflammation of the oesophagus (gullet), e.g. due to 
gastroesophageal reflux disease (disease where stomach acid goes upwards into the 
oesophagus) 

 16Ta problem with the blood vessels in the back of your eyes16T (retinopathy) 
 a lung disease where your bronchi are widened and filled with pus (bronchiectasis), or 

previous bleeding from your lung 
 you are older than 75 years  
 you weigh 60 kg or less 
 you have a coronary artery disease with severe symptomatic heart failure 

 if you have a prosthetic heart valve 
 if you know that you have a disease called antiphospholipid syndrome (a disorder of the 

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

16TIf any of the above apply to you, tell your doctor 16Tbefore you take Xarelto. Your doctor will decide, 
if you should be treated with this medicine and if you should be kept under closer observation.  
 



235 

If you need to have an operation 
 it is very important to take Xarelto before and after the operation exactly at the times you have 

been told by your doctor. 
 If your operation involves a catheter or injection into your spinal column (e.g. for epidural or 

spinal anaesthesia or pain reduction): 
 it is very important to take Xarelto before and after the injection or removal of the catheter 

exactly at the times you have been told by your doctor 
 tell your doctor immediately if you get numbness or weakness of your legs or problems 

with your bowel or bladder after the end of anaesthesia, because urgent care is necessary. 
 
16TChildren and adolescents 
Xarelto 2.5 mg tablets are 16Tnot recommended for people under 18 years of age.16T There is not enough 
information on their use in children and adolescents. 
 
Other medicines and Xarelto 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription. 
 If you are taking 

 some 16Tmedicines for fungal infections 16T(e.g. fluconazole, itraconazole, voriconazole, 
posaconazole), unless they are only applied to the skin 

 ketoconazole tablets (used to treat Cushing’s syndrome - when the body produces an 
excess of cortisol) 

 some medicines for bacterial infections (e.g. clarithromycin, erythromycin)  
 some 16Tanti-viral medicines for HIV / AIDS 16T (e.g. ritonavir) 
 other medicines to 16Treduce blood clotting 16T(e.g. enoxaparin, clopidogrel or vitamin K 

antagonists such as warfarin and acenocoumarol, prasugrel and ticagrelor (see section 
“Warnings and Precautions”))  

 16Tanti-inflammatory and pain relieving medicines16T (e.g. naproxen or acetylsalicylic acid) 
 dronedarone, a medicine to treat abnormal heart beat 
 some medicines to treat depression (selective serotonin reuptake inhibitors (SSRIs) or 

serotonin norepinephrine reuptake inhibitors (SNRIs)) 
 
16TIf any of the above apply to you, tell your doctor16T before taking Xarelto, because the effect of 
Xarelto may be increased. Your doctor will decide, if you should be treated with this medicine 
and if you should be kept under closer observation.  
16TIf your doctor thinks that you are at increased risk of developing stomach or bowel ulcers, he 
may also use a preventative ulcer treatment.  
 

 If you are taking 
 some medicines for treatment of epilepsy (phenytoin, carbamazepine, phenobarbital) 
 St John’s Wort (Hypericum perforatum), a herbal product used for depression 
 rifampicin, an antibiotic 
16TIf any of the above apply to you, tell your doctor16T before taking Xarelto, because the effect of 
Xarelto may be reduced. Your doctor will decide, if you should be treated with Xarelto and if 
you should be kept under closer observation.  

 
Pregnancy and breast---feeding 
16TDo not take Xarelto if you are pregnant or breast-feeding16T. If there is a chance that you could become 
pregnant, use a reliable contraceptive while you are taking Xarelto. If you become pregnant while you 
are taking this medicine, tell your doctor immediately, who will decide how you should be treated. 
 
Driving and using machines 
Xarelto may cause dizziness (common side effect) or fainting (uncommon side effect) (see section 4, 
”Possible side effects”). You should not drive, ride a bicycle or use any tools or machines if you are 
affected by these symptoms.  
 



236 

16TXarelto contains lactose and sodium 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ”sodium-
free”. 
 
 
3. How to take Xarelto 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.  
 
How much to take 
The recommended dose is one 2.5 mg tablet twice a day. Take Xarelto around the same time every day 
(for example, one tablet in the morning and one in the evening). This medicine can be taken with or 
without food.  
 
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take 
Xarelto. 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 Xarelto tablet through a stomach tube. 
 
Xarelto will not be given to you on its own. 
Your doctor will also tell you to take acetylsalicylic acid. If you get Xarelto after an acute coronary 
syndrome, your doctor may tell you to also take clopidogrel or ticlopidine. 
 
Your doctor will tell you how much of these to take (usually between 75 to 100 mg acetylsalicylic acid 
daily or a daily dose of 75 to 100 mg acetylsalicylic acid plus a daily dose of either 75 mg clopidogrel 
or a standard daily dose of ticlopidine). 
 
When to start Xarelto 
Treatment with Xarelto after an acute coronary syndrome should be started as soon as possible after 
stabilisation of the acute coronary syndrome, at the earliest 24 hours after admission to hospital and at 
the time when parenteral (via injection) anticoagulation therapy would normally be stopped. 
Your doctor will tell you when to start treatment with Xarelto if you have been diagnosed with 
coronary artery disease or peripheral artery disease. 
Your doctor will decide how long you must continue treatment. 
 
If you take more Xarelto than you should 
16TContact your doctor immediately 16T if you have taken too many Xarelto tablets. Taking too much Xarelto 
increases the risk of bleeding.  
 
If you forget to take Xarelto  
Do not take a double dose to make up for a missed dose. If you miss a dose, take your next dose at the 
usual time. 
 
If you stop taking Xarelto 
Take Xarelto on a regular basis and for as long as your doctor keeps prescribing it.  
 
Do not stop taking Xarelto without talking to your doctor first. If you stop taking this medicine, it may 
increase your risk of having another heart attack or stroke or dying from a disease related to your heart 
or your blood vessels. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 



237 

4. Possible side effects 
 
Like all medicines, Xarelto can cause side effects, although not everybody gets them. 
 
Like other similar medicines to reduce the formation of blood clots, Xarelto may cause bleeding which 
may potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure 
(shock). In some cases the bleeding may not be obvious. 
 
Tell your doctor immediately if you experience any of the following side effects: 
 Signs of bleeding 

- bleeding into the brain or inside the skull (symptoms can include headache, one-sided 
weakness, vomiting, seizures, decreased level of consciousness, and neck stiffness. 
A serious medical emergency. Seek medical attention immediately!) 

- long or excessive bleeding 
- exceptional weakness, tiredness, paleness, dizziness, headache, unexplained swelling, 

breathlessness, chest pain or angina pectoris 
 Your doctor may decide to keep you under closer observation or change the treatment.  
 
 Signs of severe skin reactions 

- spreading intense skin rash, blisters or mucosal lesions, e.g. in the mouth or eyes 
(Stevens-Johnson syndrome/toxic epidermal necrolysis).  

- a drug reaction that causes rash, fever, inflammation of internal organs, blood 
abnormalities and systemic illness (DRESS syndrome).  

The frequency of these side effects is very rare (up to 1 in 10,000 people). 
 
 Signs of severe allergic reactions 

- swelling of the face, lips, mouth, tongue or throat; difficulty swallowing; hives and 
breathing difficulties; sudden drop in blood pressure.  

The frequencies of severe allergic reactions are very rare (anaphylactic reactions, including 
anaphylactic shock; may affect up to 1 in 10,000 people) and uncommon (angioedema and 
allergic oedema; may affect up to 1 in 100 people). 

 
Overall list of possible side effects 
 
Common (may affect up to 1 in 10 people) 
- reduction in red blood cells which can make the skin pale and cause weakness or breathlessness 
- bleeding in the stomach or bowel, urogenital bleeding (including blood in the urine and heavy 

menstrual bleeding), nose bleed, bleeding in the gum 
- bleeding into the eye (including bleeding from the whites of the eyes) 
- bleeding into tissue or a cavity of the body (haematoma, bruising)  
- coughing up blood 
- bleeding from the skin or under the skin 
- bleeding following an operation  
- oozing of blood or fluid from surgical wound 
- swelling in the limbs 
- pain in the limbs 
- impaired function of the kidneys (may be seen in tests performed by your doctor) 
- fever 
- stomach ache, indigestion, feeling or being sick, constipation, diarrhoea 
- low blood pressure (symptoms may be feeling dizzy or fainting when standing up) 
- decreased general strength and energy (weakness, tiredness), headache, dizziness 
- rash, itchy skin 
- blood tests may show an increase in some liver enzymes 
 
Uncommon (may affect up to 1 in 100 people) 
- bleeding into the brain or inside the skull (see above, signs of bleeding)  
- bleeding into a joint causing pain and swelling 



238 

- thrombocytopenia (low number of platelets, which are cells that help blood to clot) 
- allergic reactions, including allergic skin reactions 
- impaired function of the liver (may be seen in tests performed by your doctor) 
- blood tests may show an increase in bilirubin, some pancreatic or liver enzymes or in the 

number of platelets 
- fainting 
- feeling unwell  
- faster heartbeat 
- dry mouth 
- hives 
 
Rare (may affect up to 1 in 1,000 people) 
- bleeding into a muscle 
- cholestasis (decreased bile flow), hepatitis incl. hepatocellular injury (inflamed liver incl. liver 

injury) 
- yellowing of the skin and eye (jaundice) 
- localised swelling 
- collection of blood (haematoma) in the groin as a complication of the cardiac procedure where a 

catheter is inserted in your leg artery (pseudoaneurysm)  
 
Not known (frequency cannot be estimated from the available data) 
- kidney failure after a severe bleeding 
- increased pressure within muscles of the legs or arms after a bleeding, which leads to pain, 

swelling, altered sensation, numbness or paralysis (compartment syndrome after a bleeding) 
 

Reporting of side effects 
16TIf you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet.16TYou 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 Xarelto 
 
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. 
 
Crushed tablets 
Crushed tablets are stable in water or apple puree for up tp 4 hours. 
 
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 Xarelto contains  
- The active substance is rivaroxaban. Each tablet contains 2.5 mg of rivaroxaban. 
- The other ingredients are:  

Tablet core: microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, 
hypromellose (2910), sodium laurilsulfate, magnesium stearate. See section 2 “Xarelto contains 
lactose and sodium”. 



239 

Tablet film coat: macrogol (3350), hypromellose (2910), titanium dioxide (E 171), iron oxide 
yellow (E 172).  

 
What Xarelto looks like and contents of the pack 
Xarelto 2.5 mg film-coated tablets are light yellow, round, biconvex and marked with the BAYER-
cross on one side and “2.5” and a triangle on the other side.  
They come  
-  in blisters in cartons of 14, 20, 28, 30, 56, 60, 98, 168 or 196 film-coated tablets or 
-  in unit dose blisters in cartons of 10 x 1 or 100 x 1 or  
-  in multipacks comprising 10 cartons, each containing 10 x 1 film-coated tablets or  
-  in bottles of 100 film-coated tablets. 
 
Not all pack sizes may be marketed.  
 
Marketing Authorisation Holder 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
Manufacturer 
 
The manufacturer can be identified by the batch number printed on the side flap of the carton and on 
each blister or bottle:  
 
•  If the first and second characters are BX, the manufacturer is  

Bayer AG  
Kaiser-Wilhelm-Allee  
51368 Leverkusen  
Germany  
 

•  If the first and second characters are IT, the manufacturer is  
Bayer HealthCare Manufacturing Srl.  
Via delle Groane, 126  
20024 Garbagnate Milanese  
Italy  
 

•  If the first and second characters are BT, the manufacturer is  
Bayer Bitterfeld GmbH  
Ortsteil Greppin, Salegaster Chaussee 1  
06803 Bitterfeld-Wolfen  
Germany 
 

 



240 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België / Belgique / Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 
 

Lietuva 
UAB Bayer 
Tel: +370-5-233 68 68 
 

България 
Байер България ЕООД 
Тел: +359-(0)2-424 72 80 
 

Luxembourg / Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 
 

Česká republika 
Bayer s.r.o. 
Tel: +420-266 101 111 
 

Magyarország 
Bayer Hungária KFT 
Tel: +36-1-487 4100 
 

Danmark 
Bayer A/S 
Tlf: +45-45 235 000 
 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +356-21 44 62 05 
 

Deutschland 
Bayer Vital GmbH 
Tel: +49-(0)214-30 513 48 
 

Nederland 
Bayer B.V. 
Tel: +31–(0)297-28 06 66 
 

Eesti 
Bayer OÜ 
Tel: +372-655 85 65 
 

Norge 
Bayer AS 
Tlf: +47-23 13 05 00 
 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30-210-618 75 00 
 

Österreich 
Bayer Austria Ges. m. b. H. 
Tel: +43-(0)1-711 460 
 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 
 

Polska 
Bayer Sp. z o.o. 
Tel: +48-22-572 35 00 
 

France 
Bayer HealthCare 
Tél (N° vert): +33-(0)800 87 54 54 
 

Portugal 
Bayer Portugal, Lda. 
Tel: +351-21-416 42 00 
 

Hrvatska 
Bayer d.o.o. 
Tel: + 385-(0)1-6599 900 
 

România 
SC Bayer SRL  
Tel: +40-(0)21-528 59 00 
 

Ireland 
Bayer Limited 
Tel: +353 1 216 3300 
 

Slovenija 
Bayer d. o. o. 
Tel: +386-(0)1-58 14 400 
 

Ísland 
Icepharma hf. 
Sími: +354-540 80 00 
 

Slovenská republika 
Bayer, spol. s r.o. 
Tel: +421-(0)2-59 21 31 11 
 

Italia 
Bayer S.p.A. 
Tel: +39-02-3978 1 
 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358-(0)20-78521  
 



241 

Κύπρος 
NOVAGEM Limited 
Τηλ: +357-22-48 38 58 
 

Sverige 
Bayer AB 
Tel: +46-(0)8-580 223 00  
 

Latvija 
SIA Bayer 
Tel: +371-67 84 55 63 
 

United Kingdom 
Bayer plc 
Tel: +44-(0) 118 206 3000 
 

 
This leaflet was last revised in  

 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 



242 

Package leaflet: Information for the user 
 

Xarelto 10 mg film-coated tablets 
rivaroxaban 

 

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 Xarelto is and what it is used for 
2. What you need to know before you take Xarelto 
3. How to take Xarelto 
4. Possible side effects 
5. How to store Xarelto 
6. Contents of the pack and other information 
 
 
1. What Xarelto is and what it is used for 
 
Xarelto contains the active substance rivaroxaban and is used in adults to  
-  prevent blood clots in the veins after a hip or knee replacement operation. Your doctor has 

prescribed this medicine for you because after an operation you are at an increased risk of 
getting blood clots. 

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

 
Xarelto belongs to a group of medicines called antithrombotic agents. It works by blocking a blood 
clotting factor (factor Xa) and thus reducing the tendency of the blood to form clots.  
 
 
2. What you need to know before you take Xarelto 
 
Do not take Xarelto 
- 16Tif you are allergic16T to rivaroxaban or any of the other ingredients of this medicine (listed in 

section 6) 
- 16Tif you are bleeding excessively 
16T- if you have a disease or condition in an organ of the body that increases the risk of serious 

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

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

- 16Tif you have a liver disease16T which leads to an increased risk of bleeding 
- 16Tif you are pregnant or breast-feeding 
16TDo not take Xarelto 16T 16Tand tell your doctor16T if any of these apply to you. 
 



243 

Warnings and precautions 
Talk to your doctor or pharmacist before taking Xarelto. 
 
Take special care with Xarelto 
 if you have 16Tan increased risk of bleeding, as could be the case in situations16T such as: 

▪ 16T moderate or severe kidney disease16T, since your kidney function may affect the amount of 
medicine that works in your body 

▪ if you are taking other medicines to prevent blood clotting (e.g. warfarin, dabigatran, 
apixaban or heparin), when changing anticoagulant treatment or while getting heparin 
through a venous or arterial line to keep it open (see section “Other medicines and 
Xarelto”) 

▪ 16Tbleeding disorders16T  
▪ 16Tvery high blood pressure,16T not controlled by medical treatment 
▪ diseases of your stomach or bowel that might result in bleeding, e.g. inflammation of the 

bowels or stomach, or inflammation of the oesophagus (gullet), e.g. due to 
gastroesophageal reflux disease (disease where stomach acid goes upwards into the 
oesophagus) 

▪ 16Ta problem with the blood vessels in the back of your eyes16T (retinopathy) 
▪ a lung disease where your bronchi are widened and filled with pus (bronchiectasis), or 

previous bleeding from your lung 
 if you have a prosthetic heart valve 
 if you know that you have a disease called antiphospholipid syndrome (a disorder of the 

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

 if your doctor determines that your blood pressure is unstable or another treatment or surgical 
procedure to remove the blood clot from your lungs is planned. 

 
16TIf any of the above apply to you, tell your doctor 16Tbefore you take Xarelto. Your doctor will decide, 
if you should be treated with this medicine and if you should be kept under closer observation.  
 
If you need to have an operation 
 it is very important to take Xarelto before and after the operation exactly at the times you have 

been told by your doctor.  
 If your operation involves a catheter or injection into your spinal column (e.g. for epidural or 

spinal anaesthesia or pain reduction):  
▪ it is very important to take Xarelto exactly at the times you have been told by your doctor  
▪ tell your doctor immediately if you get numbness or weakness of your legs or problems 

with your bowel or bladder after the end of anaesthesia, because urgent care is necessary. 
 
Children and adolescents 
Xarelto 10 mg tablets are 16Tnot recommended for people under 18 years of age.16T There is not enough 
information on their use in children and adolescents. 
 
Other medicines and Xarelto 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription. 
 



244 

 If you are taking 
 some medicines for fungal infections (e.g. fluconazole, itraconazole, voriconazole, 

posaconazole), unless they are only applied to the skin 
 ketoconazole tablets (used to treat Cushing’s syndrome - when the body produces an 

excess of cortisol) 
 some medicines for bacterial infections (e.g. clarithromycin, erythromycin)  
 some anti-viral medicines for HIV / AIDS (e.g. ritonavir) 
 other medicines to reduce blood clotting (e.g. enoxaparin, clopidogrel or vitamin K 

antagonists such as warfarin and acenocoumarol)  
 anti-inflammatory and pain relieving medicines (e.g. naproxen or acetylsalicylic acid) 
 dronedarone, a medicine to treat abnormal heart beat 
 some medicines to treat depression (selective serotonin reuptake inhibitors (SSRIs) or 

serotonin norepinephrine reuptake inhibitors (SNRIs)) 
 

16TIf any of the above apply to you, tell your doctor16T before taking Xarelto, because the effect of 
Xarelto may be increased. Your doctor will decide, if you should be treated with this medicine 
and if you should be kept under closer observation.  
16TIf your doctor thinks that you are at increased risk of developing stomach or bowel ulcers, he 
may also use a preventative ulcer treatment. 

 
 - If you are taking 

 some medicines for treatment of epilepsy (phenytoin, carbamazepine, phenobarbital) 
 St John’s Wort (Hypericum perforatum), a herbal product used for depression 
 rifampicin, an antibiotic 

 
16TIf any of the above apply to you, tell your doctor16T before taking Xarelto, because the effect of 
Xarelto may be reduced. Your doctor will decide, if you should be treated with Xarelto and if 
you should be kept under closer observation.  

 
Pregnancy and breast-feeding 
Do not take Xarelto16T if you are pregnant or breast-feeding16T. If there is a chance that you could become 
pregnant, use a reliable contraceptive while you are taking Xarelto. If you become pregnant while you 
are taking this medicine, tell your doctor immediately, who will decide how you should be treated. 
 
Driving and using machines 
Xarelto may cause dizziness (common side effect) or fainting (uncommon side effect) (see section 4 
”Possible side effects”). You should not drive, ride a bicycle or use any tools or machines if you are 
affected by these symptoms.  
 
16TXarelto contains lactose and sodium  
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-
free”. 
 
 
3. How to take Xarelto 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
How much to take 
- To prevent blood clots in the veins after a hip or knee replacement operation 

16TThe recommended dose is one tablet Xarelto 10 mg once a day16T.  
 
- To treat blood clots in the veins of your legs and blood clots in the blood vessels of your lungs, 

and for preventing blood clots from re-occurring 



245 

After at least 6 months blood clot treatment, the recommended dose is either one 10 mg tablet 
once a day or one 20 mg tablet once a day. Your doctor has prescribed you Xarelto 10 mg once 
a day.  

 
Swallow the tablet preferably with water. 
Xarelto can be taken with or without food. 
 
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take 
Xarelto. 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 Xarelto tablet through a stomach tube. 
 
When to take Xarelto 
Take the tablet every day until your doctor tells you to stop.  
Try to take the tablet at the same time every day to help you to remember it. 
Your doctor will decide how long you must continue treatment.  
 
To prevent blood clots in the veins after a hip or knee replacement operation: 
16TTake the first tablet 6 - 10 hours after your operation.  
16TIf you have had a major hip operation 16Tyou will usually take the tablets for 5 weeks.  
16TIf you have had a major knee operation 16T you will usually take the tablets for 2 weeks. 
 
If you take more Xarelto than you should 
16TContact your doctor immediately 16T if you have taken too many Xarelto tablets. Taking too much Xarelto 
increases the risk of bleeding.  
 
If you forget to take Xarelto  
If you have missed a dose, take it as soon as you remember. Take the next tablet on the following day 
and then carry on taking a tablet once a day as normal.  
Do not take a double dose to make up for a forgotten tablet. 
 
If you stop taking Xarelto  
Do not stop taking Xarelto without talking to your doctor first, because Xarelto prevents the 
development of a serious condition. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects  
 
Like all medicines, Xarelto can cause side effects, although not everybody gets them. 
 
Like other similar medicines to reduce the formation of blood clots, Xarelto may cause bleeding which 
may potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure 
(shock). In some cases the bleeding may not be obvious. 
 
Tell your doctor immediately if you experience any of the following side effects: 
 Signs of bleeding 

- bleeding into the brain or inside the skull (symptoms can include headache, one-sided 
weakness, vomiting, seizures, decreased level of consciousness, and neck stiffness. 
A serious medical emergency. Seek medical attention immediately!) 

- long or excessive bleeding 
- exceptional weakness, tiredness, paleness, dizziness, headache, unexplained swelling, 

breathlessness, chest pain or angina pectoris 
 Your doctor may decide to keep you under closer observation or change the treatment.  
 



246 

 Signs of severe skin reactions 
- spreading intense skin rash, blisters or mucosal lesions, e.g. in the mouth or eyes 

(Stevens-Johnson syndrome/toxic epidermal necrolysis).  
- a drug reaction that causes rash, fever, inflammation of internal organs, blood 

abnormalities and systemic illness (DRESS syndrome).  
The frequency of these side effects is very rare (up to 1 in 10,000 people). 

 
 Signs of severe allergic reactions 

- swelling of the face, lips, mouth, tongue or throat; difficulty swallowing; hives and 
breathing difficulties; sudden drop in blood pressure.  

The frequencies of severe allergic reactions are very rare (anaphylactic reactions, including 
anaphylactic shock; may affect up to 1 in 10,000 people) and uncommon (angioedema and 
allergic oedema; may affect up to 1 in 100 people). 

 
Overall list of possible side effects 
Common (may affect up to 1 in 10 people)  
- reduction in red blood cells which can make the skin pale and cause weakness or breathlessness 
- bleeding in the stomach or bowel, urogenital bleeding (including blood in the urine and heavy 

menstrual bleeding), nose bleed, bleeding in the gum 
- bleeding into the eye (including bleeding from the whites of the eyes) 
- bleeding into tissue or a cavity of the body (haematoma, bruising) 
- coughing up blood 
- bleeding from the skin or under the skin 
- bleeding following an operation  
- oozing of blood or fluid from surgical wound 
- swelling in the limbs 
- pain in the limbs 
- impaired function of the kidneys (may be seen in tests performed by your doctor) 
- fever 
- stomach ache, indigestion, feeling or being sick, constipation, diarrhoea 
- low blood pressure (symptoms may be feeling dizzy or fainting when standing up) 
- decreased general strength and energy (weakness, tiredness), headache, dizziness 
- rash, itchy skin 
- blood tests may show an increase in some liver enzymes  
 
Uncommon (may affect up to 1 in 100 people) 
- bleeding into the brain or inside the skull (see above, signs of bleeding)  
- bleeding into a joint causing pain and swelling 
- thrombocytopenia (low number of platelets, which are cells that help blood to clot) 
- allergic reactions, including allergic skin reactions 
- impaired function of the liver (may be seen in tests performed by your doctor) 
- blood tests may show an increase in bilirubin, some pancreatic or liver enzymes or in the 

number of platelets 
- fainting 
- feeling unwell  
- faster heartbeat 
- dry mouth 
- hives 
 
Rare (may affect up to 1 in 1,000 people) 
- bleeding into a muscle 
- cholestasis (decreased bile flow), hepatitis incl. hepatocellular injury (inflamed liver incl. liver 

injury) 
- yellowing of the skin and eye (jaundice) 
- localised swelling 
- collection of blood (haematoma) in the groin as a complication of the cardiac procedure where a 

catheter is inserted in your leg artery (pseudoaneurysm) 



247 

 
Not known (frequency cannot be estimated from the available data) 
- kidney failure after a severe bleeding 
- increased pressure within muscles of the legs or arms after a bleeding, which leads to pain, 

swelling, altered sensation, numbness or paralysis (compartment syndrome after a bleeding) 
 
Reporting of side effects 
16TIf you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. 16TYou 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 Xarelto 
 
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. 
 
Crushed tablets 
Crushed tablets are stable in water or apple puree for up to 4 hours. 
 
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 Xarelto contains 
- The active substance is rivaroxaban. Each tablet contains 10 mg of rivaroxaban. 
- The other ingredients are:  

Tablet core: microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, 
hypromellose (2910), sodium laurilsulfate, magnesium stearate. See section 2 “Xarelto contains 
lactose and sodium”. 
Tablet film coat: macrogol (3350), hypromellose (2910), titanium dioxide (E 171), iron oxide 
red (E 172).  

 
What Xarelto looks like and contents of the pack 
Xarelto 10 mg film-coated tablets are light red, round, biconvex and marked with the BAYER-cross 
on one side and “10” and a triangle on the other side.  
They come  
- in blisters in cartons of 5, 10, 14, 28, 30 or 98 film-coated tablets or  
- in unit dose blisters in cartons of 10 x 1 or 100 x 1 or  
- in multipacks comprising 10 cartons, each containing 10 x 1 film-coated tablets or  
- in bottles of 100 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
 
Bayer AG 
51368 Leverkusen 
Germany 
 



248 

Manufacturer 
 
The manufacturer can be identified by the batch number printed on the side flap of the carton and on 
each blister or bottle:  
 
•  If the first and second characters are BX, the manufacturer is  

Bayer AG  
Kaiser-Wilhelm-Allee  
51368 Leverkusen  
Germany  
 

•  If the first and second characters are IT, the manufacturer is  
Bayer HealthCare Manufacturing Srl.  
Via delle Groane, 126  
20024 Garbagnate Milanese  
Italy  
 

•  If the first and second characters are BT, the manufacturer is  
Bayer Bitterfeld GmbH  
Ortsteil Greppin, Salegaster Chaussee 1  
06803 Bitterfeld-Wolfen  
Germany 

 
 



249 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België / Belgique / Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 
 

Lietuva 
UAB Bayer 
Tel: +370-5-233 68 68 
 

България 
Байер България ЕООД 
Тел: +359-(0)2-424 72 80 
 

Luxembourg / Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 
 

Česká republika 
Bayer s.r.o. 
Tel: +420-266 101 111 
 

Magyarország 
Bayer Hungária KFT 
Tel: +36-1-487 4100 
 

Danmark 
Bayer A/S 
Tlf: +45-45 235 000 
 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +356-21 44 62 05 
 

Deutschland 
Bayer Vital GmbH 
Tel: +49-(0)214-30 513 48 
 

Nederland 
Bayer B.V. 
Tel: +31–(0)297-28 06 66 
 

Eesti 
Bayer OÜ 
Tel: +372-655 85 65 
 

Norge 
Bayer AS 
Tlf: +47-23 13 05 00 
 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30-210-618 75 00 
 

Österreich 
Bayer Austria Ges. m. b. H. 
Tel: +43-(0)1-711 460 
 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 
 

Polska 
Bayer Sp. z o.o. 
Tel: +48-22-572 35 00 
 

France 
Bayer HealthCare 
Tél (N° vert): +33-(0)800 87 54 54 
 

Portugal 
Bayer Portugal, Lda. 
Tel: +351-21-416 42 00 
 

Hrvatska 
Bayer d.o.o. 
Tel: + 385-(0)1-6599 900 
 

România 
SC Bayer SRL  
Tel: +40-(0)21-528 59 00 
 

Ireland 
Bayer Limited 
Tel: +353 1 216 3300 
 

Slovenija 
Bayer d. o. o. 
Tel: +386-(0)1-58 14 400 
 

Ísland 
Icepharma hf. 
Sími: +354-540 80 00 
 

Slovenská republika 
Bayer, spol. s r.o. 
Tel: +421-(0)2-59 21 31 11 
 

Italia 
Bayer S.p.A. 
Tel: +39-02-3978 1 
 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358-(0)20-78521  
 



250 

Κύπρος 
NOVAGEM Limited 
Τηλ: +357-22-48 38 58 
 

Sverige 
Bayer AB 
Tel: +46-(0)8-580 223 00  
 

Latvija 
SIA Bayer 
Tel: +371-67 84 55 63 
 

United Kingdom 
Bayer plc 
Tel: +44-(0) 118 206 3000 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 
 



251 

Package leaflet: Information for the user 
 

Xarelto 15 mg film-coated tablets 
Xarelto 20 mg film-coated tablets 

rivaroxaban 
 

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 Xarelto is and what it is used for 
2. What you need to know before you take Xarelto 
3. How to take Xarelto 
4. Possible side effects 
5. How to store Xarelto 
6. Contents of the pack and other information 
 
 
1. What Xarelto is and what it is used for 
 
Xarelto contains the active substance rivaroxaban.  
Xarelto is used in adults to:  
- prevent blood clots in brain (stroke) and other blood vessels in your body if you have a form of 

irregular heart rhythm called non-valvular atrial fibrillation.  
- treat blood clots in the veins of your legs (deep vein thrombosis) and in the blood vessels of 

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

Xarelto is used in children and adolescents below 18 years and with a body weight of 30 kg or more 
to:  
- treat blood clots and prevent re-occurrence of blood clots in the veins or in the blood vessels of 

the lungs, following initial treatment of at least 5 days with injectable medicines used to treat 
blood clots.  

 
Xarelto belongs to a group of medicines called antithrombotic agents. It works by blocking a blood 
clotting factor (factor Xa) and thus reducing the tendency of the blood to form clots.  
 
 



252 

2. What you need to know before you take Xarelto 
 
Do not take Xarelto 
- 16Tif you are allergic16T to rivaroxaban or any of the other ingredients of this medicine (listed in 

section 6) 
- 16Tif you are bleeding excessively 
- 16Tif you have a disease or condition in an organ of the body that increases the risk of serious 

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

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

- 16Tif you have a liver disease16T which leads to an increased risk of bleeding 
- 16Tif you are pregnant or are breast-feeding 
16TDo not take Xarelto 16T 16Tand tell your doctor16T if any of these apply to you. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Xarelto. 
 
Take special care with Xarelto 
 if you have 16Tan increased risk of bleeding, as could be the case in situations16T such as: 

▪ severe kidney disease for adults, and moderate or severe kidney disease for children and 
adolescents, since your kidney function may affect the amount of medicine that works in 
your body 

▪ if you are taking other medicines to prevent blood clotting (e.g. warfarin, dabigatran, 
apixaban or heparin), when changing anticoagulant treatment or while getting heparin 
through a venous or arterial line to keep it open (see section “Other medicines and 
Xarelto”) 

▪ 16Tbleeding disorders16T  
▪ 16Tvery high blood pressure,16T not controlled by medical treatment 
▪ diseases of your stomach or bowel that might result in bleeding, e.g. inflammation of the 

bowels or stomach, or inflammation of the oesophagus (gullet), e.g. due to 
gastroesophageal reflux disease (disease where stomach acid goes upwards into the 
oesophagus) 

▪ 16Ta problem with the blood vessels in the back of your eyes16T (retinopathy) 
▪ a lung disease where your bronchi are widened and filled with pus (bronchiectasis), or 

previous bleeding from your lung 
 if you have a prosthetic heart valve 
 if you know that you have a disease called antiphospholipid syndrome (a disorder of the 

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

 if your doctor determines that your blood pressure is unstable or another treatment or surgical 
procedure to remove the blood clot from your lungs is planned 

 
16TIf any of the above apply to you, tell your doctor 16Tbefore you take Xarelto. Your doctor will decide, 
if you should be treated with this medicine and if you should be kept under closer observation.  
 
If you need to have an operation 
 it is very important to take Xarelto before and after the operation exactly at the times you have 

been told by your doctor. 
 If your operation involves a catheter or injection into your spinal column (e.g. for epidural or 

spinal anaesthesia or pain reduction): 
 16Tit is very important to take Xarelto before and after the injection or removal of the catheter 

exactly at the times you have been told by your doctor 
 tell your doctor immediately if you get numbness or weakness of your legs or problems 

with your bowel or bladder after the end of anaesthesia, because urgent care is necessary. 
 



253 

16TChildren and adolescents 
Xarelto tablets are16T not recommended for children with a body weight below 30 kg.16T  
There is not enough information on the use of Xarelto in children and adolescents in the adult 
indications.  
 
Other medicines and Xarelto 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription. 
 If you are taking 

 some medicines for fungal infections (e.g. fluconazole, itraconazole, voriconazole, 
posaconazole), unless they are only applied to the skin 

 ketoconazole tablets (used to treat Cushing’s syndrome - when the body produces an 
excess of cortisol) 

 some medicines for bacterial infections (e.g. clarithromycin, erythromycin)  
 some anti-viral medicines for HIV / AIDS (e.g. ritonavir) 
 other medicines to reduce blood clotting (e.g. enoxaparin, clopidogrel or vitamin K 

antagonists such as warfarin and acenocoumarol)  
 anti-inflammatory and pain relieving medicines (e.g. naproxen or acetylsalicylic acid) 
 dronedarone, a medicine to treat abnormal heart beat 
 some medicines to treat depression (selective serotonin reuptake inhibitors (SSRIs) or 

serotonin norepinephrine reuptake inhibitors (SNRIs)) 
 
16TIf any of the above apply to you, tell your doctor16T before taking Xarelto, because the effect of 
Xarelto may be increased. Your doctor will decide, if you should be treated with this medicine 
and if you should be kept under closer observation.  
16TIf your doctor thinks that you are at increased risk of developing stomach or bowel ulcers, he 
may also use a preventative ulcer treatment.  
 

 If you are taking 
 some medicines for treatment of epilepsy (phenytoin, carbamazepine, phenobarbital) 
 St John’s Wort (Hypericum perforatum), a herbal product used for depression 
 rifampicin, an antibiotic 
 
16TIf any of the above apply to you, tell your doctor16T before taking Xarelto, because the effect of 
Xarelto may be reduced. Your doctor will decide, if you should be treated with Xarelto and if 
you should be kept under closer observation.  

 
Pregnancy and breast-feeding 
Do not take Xarelto16T if you are pregnant or breast-feeding16T. If there is a chance that you could become 
pregnant, use a reliable contraceptive while you are taking Xarelto. If you become pregnant while you 
are taking this medicine, tell your doctor immediately, who will decide how you should be treated. 
 
Driving and using machines 
Xarelto may cause dizziness (common side effect) or fainting (uncommon side effect) (see section 4, 
”Possible side effects”). You should not drive, ride a bicycle or use any tools or machines if you are 
affected by these symptoms.  
 
Xarelto contains lactose and sodium 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-
free”. 
 
 



254 

3. How to take Xarelto 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.  
 
You must take Xarelto together with a meal.  
Swallow the tablet(s) preferably with water. 
 
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take 
Xarelto. The tablet may be crushed and mixed with water or apple puree immediately before you take 
it. This mixture should be immediately followed by food. 
If necessary, your doctor may also give you the crushed Xarelto tablet through a stomach tube. 
 
How much to take 
 Adults 

 To prevent blood clots in brain (stroke) and other blood vessels in your body 
The recommended dose is one tablet Xarelto 20 mg once a day.  
If you have kidney problems, the dose may be reduced to one tablet Xarelto 15 mg once a 
day.  
 
If you need a procedure to treat blocked blood vessels in your heart (called a 
percutaneous coronary intervention - PCI with an insertion of a stent), there is limited 
evidence to reduce the dose to one tablet Xarelto 15 mg once a day (or to one tablet 
Xarelto 10 mg once a day in case your kidneys are not working properly) in addition to an 
antiplatelet medicine such as clopidogrel. 

 
 To treat blood clots in the veins of your legs and blood clots in the blood vessels of your 

lungs, and for preventing blood clots from re-occurring 
The recommended dose is one tablet Xarelto 15 mg twice a day for the first 3 weeks. For 
treatment after 3 weeks, the recommended dose is one tablet Xarelto 20 mg once a day.  
After at least 6 months blood clot treatment your doctor may decide to continue treatment 
with either one 10 mg tablet once a day or one 20 mg tablet once a day. 
If you have kidney problems and take one tablet Xarelto 20 mg once a day, your doctor 
may decide to reduce the dose for the treatment after 3 weeks to one tablet Xarelto 15 mg 
once a day if the risk for bleeding is greater than the risk for having another blood clot.  

 
 Children and adolescents  

The dose of Xarelto depends on the body weight, and will be calculated by the doctor.  
 The recommended dose for children and adolescents with a body weight between 30 kg 

and less than 50 kg is one Xarelto 15 mg tablet once a day. 
 The recommended dose for children and adolescents with a body weight of 50 kg or 

more is one Xarelto 20 mg tablet once a day.  
Take each Xarelto dose with a drink (e.g. water or juice) during a meal. Take the tablets every 
day at approximately the same time. Consider setting an alarm to remind you. 
For parents or caregivers: please observe the child to ensure the full dose is taken.  
 
As the Xarelto dose is based on body weight it is important to keep scheduled doctor’s visits 
because the dose may need to be adjusted as the weight changes. 
Never adjust the dose of Xarelto by yourself. The doctor will adjust the dose if necessary. 
 
Do not split the tablet in an attempt to provide a fraction of a tablet dose. If a lower dose is 
required please use the alternative presentation of Xarelto granules for oral suspension. 
For children and adolescents who are unable to swallow tablets whole, please use Xarelto 
granules for oral suspension.  
If the oral suspension is not available, you may crush the Xarelto tablet and mix with water or 
apple puree immediately before taking. Take some food after taking this mixture. If necessary, 
your doctor may also give the crushed Xarelto tablet through a stomach tube. 



255 

 
If you spit up the dose or vomit 
 less than 30 minutes after you have taken Xarelto, take a new dose.  
 more than 30 minutes after you have taken Xarelto, do not take a new dose. In this case, 

take the next Xarelto dose at the usual time. 
 
Contact the doctor if you repeatedly spit up the dose or vomit after taking Xarelto. 

 
When to take Xarelto 
Take the tablet(s) every day until your doctor tells you to stop.  
Try to take the tablet(s) at the same time every day to help you to remember it. 
Your doctor will decide how long you must continue treatment.  
 
To prevent blood clots in the brain (stroke) and other blood vessels in your body: 
If your heart beat needs to be restored to normal by a procedure called cardioversion, take Xarelto at 
the times your doctor tells you. 
 
If you forget to take Xarelto 
- Adults, children and adolescents:  

If you are taking one 20 mg tablet or one 15 mg tablet once a day and have missed a dose, take 
it as soon as you remember. Do not take more than one tablet in a single day to make up for a 
forgotten dose. Take the next tablet on the following day and then carry on taking one tablet 
once a day. 

 
- Adults: 

If you are taking one 15 mg tablet twice a day and have missed a dose, take it as soon as you 
remember. Do not take more than two 15 mg tablets in a single day. If you forget to take a dose 
you can take two 15 mg tablets at the same time to get a total of two tablets (30 mg) on one day. 
On the following day you should carry on taking one 15 mg tablet twice a day. 

 
If you take more Xarelto than you should 
16TContact your doctor immediately 16T if you have taken too many Xarelto tablets. Taking too much Xarelto 
increases the risk of bleeding.  
 
If you stop taking Xarelto 
Do not stop taking Xarelto without talking to your doctor first, because Xarelto treats and prevents 
serious conditions.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, Xarelto can cause side effects, although not everybody gets them. 
 
Like other similar medicines to reduce the formation of blood clots, Xarelto may cause bleeding which 
may potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure 
(shock). In some cases the bleeding may not be obvious. 
 



256 

Tell your doctor immediately if you or the child experience any of the following side effects: 
 Signs of bleeding 

- bleeding into the brain or inside the skull (symptoms can include headache, one-sided 
weakness, vomiting, seizures, decreased level of consciousness, and neck stiffness. 
A serious medical emergency. Seek medical attention immediately!) 

- long or excessive bleeding 
- exceptional weakness, tiredness, paleness, dizziness, headache, unexplained swelling, 

breathlessness, chest pain or angina pectoris 
 Your doctor may decide to keep you under closer observation or change the treatment.  
 
 Signs of severe skin reactions 

- spreading intense skin rash, blisters or mucosal lesions, e.g. in the mouth or eyes 
(Stevens-Johnson syndrome/toxic epidermal necrolysis).  

- a drug reaction that causes rash, fever, inflammation of internal organs, blood 
abnormalities and systemic illness (DRESS syndrome).  

The frequency of these side effects is very rare (up to 1 in 10,000 people). 
 
 Signs of severe allergic reactions 

- swelling of the face, lips, mouth, tongue or throat; difficulty swallowing; hives and 
breathing difficulties; sudden drop in blood pressure.  

The frequencies of severe allergic reactions are very rare (anaphylactic reactions, including 
anaphylactic shock; may affect up to 1 in 10,000 people) and uncommon (angioedema and 
allergic oedema; may affect up to 1 in 100 people). 

 
Overall list of possible side effects found in adults, children and adolescents 
Common (may affect up to 1 in 10 people) 
- reduction in red blood cells which can make the skin pale and cause weakness or breathlessness 
- bleeding in the stomach or bowel, urogenital bleeding (including blood in the urine and heavy 

menstrual bleeding), nose bleed, bleeding in the gum 
- bleeding into the eye (including bleeding from the whites of the eyes) 
- bleeding into tissue or a cavity of the body (haematoma, bruising)  
- coughing up blood 
- bleeding from the skin or under the skin 
- bleeding following an operation  
- oozing of blood or fluid from surgical wound 
- swelling in the limbs 
- pain in the limbs 
- impaired function of the kidneys (may be seen in tests performed by your doctor) 
- fever 
- stomach ache, indigestion, feeling or being sick, constipation, diarrhoea 
- low blood pressure (symptoms may be feeling dizzy or fainting when standing up) 
- decreased general strength and energy (weakness, tiredness), headache, dizziness 
- rash, itchy skin 
- blood tests may show an increase in some liver enzymes 
 



257 

Uncommon (may affect up to 1 in 100 people) 
- bleeding into the brain or inside the skull (see above, signs of bleeding) 
- bleeding into a joint causing pain and swelling 
- thrombocytopenia (low number of platelets, which are cells that help blood to clot) 
- allergic reactions, including allergic skin reactions 
- impaired function of the liver (may be seen in tests performed by your doctor) 
- blood tests may show an increase in bilirubin, some pancreatic or liver enzymes or in the 

number of platelets 
- fainting 
- feeling unwell  
- faster heartbeat 
- dry mouth 
- hives 
 
Rare (may affect up to 1 in 1,000 people) 
- bleeding into a muscle 
- cholestasis (decreased bile flow), hepatitis incl. hepatocellular injury (inflamed liver incl. liver 

injury) 
- yellowing of the skin and eye (jaundice) 
- localised swelling 
- collection of blood (haematoma) in the groin as a complication of the cardiac procedure where a 

catheter is inserted in your leg artery (pseudoaneurysm) 
 
Not known (frequency cannot be estimated from the available data)  
- kidney failure after a severe bleeding 
- increased pressure within muscles of the legs or arms after a bleeding, which leads to pain, 

swelling, altered sensation, numbness or paralysis (compartment syndrome after a bleeding) 
 
Side effects in children and adolescents  
In general, the side effects observed in children and adolescents treated with Xarelto were similar in 
type to those observed in adults and were primarily mild to moderate in severity. 
 
Side effects that were observed more often in children and adolescents: 
 
Very common (may affect more than 1 in 10 people) 
- headache 
- fever 
- nose bleeding 
- vomiting 
Common (may affect up to 1 in 10 people) 
- raised heartbeat 
- blood tests may show an increase in bilirubin (bile pigment) 
- thrombocytopenia (low number of platelets which are cells that help blood to clot)  
- heavy menstrual bleeding  
Uncommon (may affect up to 1 in 100 people) 
- blood tests may show an increase in a subcategory of bilirubin (direct bilirubin, bile pigment) 
 
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 Xarelto 
 
Keep this medicine out of the sight and reach of children. 



258 

 
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. 
 
Crushed tablets 
Crushed tablets are stable in water or apple puree for up to 4 hours. 
 
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 Xarelto contains  
- The active substance is rivaroxaban. Each tablet contains 15 mg or 20 mg of rivaroxaban. 
- The other ingredients are:  

Tablet core: microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, 
hypromellose (2910), sodium laurilsulfate, magnesium stearate. See section 2 “Xarelto contains 
lactose and sodium” 
Tablet film coat: macrogol (3350), hypromellose (2910), titanium dioxide (E 171), iron oxide 
red (E 172).  

 
What Xarelto looks like and contents of the pack 
Xarelto 15 mg film-coated tablets are red, round, biconvex and marked with the BAYER-cross on one 
side and “15” and a triangle on the other side.  
They come  
- in blisters in cartons of 10, 14, 28, 42 or 98 film-coated tablets or  
- in unit dose blisters in cartons of 10 x 1 or 100 x 1 or  
- in multipacks comprising 10 cartons, each containing 10 x 1 film-coated tablets or  
- in bottles of 100 film-coated tablets. 
 
Xarelto 20 mg film-coated tablets are brown-red, round, biconvex and marked with the BAYER-cross 
on one side and “20” and a triangle on the other.  
They come  
- in blisters in cartons of 10, 14, 28 or 98 film-coated tablets or  
- in unit dose blisters in cartons of 10 x 1 or 100 x 1 or  
- in multipacks comprising 10 cartons, each containing 10 x 1 film-coated tablets or  
- in bottles of 100 film-coated tablets. 
 
Not all pack sizes may be marketed.  
 
Marketing Authorisation Holder 
 
Bayer AG 
51368 Leverkusen 
Germany 
 



259 

Manufacturer 
 
The manufacturer can be identified by the batch number printed on the side flap of the carton and on 
each blister or bottle:  
 
•  If the first and second characters are BX, the manufacturer is  

Bayer AG  
Kaiser-Wilhelm-Allee  
51368 Leverkusen  
Germany  
 

•  If the first and second characters are IT, the manufacturer is  
Bayer HealthCare Manufacturing Srl.  
Via delle Groane, 126  
20024 Garbagnate Milanese  
Italy  
 

•  If the first and second characters are BT, the manufacturer is  
Bayer Bitterfeld GmbH  
Ortsteil Greppin, Salegaster Chaussee 1  
06803 Bitterfeld-Wolfen  
Germany 

 



260 

 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België / Belgique / Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 
 

Lietuva 
UAB Bayer 
Tel: +370-5-233 68 68 
 

България 
Байер България ЕООД 
Тел: +359-(0)2-424 72 80 
 

Luxembourg / Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 
 

Česká republika 
Bayer s.r.o. 
Tel: +420-266 101 111 
 

Magyarország 
Bayer Hungária KFT 
Tel: +36-1-487 4100 
 

Danmark 
Bayer A/S 
Tlf: +45-45 235 000 
 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +356-21 44 62 05 
 

Deutschland 
Bayer Vital GmbH 
Tel: +49-(0)214-30 513 48 
 

Nederland 
Bayer B.V. 
Tel: +31–(0)297-28 06 66 
 

Eesti 
Bayer OÜ 
Tel: +372-655 85 65 
 

Norge 
Bayer AS 
Tlf: +47-23 13 05 00 
 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30-210-618 75 00 
 

Österreich 
Bayer Austria Ges. m. b. H. 
Tel: +43-(0)1-711 460 
 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 
 

Polska 
Bayer Sp. z o.o. 
Tel: +48-22-572 35 00 
 

France 
Bayer HealthCare 
Tél (N° vert): +33-(0)800 87 54 54 
 

Portugal 
Bayer Portugal, Lda. 
Tel: +351-21-416 42 00 
 

Hrvatska 
Bayer d.o.o. 
Tel: + 385-(0)1-6599 900 
 

România 
SC Bayer SRL  
Tel: +40-(0)21-528 59 00 
 

Ireland 
Bayer Limited 
Tel: +353 1 216 3300 
 

Slovenija 
Bayer d. o. o. 
Tel: +386-(0)1-58 14 400 
 

Ísland 
Icepharma hf. 
Sími: +354-540 80 00 
 

Slovenská republika 
Bayer, spol. s r.o. 
Tel: +421-(0)2-59 21 31 11 
 

Italia 
Bayer S.p.A. 
Tel: +39-02-3978 1 
 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358-(0)20-78521  
 



261 

Κύπρος 
NOVAGEM Limited 
Τηλ: +357-22-48 38 58 
 

Sverige 
Bayer AB 
Tel: +46-(0)8-580 223 00  
 

Latvija 
SIA Bayer 
Tel: +371-67 84 55 63 
 

United Kingdom 
Bayer plc 
Tel: +44-(0) 118 206 3000 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 



262 

Package leaflet: Information for the user 
 

Xarelto 15 mg film-coated tablets 
Xarelto 20 mg film-coated tablets 

 
Treatment Initiation Pack 

Not for use in children. 
rivaroxaban 

 

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 Xarelto is and what it is used for 
2. What you need to know before you take Xarelto 
3. How to take Xarelto 
4. Possible side effects 
5. How to store Xarelto 
6. Contents of the pack and other information 
 
 
1. What Xarelto is and what it is used for 
 
Xarelto contains the active substance rivaroxaban and is used in adults to:  
- treat blood clots in the veins of your legs (deep vein thrombosis) and in the blood vessels of 

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

 
Xarelto belongs to a group of medicines called antithrombotic agents. It works by blocking a blood 
clotting factor (factor Xa) and thus reducing the tendency of the blood to form clots.  
 
 
2. What you need to know before you take Xarelto 
 
Do not take Xarelto 
- 16Tif you are allergic16T to rivaroxaban or any of the other ingredients of this medicine (listed in 

section 6) 
- 16Tif you are bleeding excessively 
- 16Tif you have a disease or condition in an organ of the body that increases the risk of serious 

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

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

- 16Tif you have a liver disease16T which leads to an increased risk of bleeding 
- 16Tif you are pregnant or breast-feeding 
16TDo not take Xarelto 16T 16Tand tell your doctor16T if any of these apply to you. 



263 

 
Warnings and precautions 
Talk to your doctor or pharmacist before taking Xarelto. 
 
Take special care with Xarelto 
 if you have 16Tan increased risk of bleeding, as could be the case in situations16T such as: 

▪ severe kidney disease, since your kidney function may affect the amount of medicine that 
works in your body 

▪ if you are taking other medicines to prevent blood clotting (e.g. warfarin, dabigatran, 
apixaban or heparin), when changing anticoagulant treatment or while getting heparin 
through a venous or arterial line to keep it open (see section “Other medicines and 
Xarelto”) 

▪ 16Tbleeding disorders16T  
▪ 16Tvery high blood pressure,16T not controlled by medical treatment 
▪ diseases of your stomach or bowel that might result in bleeding, e.g. inflammation of the 

bowels or stomach, or inflammation of the oesophagus (gullet), e.g. due to 
gastroesophageal reflux disease (disease where stomach acid goes upwards into the 
oesophagus) 

▪ 16Ta problem with the blood vessels in the back of your eyes16T (retinopathy) 
▪ a lung disease where your bronchi are widened and filled with pus (bronchiectasis), or 

previous bleeding from your lung 
 if you have a prosthetic heart valve 
 if you know that you have a disease called antiphospholipid syndrome (a disorder of the 

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

 if your doctor determines that your blood pressure is unstable or another treatment or surgical 
procedure to remove the blood clot from your lungs is planned 

 
16TIf any of the above apply to you, tell your doctor 16Tbefore you take Xarelto. Your doctor will decide, 
if you should be treated with this medicine and if you should be kept under closer observation.  
 
If you need to have an operation 
 it is very important to take Xarelto before and after the operation exactly at the times you have 

been told by your doctor. 
 If your operation involves a catheter or injection into your spinal column (e.g. for epidural or 

spinal anaesthesia or pain reduction): 
 16Tit is very important to take Xarelto before and after the injection or removal of the catheter 

exactly at the times you have been told by your doctor 
 tell your doctor immediately if you get numbness or weakness of your legs or problems 

with your bowel or bladder after the end of anaesthesia, because urgent care is necessary. 
 
16TChildren and adolescents 
Xarelto treatment initiation pack is 16Tnot recommended for people under 18 years of age as it is 
16Tspecifically designed for initiation of treatment in adult patients and is not appropriate for use in 
children and adolescents. 
 
Other medicines and Xarelto 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription. 



264 

 If you are taking 
 some medicines for fungal infections (e.g. fluconazole, itraconazole, voriconazole, 

posaconazole), unless they are only applied to the skin 
 ketoconazole tablets (used to treat Cushing’s syndrome - when the body produces an 

excess of cortisol) 
 some medicines for bacterial infections (e.g. clarithromycin, erythromycin)  
 some anti-viral medicines for HIV / AIDS (e.g. ritonavir) 
 other medicines to reduce blood clotting (e.g. enoxaparin, clopidogrel or vitamin K 

antagonists such as warfarin and acenocoumarol)  
 anti-inflammatory and pain relieving medicines (e.g. naproxen or acetylsalicylic acid) 
 dronedarone, a medicine to treat abnormal heart beat 
 some medicines to treat depression (selective serotonin reuptake inhibitors (SSRIs) or 

serotonin norepinephrine reuptake inhibitors (SNRIs)) 
16TIf any of the above apply to you, tell your doctor16T before taking Xarelto, because the effect of 
Xarelto may be increased. Your doctor will decide, if you should be treated with this medicine 
and if you should be kept under closer observation.  
16TIf your doctor thinks that you are at increased risk of developing stomach or bowel ulcers, he 
may also use a preventative ulcer treatment.  
 

 If you are taking 
 some medicines for treatment of epilepsy (phenytoin, carbamazepine, phenobarbital) 
 St John’s Wort (Hypericum perforatum), a herbal product used for depression 
 rifampicin, an antibiotic 
 
16TIf any of the above apply to you, tell your doctor16T before taking Xarelto, because the effect of 
Xarelto may be reduced. Your doctor will decide, if you should be treated with Xarelto and if 
you should be kept under closer observation.  

 
Pregnancy and breast-feeding 
Do not take Xarelto16T if you are pregnant or breast-feeding16T. If there is a chance that you could become 
pregnant, use a reliable contraceptive while you are taking Xarelto. If you become pregnant while you 
are taking this medicine, tell your doctor immediately, who will decide how you should be treated. 
 
Driving and using machines 
Xarelto may cause dizziness (common side effect) or fainting (uncommon side effect) (see section 4, 
”Possible side effects”). You should not drive, ride a bicycle or use any tools or machines if you are 
affected by these symptoms.  
 
Xarelto contains lactose and sodium 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-
free”. 
 
 
3. How to take Xarelto 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure.  
 
You must take Xarelto together with a meal.  
Swallow the tablet(s) preferably with water. 
 
If you have difficulty swallowing the tablet whole, talk to your doctor about other ways to take 
Xarelto. The tablet may be crushed and mixed with water or apple puree immediately before you take 
it. This mixture should be immediately followed by food. 
If necessary, your doctor may also give you the crushed Xarelto tablet through a stomach tube. 



265 

 
How much to take 
The recommended dose is one tablet Xarelto 15 mg twice a day for the first 3 weeks. For treatment 
after 3 weeks, the recommended dose is one tablet Xarelto 20 mg once a day.  
This Xarelto 15 mg and 20 mg treatment initiation pack is only for the first 4 weeks of treatment.  
Upon completion of this pack, treatment will continue on Xarelto 20 mg once daily as your doctor has 
told you.  
If you have kidney problems, your doctor may decide to reduce the dose for the treatment after 3 
weeks to one tablet Xarelto 15 mg once a day if the risk for bleeding is greater than the risk for having 
another blood clot.  
 
When to take Xarelto 
Take the tablet(s) every day until your doctor tells you to stop.  
Try to take the tablet(s) at the same time every day to help you to remember it. 
Your doctor will decide how long you must continue treatment.  
 
If you take more Xarelto than you should 
16TContact your doctor immediately 16T if you have taken too many Xarelto tablets. Taking too much Xarelto 
increases the risk of bleeding.  
 
If you forget to take Xarelto 
- If you are taking one 15 mg tablet twice a day and have missed a dose, take it as soon as you 

remember. Do not take more than two 15 mg tablets in a single day. If you forget to take a dose 
you can take two 15 mg tablets at the same time to get a total of two tablets (30 mg) on one day. 
On the following day you should carry on taking one 15 mg tablet twice a day. 
 

- If you are taking one 20 mg tablet once a day and have missed a dose, take it as soon as you 
remember. Do not take more than one tablet in a single day to make up for a forgotten dose. 
Take the next tablet on the following day and then carry on taking one tablet once a day. 

 
If you stop taking Xarelto 
Do not stop taking Xarelto without talking to your doctor first, because Xarelto treats and prevents 
serious conditions.  
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, Xarelto can cause side effects, although not everybody gets them. 
 
Like other similar medicines to reduce the formation of blood clots, Xarelto may cause bleeding which 
may potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure 
(shock). In some cases the bleeding may not be obvious. 
 
Tell your doctor immediately if you experience any of the following side effects: 
 Signs of bleeding 

- bleeding into the brain or inside the skull (symptoms can include headache, one-sided 
weakness, vomiting, seizures, decreased level of consciousness, and neck stiffness. 
A serious medical emergency. Seek medical attention immediately!) 

- long or excessive bleeding 
- exceptional weakness, tiredness, paleness, dizziness, headache, unexplained swelling, 

breathlessness, chest pain or angina pectoris 
 Your doctor may decide to keep you under closer observation or change the treatment.  
 



266 

 Signs of severe skin reactions 
- spreading intense skin rash, blisters or mucosal lesions, e.g. in the mouth or eyes 

(Stevens-Johnson syndrome/toxic epidermal necrolysis).  
- a drug reaction that causes rash, fever, inflammation of internal organs, blood 

abnormalities and systemic illness (DRESS syndrome).  
The frequency of these side effects is very rare (up to 1 in 10,000 people). 

 
 Signs of severe allergic reactions 

- swelling of the face, lips, mouth, tongue or throat; difficulty swallowing; hives and 
breathing difficulties; sudden drop in blood pressure.  

The frequencies of severe allergic reactions are very rare (anaphylactic reactions, including 
anaphylactic shock; may affect up to 1 in 10,000 people) and uncommon (angioedema and 
allergic oedema; may affect up to 1 in 100 people). 

 
Overall list of possible side effects 
 
Common (may affect up to 1 in 10 people) 
- reduction in red blood cells which can make the skin pale and cause weakness or breathlessness 
- bleeding in the stomach or bowel, urogenital bleeding (including blood in the urine and heavy 

menstrual bleeding), nose bleed, bleeding in the gum 
- bleeding into the eye (including bleeding from the whites of the eyes) 
- bleeding into tissue or a cavity of the body (haematoma, bruising)  
- coughing up blood 
- bleeding from the skin or under the skin 
- bleeding following an operation  
- oozing of blood or fluid from surgical wound 
- swelling in the limbs 
- pain in the limbs 
- impaired function of the kidneys (may be seen in tests performed by your doctor) 
- fever 
- stomach ache, indigestion, feeling or being sick, constipation, diarrhoea 
- low blood pressure (symptoms may be feeling dizzy or fainting when standing up) 
- decreased general strength and energy (weakness, tiredness), headache, dizziness 
- rash, itchy skin 
- blood tests may show an increase in some liver enzymes 
 
Uncommon (may affect up to 1 in 100 people) 
- bleeding into the brain or inside the skull (see above, signs of bleeding) 
- bleeding into a joint causing pain and swelling 
- thrombocytopenia (low number of platelets, which are cells that help blood to clot) 
- allergic reactions, including allergic skin reactions 
- impaired function of the liver (may be seen in tests performed by your doctor) 
- blood tests may show an increase in bilirubin, some pancreatic or liver enzymes or in the 

number of platelets 
- fainting 
- feeling unwell  
- faster heartbeat 
- dry mouth 
- hives 
 
Rare (may affect up to 1 in 1,000 people) 
- bleeding into a muscle 
- cholestasis (decreased bile flow), hepatitis incl. hepatocellular injury (inflamed liver incl. liver 

injury) 
- yellowing of the skin and eye (jaundice) 
- localised swelling 



267 

- collection of blood (haematoma) in the groin as a complication of the cardiac procedure where a 
catheter is inserted in your leg artery (pseudoaneurysm) 

 
Not known (frequency cannot be estimated from the available data)  
- kidney failure after a severe bleeding 
- increased pressure within muscles of the legs or arms after a bleeding, which leads to pain, 

swelling, altered sensation, numbness or paralysis (compartment syndrome after a bleeding) 
 
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 Xarelto 
 
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 wallet after 
EXP. 
The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Crushed tablets 
Crushed tablets are stable in water or apple puree for up to 4 hours. 
 
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 Xarelto contains  
- The active substance is rivaroxaban. Each tablet contains 15 mg or 20 mg of rivaroxaban, 

respectively. 
- The other ingredients are:  

Tablet core: microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, 
hypromellose (2910), sodium laurilsulfate, magnesium stearate. See section 2 “Xarelto contains 
lactose and sodium”. Tablet film coat: macrogol (3350), hypromellose (2910), titanium dioxide 
(E 171), iron oxide red (E 172).  

 
What Xarelto looks like and contents of the pack 
Xarelto 15 mg film-coated tablets are red, round, biconvex and marked with the BAYER-cross on one 
side and “15” and a triangle on the other side.  
Xarelto 20 mg film-coated tablets are brown-red, round, biconvex and marked with the BAYER-cross 
on one side and “20” and a triangle on the other.  
First 4 weeks treatment initiation pack: each pack of 49 film-coated tablets for the first 4 weeks of 
treatment contains:  
42 film-coated tablets of 15 mg rivaroxaban and 7 film-coated tablets of 20 mg rivaroxaban in a 
wallet.  
 



268 

Marketing Authorisation Holder 
 
Bayer AG 
51368 Leverkusen 
Germany 
 
Manufacturer 
 
The manufacturer can be identified by the batch number printed on the side flap of the carton and on 
each blister or bottle:  
 
•  If the first and second characters are BX, the manufacturer is  

Bayer AG  
Kaiser-Wilhelm-Allee  
51368 Leverkusen  
Germany  
 

•  If the first and second characters are IT, the manufacturer is  
Bayer HealthCare Manufacturing Srl.  
Via delle Groane, 126  
20024 Garbagnate Milanese  
Italy  
 

•  If the first and second characters are BT, the manufacturer is  
Bayer Bitterfeld GmbH  
Ortsteil Greppin, Salegaster Chaussee 1  
06803 Bitterfeld-Wolfen  
Germany 

 



269 

 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België / Belgique / Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 
 

Lietuva 
UAB Bayer 
Tel: +370-5-233 68 68 
 

България 
Байер България ЕООД 
Тел: +359-(0)2-424 72 80 
 

Luxembourg / Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 
 

Česká republika 
Bayer s.r.o. 
Tel: +420-266 101 111 
 

Magyarország 
Bayer Hungária KFT 
Tel: +36-1-487 4100 
 

Danmark 
Bayer A/S 
Tlf: +45-45 235 000 
 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +356-21 44 62 05 
 

Deutschland 
Bayer Vital GmbH 
Tel: +49-(0)214-30 513 48 
 

Nederland 
Bayer B.V. 
Tel: +31–(0)297-28 06 66 
 

Eesti 
Bayer OÜ 
Tel: +372-655 85 65 
 

Norge 
Bayer AS 
Tlf: +47-23 13 05 00 
 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30-210-618 75 00 
 

Österreich 
Bayer Austria Ges. m. b. H. 
Tel: +43-(0)1-711 460 
 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 
 

Polska 
Bayer Sp. z o.o. 
Tel: +48-22-572 35 00 
 

France 
Bayer HealthCare 
Tél (N° vert): +33-(0)800 87 54 54 
 

Portugal 
Bayer Portugal, Lda. 
Tel: +351-21-416 42 00 
 

Hrvatska 
Bayer d.o.o. 
Tel: + 385-(0)1-6599 900 
 

România 
SC Bayer SRL  
Tel: +40-(0)21-528 59 00 
 

Ireland 
Bayer Limited 
Tel: +353 1 216 3300 
 

Slovenija 
Bayer d. o. o. 
Tel: +386-(0)1-58 14 400 
 

Ísland 
Icepharma hf. 
Sími: +354-540 80 00 
 

Slovenská republika 
Bayer, spol. s r.o. 
Tel: +421-(0)2-59 21 31 11 
 

Italia 
Bayer S.p.A. 
Tel: +39-02-3978 1 
 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358-(0)20-78521  
 



270 

Κύπρος 
NOVAGEM Limited 
Τηλ: +357-22-48 38 58 
 

Sverige 
Bayer AB 
Tel: +46-(0)8-580 223 00  
 

Latvija 
SIA Bayer 
Tel: +371-67 84 55 63 
 

United Kingdom 
Bayer plc 
Tel: +44-(0) 118 206 3000 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 



271 

Package leaflet: Information for the user 
 

Xarelto 1 mg/mL granules for oral suspension 
rivaroxaban 

 

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. This leaflet has been written for the patient (“you”) and the parent or 
caregiver who will give this medicine to the child.  
- 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 or the child only. Do not pass it on to others. It may 

harm them, even if their signs of illness are the same. 
- If you or the child 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 Xarelto is and what it is used for 
2. What you need to know before you take or give Xarelto 
3. How to take or give Xarelto 
4. Possible side effects 
5. How to store Xarelto 
6. Contents of the pack and other information 
 
 
1. What Xarelto is and what it is used for 
 
Xarelto contains the active substance rivaroxaban. 
Xarelto belongs to a group of medicines called antithrombotic agents. It works by blocking a blood 
clotting factor (factor Xa) and thus reducing the tendency of the blood to form clots. 
 
Xarelto is used in full-term newborn babies, infants and toddlers, children and adolescents below 
18 years to: 
- treat blood clots and prevent re-occurrence of blood clots in the veins or in the blood vessels of 

the lungs, following an initial treatment of at least 5 days with injectable medicines used to treat 
blood clots. 

 
Read and follow the Instructions for Use provided with this medicine because it will show you how to 
prepare and take or give Xarelto oral suspension. 
 
 



272 

2. What you need to know before you take or give Xarelto 
 
Do not take or give Xarelto if you or the child  
- 16Tare allergic16T to rivaroxaban or any of the other ingredients of this medicine (listed in section 6) 
- 16Tare bleeding excessively 
- 16Thave a disease or condition in an organ of the body that increases the risk of serious bleeding 

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

except 
• when changing medicines to prevent blood clotting or  
• while getting heparin through a venous or arterial line to keep it open. 

- 16Thave a liver disease16T associated with an increased risk of bleeding 
- 16Tare pregnant or breast-feeding 
16TDo not take or give Xarelto 16T 16Tand tell your doctor16T if any of these apply to you or the child. 
 
Warnings and precautions 
Talk to your doctor or pharmacist before using Xarelto if: 
 you or the child have 16Tan increased risk of bleeding. This could be the case in situations16T such as: 

▪ moderate or severe kidney disease; as the kidney function may affect the amount of 
medicine that works in the body 

▪ if you or the child are taking other medicines to prevent blood clotting (e.g. warfarin, 
dabigatran, apixaban or heparin), if these are absolutely necessary (see section “Do not 
take or give Xarelto”) 

▪ 16Tbleeding disorders 
▪ 16Tvery high blood pressure,16T not controlled by medical treatment 
▪ diseases of stomach or bowel that might result in bleeding, e.g. inflammation of the 

bowels or stomach, or inflammation of the food pipe due to a disease where stomach acid 
goes upwards into the food pipe 

▪ 16Ta problem with the blood vessels in the back of the eyes 16T (retinopathy) 
▪ a lung disease where the bronchi are widened and filled with pus (bronchiectasis), or 

previous bleeding from the lung 
 you or the child have a prosthetic heart valve 
 you or the child have a disease called antiphospholipid syndrome (a disorder of the immune 

system that causes an increased risk of blood clots) 
 your or the child’s blood pressure is unstable  
 another treatment or surgical procedure is planned to remove the blood clot from the lungs  
 
16TIf any of the above apply to you or to the child, tell your doctor 16Tbefore you take or give Xarelto. The 
doctor will decide, if you or the child should be treated with this medicine and should be kept under 
closer observation.  
 
Do not give Xarelto to children under 6 months of age who  
- were born before 37 weeks of pregnancy, or 
- weigh less than 2.6 kg, or 
- had less than 10 days of breast or formula feeding 
In these cases, dosing of Xarelto cannot be reliably determined and has not been studied in these 
children. 
 
If you or the child need to have an operation 
 It is very important to take or give Xarelto before and after the operation exactly at the times 

your doctor has told you. 
 If the operation involves a catheter or injection into the spinal column (e.g. for epidural or spinal 

anaesthesia or pain reduction): 
 16Tit is very important to take or give Xarelto before and after the injection or removal of the 

catheter exactly at the times your doctor has told you  



273 

 tell your doctor immediately if you or the child get numbness or weakness of the legs or 
problems with the bowel or bladder after the end of anaesthesia. In this case, urgent care is 
necessary. 

 
16TChildren and adolescents 
Xarelto oral suspension is to be used for patients below 18 years to treat blood clots and prevent 
re-occurrence of blood clots in the veins or in the blood vessels of the lungs. There is not enough 
information on its use in children and adolescents in other indications. 
 
Other medicines and Xarelto 
Tell your doctor or pharmacist if you or the child are taking, have recently taken or might take any 
other medicines, including medicines obtained without a prescription. 
 If you or the child are taking: 

 some medicines for fungal infections (e.g. fluconazole, itraconazole, voriconazole, 
posaconazole), unless they are only applied to the skin 

 ketoconazole tablets (used to treat Cushing’s syndrome - when the body produces an 
excess of cortisol) 

 some medicines for bacterial infections (e.g. clarithromycin, erythromycin)  
 some medicines for HIV/AIDS (e.g. ritonavir) 
 other medicines to reduce blood clotting (e.g. enoxaparin, clopidogrel or vitamin K 

antagonists such as warfarin and acenocoumarol)  
 medicines to relieve inflammation and pain (e.g. naproxen or acetylsalicylic acid) 
 dronedarone, a medicine to treat abnormal heart beat 
 some medicines to treat depression (selective serotonin reuptake inhibitors (SSRIs) or 

serotonin norepinephrine reuptake inhibitors (SNRIs) 
 
16TIf any of the above apply to you or the child, tell your doctor16T before taking or giving Xarelto, 
because the effect of Xarelto may be increased. Your doctor will decide, if you or the child 
should be treated with this medicine and should be kept under closer observation. 
16TIf the doctor thinks that you or the child are at increased risk of developing stomach or bowel 
ulcers, a preventive ulcer treatment might be necessary.  
 

 If you or the child are taking: 
 some medicines to treat epilepsy (phenytoin, carbamazepine, phenobarbital) 
 St John’s Wort (Hypericum perforatum), a herbal product used for depression 
 rifampicin, an antibiotic 
 
16TIf any of the above apply to you or the child, tell your doctor16T before taking or giving Xarelto, 
because the effect of Xarelto may be reduced. The doctor will decide, if you or the child should 
be treated with Xarelto and should be kept under closer observation.  

 
Pregnancy and breast-feeding 
• If you or the adolescent are pregnant or breast-feeding do not take or give Xarelto.  
• If there is a chance that you or the adolescent could become pregnant, a reliable contraceptive 

should be used while taking Xarelto.  
• If you or the adolescent become pregnant while taking this medicine, tell your doctor 

immediately, who will decide how the treatment should be continued. 
 
Driving and using machines 
Xarelto may cause dizziness or fainting. You or the child should not drive, ride a bicycle or use any 
tools or machines if affected by these symptoms.  
 
Xarelto contains sodium benzoate and sodium 
This medicine contains 1.8 mg sodium benzoate (E 211) in each mL oral suspension. Sodium benzoate 
(E 211) may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old). 
This medicine contains less than 1 mmol sodium (23 mg) per millilitre, that is to say essentially 
“sodium-free”. 



274 

 
 
3. How to take or give Xarelto 
 
Always take this medicine or give this medicine to the child exactly as your doctor has told you. 
Check with your doctor or pharmacist if you are not sure.  
 
Make sure that the correct information on how much and how often to take or give Xarelto is written 
on the designated area of the carton. If not, ask your pharmacist or doctor to provide the relevant 
information.  
 
Instructions for Use 
For how to prepare and take or give the Xarelto oral suspension:   
- See the Instructions for Use booklet included in the carton and  
- Watch the educational video which you can access via the QR code which is displayed on the 

Patient Alert Card that is provided with this medicine.  
 
How to take or give  
Take or give Xarelto oral suspension with feeding (breast milk or formula feeding) or with a meal. 
Each Xarelto dose has to be swallowed along with one typical serving of liquid (for example 20 mL in 
children aged 6 months up to 240 mL in adolescents). This typical serving may include usual amount 
of drink used for feeding (e.g. breast milk, infant formula, nutrition drink). 
 
Your doctor may give the oral suspension also via a stomach tube. 
 
How much to take or give 
The dose of Xarelto depends on the patient’s body weight. It will be calculated by the doctor as an 
amount (volume) in millilitres (mL) of the oral suspension. This should be measured out using the 
blue syringe (either 1 mL or 5 mL or 10 mL syringe, see table 1) supplied with this medicine. Your 
doctor will prescribe the volume required including the particular syringe you should use.  
Your doctor will tell you how much of the oral suspension you or the child must take. 
Below is the table that your doctor will use. Do not adjust the dose yourself. 
 
All materials to prepare and administer the oral suspension are provided with the medicine (except for 
drinking water.) Only use non-carbonated water to avoid bubbles. Only use the syringe provided to 
administer Xarelto to ensure accurate dosing. Do not use any other method to administer the solution, 
e.g. alternative syringe, spoon etc. 
 
As the Xarelto dose is based on body weight it is important to keep scheduled doctor’s visits because 
the dose may need to be adjusted as the weight changes, especially for children below 12 kg. This 
ensures that the child receives the correct dose of Xarelto. 
 



275 

Table 1: Recommended dose for Xarelto in children   

Body weight [kg] Single dose* 
Daily frequency of 
intake  

Total daily dose*  Suitable blue 
syringe 

2.6 to under 3 0.8 mL 

3 times 

2.4 mL 
1 mL 

3 to under 4 0.9 mL 2.7 mL 

4 to under 5 1.4 mL 4.2 mL 

5 mL 

5 to under 7 1.6 mL 4.8 mL 
7 to under 8 1.8 mL 5.4 mL 
8 to under 9 2.4 mL 7.2 mL 
9 to under 10 2.8 mL 8.4 mL 
10 to under 12 3.0 mL 9.0 mL 
12 to under 30 5.0 mL 2 times 10.0 mL 5 mL or 10 mL 
30 to under 50 15.0 mL 

once 
15.0 mL 

10 mL 
50 or more 20.0 mL 20.0 mL 
* 1 mL of the oral suspension corresponds to 1 mg rivaroxaban.  

 
Your doctor may also prescribe tablets if you or the child are able to swallow the tablet and are 
weighing at least 30 kg. 
 
When to take or give Xarelto 
Take or give the oral suspension as directed every day until the doctor tells you to stop. 
Take or give the oral suspension at the same time every day to help you to remember it. Consider 
setting an alarm to remind you.  
Please observe the child to ensure the full dose is taken.  
 
If the doctor has told you to take or give Xarelto: 
- once a day, do this approximately 24 hours apart 
- twice a day, do this approximately 12 hours apart 
- three times a day, do this approximately 8 hours apart 
 
Your doctor will decide how long you or the child must continue treatment. 
 
If you or the child spits up the dose or vomits 
- less than 30 minutes after the intake of Xarelto, take or give a new dose.  
- more than 30 minutes after the intake of Xarelto, do not take or give a new dose. Continue to 

take or give the next Xarelto dose at the next scheduled time. 
 

Contact the doctor if you or the child repeatedly spit up the dose or vomit after taking Xarelto. 
 
If you forget to take or give Xarelto  
- If you are taking or giving Xarelto once a day, take or give the missed Xarelto dose as soon 

as you remember on the same day. If this is not possible, skip this dose. Then take or give the 
next Xarelto dose on the following day. Do not take or give more than one dose per day.  

- If you are taking or giving Xarelto twice a day:  
• Missed morning dose: Take or give the missed dose as soon as you remember. You may 

take or give it together with the evening dose.  
• Missed evening dose: You may take or give the missed dose only in the same evening. 

Do not take or give two doses the next morning.  
- If you are taking or giving Xarelto three times a day, do not make up for the missed dose. 

Continue with the next scheduled dose (given every 8 hours). 
 
On the day following a missed dose, continue as prescribed by the doctor once, twice or three times a 
day. 
 



276 

If you take or give more Xarelto than you should 
Contact your doctor immediately if you have taken or given too much Xarelto oral suspension. Taking 
or giving too much Xarelto increases the risk of bleeding. 
 
If you stop taking or giving Xarelto  
Do not stop Xarelto without talking to your doctor first, because Xarelto treats and prevents serious 
conditions. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Like other similar medicines to reduce the formation of blood clots, Xarelto may cause bleeding which 
may potentially be life threatening. Excessive bleeding may lead to a sudden drop in blood pressure 
(shock). In some cases the bleeding may not be obvious. 
 
Tell your doctor immediately if you or the child experience any of the following side effects: 
 Signs of bleeding 

- bleeding into the brain or inside the skull (symptoms can include headache, one-sided 
weakness, vomiting, seizures, decreased level of consciousness, and neck stiffness. 
A serious medical emergency. Seek medical attention immediately!) 

- long or excessive bleeding 
- exceptional weakness, tiredness, paleness, dizziness, headache, unexplained swelling, 

breathlessness, chest pain or angina pectoris 
Your doctor may decide to keep you or the child under closer observation or change the 
treatment. 

 
 Signs of severe skin reactions 

- spreading intense skin rash, blisters or mucosal lesions, e.g. in the mouth or eyes 
(Stevens-Johnson syndrome/toxic epidermal necrolysis) 

- a drug reaction that causes rash, fever, inflammation of internal organs, blood 
abnormalities and systemic illness (DRESS syndrome) 

The frequency of these side effects is very rare (up to 1 in 10,000 people). 
 
 Signs of severe allergic reactions 

- swelling of the face, lips, mouth, tongue or throat; difficulty swallowing; hives and 
breathing difficulties; sudden drop in blood pressure 

The frequencies of severe allergic reactions are very rare (anaphylactic reactions, including 
anaphylactic shock; may affect up to 1 in 10,000 people) and uncommon (angioedema and 
allergic oedema; may affect up to 1 in 100 people). 

 
Overall list of possible side effects found in adults and children and adolescents: 
 
Common (may affect up to 1 in 10 people) 
- reduction in red blood cells which can make the skin pale and cause weakness or breathlessness 
- bleeding in the stomach or bowel, urogenital bleeding (including blood in the urine and heavy 

menstrual bleeding), nose bleed, bleeding in the gum 
- bleeding into the eye (including bleeding from the whites of the eyes) 
- bleeding into tissue or a cavity of the body (haematoma, bruising)  
- coughing up blood 
- bleeding from the skin or under the skin 
- bleeding following an operation  
- oozing of blood or fluid from surgical wound 
- swelling in the limbs 



277 

- pain in the limbs 
- impaired function of the kidneys (may be seen in tests performed by your doctor) 
- fever 
- stomach ache, indigestion, feeling or being sick, constipation, diarrhoea 
- low blood pressure (symptoms may be feeling dizzy or fainting when standing up) 
- decreased general strength and energy (weakness, tiredness), headache, dizziness 
- rash, itchy skin 
- blood tests may show an increase in some liver enzymes 
 
Uncommon (may affect up to 1 in 100 people) 
- bleeding into the brain or inside the skull (see above, possible side effects which may be a sign 

of bleeding) 
- bleeding into a joint causing pain and swelling 
- thrombocytopenia (low number of platelets, which are cells that help blood to clot) 
- allergic reactions, including allergic skin reactions 
- impaired function of the liver (may be seen in tests performed by your doctor) 
- blood tests may show an increase in bilirubin, some pancreatic or liver enzymes or in the 

number of platelets 
- fainting 
- feeling unwell  
- faster heartbeat 
- dry mouth 
- hives 
 
Rare (may affect up to 1 in 1,000 people) 
- bleeding into a muscle 
- cholestasis (decreased bile flow), hepatitis incl. hepatocellular injury (inflamed liver incl. liver 

injury) 
- yellowing of the skin and eye (jaundice) 
- localised swelling 
- collection of blood (haematoma) in the groin as a complication of the cardiac procedure where a 

catheter is inserted in your leg artery (pseudoaneurysm) 
 
Not known (frequency cannot be estimated from the available data)  
- kidney failure after a severe bleeding 
- increased pressure within muscles of the legs or arms after a bleeding, which leads to pain, 

swelling, altered sensation, numbness or paralysis (compartment syndrome after a bleeding) 
 
Side effects in children and adolescents 
In general, the side effects observed in children and adolescents treated with Xarelto were similar in 
type to those observed in adults and were primarily mild to moderate in severity. 
 
Side effects that were observed more often in children and adolescents: 
 
Very common (may affect more than 1 in 10 people) 
- Headache 
- fever 
- nose bleeding 
- vomiting 
Common (may affect up to 1 in 10 people) 
- raised heartbeat 
- blood tests may show an increase in bilirubin (bile pigment) 
- thrombocytopenia (low number of platelets which are cells that help blood to clot)  
- heavy menstrual bleeding  
Uncommon (may affect up to 1 in 100 people) 
- blood tests may show an increase in a subcategory of bilirubin (direct bilirubin, bile pigment) 

 



278 

Reporting of side effects 
If you or the child 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 Xarelto 
 
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 the bottle after 
EXP. 
The expiry date refers to the last day of that month. 
After preparation, the shelf life of the suspension is 14 days at room temperature.  
 
Do not store above 30 °C. 
Do not freeze. Store the prepared suspension upright. 
 
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 Xarelto contains  
- The active substance is rivaroxaban. One glass bottle contains 51.7 mg (for the 100 mL bottle) 

or 103.4 mg (for the 250 mL bottle) of rivaroxaban. After preparation, each mL of the 
suspension contains 1 mg of rivaroxaban. 

- The other ingredients are:  
Citric acid, anhydrous (E 330), hypromellose (2910), mannitol (E 421), microcrystalline 
cellulose, carboxymethylcellulose sodium, sodium benzoate (E 211) (see section 2 “Xarelto 
contains sodium benzoate and sodium”), sucralose (E 955), xanthan gum (E 415), flavour sweet 
and creamy (consist of flavouring substances, maltodextrin (maize), propylene glycol (E 1520) 
and acacia gum (E 414)). 

 
What Xarelto looks like and contents of the pack 
Xarelto granules for oral suspension are white granules in a glass bottle with child resistant srew cap.  
 
Pack sizes  
- For children weighing less than 4 kg:  

Folding box with one brown glass bottle (100 mL) containing 2.625 g granules (corresponding 
to 51.7 mg rivaroxaban), two 1 mL blue syringes, one 50 mL water syringe and one adapter. 

- For children weighing 4 kg or more:  
Folding box with one brown glass bottle (250 mL) containing 5.25 g granules (corresponding to 
103.4 mg rivaroxaban), two 5 mL and two 10 mL blue syringes, one 100 mL water syringe and 
one adapter. 

 
Not all pack sizes may be marketed.  
 
The individual weight-adjusted dose volume and frequency should be specified by the prescriber. It 
should be written on the outer carton when provided to the parents, caregivers or patients. 
Please follow carefully the Instructions for Use booklet which is provided in each pack.  
Watch the educational video which you can access via the QR code which is displayed on the Patient 
Alert Card that is provided with this medicine. 
 
 



279 

Marketing Authorisation Holder and Manufacturer  
 
Bayer AG 
51368 Leverkusen 
Germany 
 
 



280 

 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België / Belgique / Belgien 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 
 

Lietuva 
UAB Bayer 
Tel: +370-5-233 68 68 
 

България 
Байер България ЕООД 
Тел: +359-(0)2-424 72 80 
 

Luxembourg / Luxemburg 
Bayer SA-NV 
Tél/Tel: +32-(0)2-535 63 11 
 

Česká republika 
Bayer s.r.o. 
Tel: +420-266 101 111 
 

Magyarország 
Bayer Hungária KFT 
Tel: +36-1-487 4100 
 

Danmark 
Bayer A/S 
Tlf: +45-45 235 000 
 

Malta 
Alfred Gera and Sons Ltd. 
Tel: +356-21 44 62 05 
 

Deutschland 
Bayer Vital GmbH 
Tel: +49-(0)214-30 513 48 
 

Nederland 
Bayer B.V. 
Tel: +31–(0)297-28 06 66 
 

Eesti 
Bayer OÜ 
Tel: +372-655 85 65 
 

Norge 
Bayer AS 
Tlf: +47-23 13 05 00 
 

Ελλάδα 
Bayer Ελλάς ΑΒΕΕ 
Τηλ: +30-210-618 75 00 
 

Österreich 
Bayer Austria Ges. m. b. H. 
Tel: +43-(0)1-711 460 
 

España 
Bayer Hispania S.L. 
Tel: +34-93-495 65 00 
 

Polska 
Bayer Sp. z o.o. 
Tel: +48-22-572 35 00 
 

France 
Bayer HealthCare 
Tél (N° vert): +33-(0)800 87 54 54 
 

Portugal 
Bayer Portugal, Lda. 
Tel: +351-21-416 42 00 
 

Hrvatska 
Bayer d.o.o. 
Tel: + 385-(0)1-6599 900 
 

România 
SC Bayer SRL  
Tel: +40-(0)21-528 59 00 
 

Ireland 
Bayer Limited 
Tel: +353 1 216 3300 
 

Slovenija 
Bayer d. o. o. 
Tel: +386-(0)1-58 14 400 
 

Ísland 
Icepharma hf. 
Sími: +354-540 80 00 
 

Slovenská republika 
Bayer, spol. s r.o. 
Tel: +421-(0)2-59 21 31 11 
 

Italia 
Bayer S.p.A. 
Tel: +39-02-3978 1 
 

Suomi/Finland 
Bayer Oy 
Puh/Tel: +358-(0)20-78521  
 



281 

Κύπρος 
NOVAGEM Limited 
Τηλ: +357-22-48 38 58 
 

Sverige 
Bayer AB 
Tel: +46-(0)8-580 223 00  
 

Latvija 
SIA Bayer 
Tel: +371-67 84 55 63 
 

United Kingdom 
Bayer plc 
Tel: +44-(0) 118 206 3000 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu. 
 



282 

Instructions for Use (IFU) 
 
Instructions for Use  
 
Xarelto 1 mg/mL 
 
100 mL bottle with 2.625 g granules for preparation of oral suspension  
Active pharmaceutical ingredient: Rivaroxaban 
 
Preparation and administration of the oral suspension (granules-water-mixture) 
 
 
Glossary and symbols  
 
 Granules: powder (provided in the bottle) which contains active pharmaceutical 

ingredient 
 Water syringe: 50 mL syringe used to measure and add 50 mL of water to the bottle 

containing Xarelto granules. 
 Suspension: granules-water-mixture (for oral application) 
 Blue syringe: syringe with blue plunger to extract and orally administer Xarelto. 
 

 

Caution: Consult Instructions for Use for relevant information related to warnings 
and precautions. 
 

 

Consult Instructions for Use (IFU). 
 

 

Keep away from sunlight 
 

 

Protect from moisture 
 

 

Manufacturing date 
 

 

Expiry date  
 

 

Reference number  
 

 

Batch number 
 

 

For oral use only  



283 

 
Before you start  
 
 Read all sections of the Instructions for Use carefully before using Xarelto for the first 

time and before administering each dose. 
 Watch the educational video which you can access via the QR code displayed on the 

Patient Alert Card that is provided with this medicine.  
 Be sure you understand the instructions before starting. If not, call your doctor. 
 Further information regarding Xarelto can be found in the Package Leaflet 
 
Packaging contents 
 
Every Xarelto box contains the following components: 
 

 

1 bottle with child resistant screw cap containing Xarelto granules. 
 

 

1 packaged 50 mL water syringe (for single use only) 
 
The water syringe is used to extract the exact quantity of water required 
to prepare Xarelto suspension.  

 

1 packaged bottle adapter 
The adapter is inserted into the neck of the bottle containing Xarelto 
granules after the exact quantity of water is added to the bottle. 
This bottle adapter connects the blue syringe to the bottle to ensure the 
correct amount of suspension can be extracted from the bottle into the blue 
syringe. 
 

 

2 packaged 1 mL blue syringes (one is a spare syringe): 
This blue syringe is used to administer volumes up to 1 mL 
 
Use the appropriate blue syringe for the volume of suspension that is to 
be administered. 
The blue syringes have a red button under the label. This button serves to 
fix the required dosing volume. 
Keep the label at this place on the blue syringe until instructed to remove 
it. 



284 

 

1 Instructions for Use (IFU) (this document) 
The IFU contains a description of the preparation of the suspension and 
how the blue syringe is set up and handled. 

 

1 Package Leaflet  
Provides important information about Xarelto. 
 
 

 

1 Patient Alert Card  
Important information in case of emergency. 
To be kept with the patient at all times and presented to every physician 
or dentist prior to treatment  
 

 

Cautionary Information:  

Do not unpack the single components until the instructions tell you to do so. 
Do not use Xarelto if any of the parts have been opened or are damaged. 
Do not use Xarelto after the expiry date which is stated on the box. 
 
Warnings and precautions 
 
 Only use non-carbonated drinking water to prepare the suspension to avoid bubbles. That 

means you can use either 
 fresh tap water or 
 non-carbonated (still) mineral water 

 It is very important that the precise amount of water is added to the granules in the bottle to 
ensure the correct concentration of Xarelto. 
 Use the water syringe for measurement of 50 mL water, see below for more information. 
 Measure the amount water to be provided to the bottle very carefully. 

 After preparation the suspension can be used for 14 days if stored at room temperature.  
Ensure to write the expiry date of the suspension (date of preparation plus 14 days) on the 
dedicated field on the bottle label. 

 Do not store the suspension above 30 °C. Do not freeze.  
If the suspension has been stored in the refrigerator, allow the suspension to adjust to room 
temperature before extracting the relevant dose. 

 Shake the suspension for initial preparation for at least 60 seconds.  
 Shake the suspension in the bottle for at least 10 seconds before each administration. 
 It is very important that the prescribed dose volume of Xarelto is being administered. 

 Make sure that you know the prescribed dose and frequency of administration. Ask your 
doctor or pharmacist if you do not know the prescribed dose and frequency.  

 Carefully adjust the blue syringe according the prescribed volume. 
 Administer the prescribed dose by using the blue syringe. Follow the doctor’s instructions 



285 

on how often per day you should administer the prescribed dose.   
 Check for air bubbles in the blue syringe before administration of the oral suspension. 

 If your child repeatedly does not take all the required dose or spits some of it out, call your 
child’s doctor to find out what to do. 

 Between dosing, store the oral suspension out of sight and reach of children. 
 Keep the Instructions for Use so that you can refer to them later during the use of Xarelto. 
 
Using Xarelto  
 
 Xarelto suspension is for oral use only. 
 Volume and frequency of administration of Xarelto depend on your child’s weight, so it 

will change over time if your child will receive Xarelto for a longer time. 
 Your child's doctor will tell you the right dose volume . 
 Do not change the dose yourself. 
 Always use the volume prescribed by your child's doctor and have the correct dosing of 

administration written on the designated field on the outside of the box. 
If it is not written on the field, ask your child's doctor or pharmacist to provide the 
relevant information. 

 Follow the detailed Instructions for Use given in the chapters below. 
 Take care to comply with the instructions concerning administration: 
 

 Intake: Three times a day 
 Administration: Approximately 8 hours apart with feeding  

 
1. Preparing the oral suspension  
 
Step 1.1: Preparation – Get ready 
 
The preparation of the suspension is done once with every new package.  
Before preparing the suspension: 
 

 

a. Thoroughly wash your hands with soap and dry them afterwards 
 

 

b. Check the expiry date on the label provided on the box. 
Do not use the medicine if the medicine has expired. 
 



286 

 c. Obtain the following additional items: 
 Container with at least 150 mL of water: 

 Either fresh tap water or non-carbonated (still) mineral 
water 

 Water should be at room temperature 
 

  Tissue for soaking up any excess water 

 
Step 1.2: Filling the required volume of water 
 
Every time you start a new pack, use only the new materials contained in the new package. 
 
 a. Unpack the water syringe. 

 

 

b. Dip the opening of the water syringe into the container with 
water. 

c. Extract a volume of more than 50 mL. 
To do this, pull the plunger rod towards you, and make sure 
that the opening of the water syringe stays below the water 
surface all the time. This will avoid air bubbles in the syringe. 

d. Take the syringe out of the water. 
 

 e. Turn the water syringe in a way that the opening is facing 
upwards. 
 Any air bubbles will move to the top when holding the 

syringe upwards. 
Tap it with your fingers to further move any air bubble to the 
top. 

 

 

f. Push the plunger rod until the upper ring of the plunger 
reaches the 50 mL mark. 
 When pressing the plunger, water can come out of the tip 
of the water syringe. This waste water can be soaked up with 
a tissue. 

 



287 

 
Step 1.3: Adding water to the granules 
 
 a. If the granules in the bottle appear to be clumpy: 

 Gently tap the bottle on your hand. 
 Be careful since the bottle is made of glass. 

 

 

 

 

Cautionary Information:  

The upper ring of the black plunger must be precisely in line 
with the 50 mL mark to be able to achieve the correct 
concentration of the suspension. 
 

  

g. Continue to hold the water syringe with the opening facing 
upwards and check the water in the syringe carefully: 

 for correct volume, 
 for air bubbles. 
Small air bubbles are uncritical, but big air bubbles are 
critical. See below for more explanation on what to do. 

 

h. If the syringe is not loaded correctly or contains too much 
air: 

 Empty the water syringe 
 Repeat steps b. to h  

 



288 

 

b. Unscrew the child resistant cap of the bottle (push down and 
turn counterclockwise). 

 

 

c. Place the filled water syringe on the upper edge of the bottle 
opening 

 

d. Hold the bottle firmly. 
e. Press the plunger rod down slowly. 
 The full volume of water must be transferred to the 

bottle. 
f. Dispose of the water syringe in household waste. 
 

 
Step 1.4: Fitting the adapter and mixing the oral suspension 
 
The adapter is used to fill the blue syringe with suspension. 

 
 a. Unpack the bottle adapter 

 

 

b. Push the adapter completely into the neck of the bottle  
 



289 

 

c. Close the bottle tightly with the screw cap. 
 

 

d. Shake the bottle gently for at least 60 seconds. 
 This is intended to provide a well-mixed suspension. 

 

 

e. Check whether the suspension is thoroughly mixed: 
 no clumps 
 no deposit. 

 

Cautionary Information:  

To guarantee correct dose, the suspension must not contain any 
clumps or deposit. 
 

 f. If there are clumps or sediment repeat steps d. to f. 
 
 When no clumps or deposits are left, the suspension is 
ready for use. 
Do not add more water to the bottle. 
The suspension has a shelf life of 14 days at room 
temperature.  

 

 

g. Write the date of expiry of the just prepared suspension on the 
label of the bottle. 
Date of preparation + 14 days 
The shown pictogram is only an example.  
 

 
2. Setting the prescribed dose with every new blue syringe 
 



290 

To prevent overdosing or underdosing an exact dose of suspension is required. 
Before you take the first dose out of the bottle, the enclosed blue syringe must be set up in 
accordance with the dose prescribed by your child's doctor. This information can be found on the 
dedicated area of the box. If no information has been entered here check back with the child's 
doctor or pharmacist. 
After setting the dose the same blue syringe can be used for all administrations from the bottle of 
suspension prepared in step 1. 
Once the dose has been fixed on the blue syringe, it cannot be changed. 
 
 The blue syringe features a scale (mL). 

The scale of the 1 mL blue syringe starts with 0.2 mL. 
The graduation marks are in increments of 0.1 mL. 
 
Note: 
Do not remove the peelable label until you are prompted 
in the Instructions for Use. 
The blue syringe features a red button to adjust the volume. 
This button is initially covered by a peelable label. 
By pressing the red button the volume of the syringe is set, 
which can only be done once. Do not press the red button 
until the Instructions for Use tell you to do so. 
Once the red button has been pressed, the volume can no 
longer be adjusted. 
 

 

a. Review the dose provided in the respective field on the 
outside of the box. 
 

 b. If the information is not available: 
Ask your pharmacist or doctor to provide it. 

 
 c. Hold the blue syringe with the opening pointing upwards 

 

d. Pull the plunger rod slowly until the upper margin reaches 
the mark of the volume to be administered. 

 When moving the plunger rod, you can hear a “Click” for 
each adjustable volume step. 

 

Cautionary Information:  

The upper edge of the plunger must be exactly in line with the 
correct mark of the volume to be administered. 
 
 



291 

 

The shown pictogram is only an example. Your volume might 
be different. 
Be careful, do not pull the plunger past the volume to be 
administered. 
Be careful, do not press on the label when pulling the plunger. 
 

  

e.  Remove the label of the blue syringe completely. 
 You can now see the red button for setting the volume. 
f.  Check the position of the plunger again. Ensure the upper 

edge of the plunger is exactly in line with the correct mark 
of the volume to be administered. 

g.  If the position of the blue plunger does not match the 
required volume:  
Adjust it accordingly  

 

 

h. If the position of the blue plunger matches the required 
volume, push the red button to fix the adjustment. 
 The required dose is now set. 
 Pressing the red button will produce another clicking sound. 
 The clicking sound will not be audible afterwards. 

 

Cautionary Information:  

If you notice that the wrong dose has been selected (the red 
button has been pushed, when the plunger was in the wrong 
position) use the appropriate spare blue syringe. 
Repeat steps a. to h. with a new blue syringe. 
 

 

i. Push the plunger upwards in the blue syringe as far as it 
goes. 
The blue syringe can now be used. 

 
3. Administering the oral suspension  

 
Follow the steps described below for each required administration. 
 
Step 3.1: Mixing the oral suspension  
 



292 

 

Cautionary Information:  

Allow the suspension to adjust to room temperature if it has been stored in the refrigerator. 
 

 

a. Gently shake the bottle for at least 10 seconds before each 
dose. 
 This is intended to provide a well-mixed suspension. 

 

 

b. Check whether the suspension is mixed thoroughly, i.e.: 
 no clumps 
 no deposit. 

c. If there are clumps or deposit:  
Repeat steps a. and b. 

 

 d. Shaking can lead to formation of foam.  
Let the bottle stand until the foam dissolves. 
 

 

 

e. Unscrew the bottle cap, but keep the adapter on the top of the 
bottle. 

Note: 
The larger opening visible on the adapter is used to connect the 
blue syringe. 
The surface of the bottle adapter should be free of liquid. 

f. If there is any liquid on the adapter:  
Remove the liquid with a clean tissue  
 

 
Step 3.2: Extracting the required dose 
 



293 

 

a. Keep the bottle in the upright position. Insert the tip of the 
blue syringe fully into the large opening of the adapter 

 

b. Turn the bottle upside down. 
c. Pull the blue plunger rod slowly until it stops (i.e. until the set 

dose is reached). 

 

d. Carefully check for air in the blue syringe.  
Smaller air bubbles are not critical. 

 



294 

 
Step 3.3: Administration of prescribed dose 
 

 

e. If there are bigger air bubbles: 
 Return the suspension to the bottle by pushing back the 

plunger rod into the blue syringe as far as possible. 
 Repeat steps b. to e. 

f. Return the bottle to the upright position. 
g. Remove the blue syringe carefully from the adapter 
 

  

h. Hold the blue syringe upright and check: 
 that the tip of the blue syringe is filled 
 whether the right dose has been filled into the blue 

syringe 
 that no big air bubbles are present. 

 

 

i. If there are bigger air bubbles or air in the tip: 
 Insert the tip of the blue syringe again fully into the 

large opening of the adapter 
 Return the suspension to the bottle by pushing back the 

plunger rod into the blue syringe as far as it goes. 
 Repeat steps b. to h. until no bigger air bubbles are 

visible. 
 

j. Close the bottle with the screw cap. 
Administer the suspension immediately after filling the blue 
syringe (step 3.3) 
 



295 

 

a. Place the blue syringe into the mouth of the patient. 
b. Direct its tip into the cheek to allow for natural swallowing. 
c. Push the plunger rod down slowly until the plunger stops 

(blue syringe is completely empty). 
d. Ensure that the patient swallows the entire dose. 

 

Cautionary Information:  

The patient must swallow the full dose of medicine. 
If the dose repeatedly is not completely swallowed or if the 
patient is vomiting, consult your doctor for further instructions. 
 

 

e. Encourage the patient to drink one typical serving of liquid. 
 For an infant of 6 months, for example, this may be 

20 mL. 
 This can also be breast-feeding.  

 

 
4. Cleaning and storage 
 
The blue syringe must be cleaned following every application. 
Follow the steps listed below to clean the device. Altogether, three cycles of cleaning are necessary to 
ensure proper cleaning. 
 
 Before you start, you will need the following equipment for step 4.1: 

 Get two containers (such as a cup or bowl) 
o one container filled with drinking water, 
o the other container empty 

 

 
Step 4.1: Cleaning 
 

 

a. Dip the tip of the blue syringe into the container of water. 
b. Withdraw water until plunger rod stops. 

 



296 

 

c. Empty the blue syringe into the prepared empty container 
 

 d. Repeat steps a. to c. an additional two times. 
e. After cleaning, push the plunger rod back in until it stops. 
f. Dry the outer surface of the syringe with a clean tissue 

 
 

 

Cautionary Information:  

 Do not clean the blue syringe in the dish washer. 
 Never boil the blue syringe. 

 
 
Step 4.2: Storage 
 
Store the blue syringe in a clean and dry place until next use, e.g. keep it in the box Xarelto 
was given to you.  
Keep away from sunlight. 
 

 

Cautionary Information:  

The blue syringe can be used for up to 14 days. 
 
Store the suspension below 30 °C. 
 

 

Cautionary Information:  

Do not freeze the suspension. 
The prepared suspension is stable at room teperature for up to 14 days (preparation date plus 14 days). 
Keep Xarelto out of the sight and reach of children. 
Store the prepared suspension upright. 
 
5. Disposal 
 
Any unused medicine or waste material should be disposed of in accordance with local requirements. 
 



297 

Instructions for Use (IFU) 
 
Instructions for Use 
 
Xarelto 1 mg/mL 
 
250 mL bottle with 5.25 g granules for preparation of oral suspension  
Active pharmaceutical ingredient: Rivaroxaban 
 
Preparation and administration of the oral suspension (granules-water-mixture) 
 
 
Glossary and symbols  
 
 Granules: powder (provided in the bottle) which contains active pharmaceutical 

ingredient 
 Water syringe: 100 mL syringe used to measure and add 100 mL of water to the bottle 

containing Xarelto granules. 
 Suspension: granules-water-mixture (for oral application) 
 Blue syringe: syringe with blue plunger to extract and orally administer Xarelto. 
 

 

Caution: Consult Instructions for Use for relevant information related to warnings 
and precautions. 
 

 

Consult Instructions for Use (IFU). 
 

 

Keep away from sunlight 
 

 

Protect from moisture 
 

 

Manufacturing date 
 

 

Expiry date  
 

 

Reference number  
 

 

Batch number 
 

 

For oral use only 



298 

 
Before you start  
 
 Read all sections of the Instructions for Use carefully before using Xarelto for the first 

time and before administering each dose. 
 Watch the educational video which you can access via the QR code displayed on the 

Patient Alert Card that is provided with this medicine.  
 Be sure you understand the instructions before starting. If not, call your doctor. 
 Further information regarding Xarelto can be found in the Package Leaflet 
 
Packaging contents 
 
Every Xarelto box contains the following components: 
 

 

1 bottle with child resistant screw cap containing Xarelto granules. 
 

 

1 packaged 100 mL water syringe (for single use only) 
 
The water syringe is used to extract the exact quantity of water required 
to prepare Xarelto suspension. 

 

1 packaged bottle adapter 
The adapter is inserted into the neck of the bottle containing Xarelto 
granules after the exact quantity of water is added to the bottle. 
This bottle adapter connects the blue syringe to the bottle to ensure the 
correct amount of suspension can be extracted from the bottle into the blue 
syringe.  
 

 

2 packaged 5 mL blue syringes (one is a spare syringe) : 
This blue syringe is used to administer volumes up to 5 mL 
 



299 

 

2 packaged 10 mL blue syringes (one is a spare syringe):  
This blue syringe is used to administer volumes of 5 mL up to 10 mL. 
 
 
 
 
Use the appropriate blue syringe for the volume of suspension that is to 
be administered. 
The blue syringes have a red button under the label. This button serves to 
fix the required dosing volume. 
Keep the label at this place on the blue syringe until instructed to remove 
it. 

 

1 Instructions for Use (IFU) (this document) 
The IFU contains a description of the preparation of the suspension and 
how the blue syringe is set up and handled. 

 

1 Package Leaflet  
Provides important information about Xarelto. 
 
 

 

1 Patient Alert Card  
Important information in case of emergency. 
To be kept with the patient at all times and presented to every physician 
or dentist prior to treatment  
 

 

Cautionary Information:  

Do not unpack the single components until the instructions tell you to do so. 
Do not use Xarelto if any of the parts have been opened or are damaged. 
Do not use Xarelto after the expiry date which is stated on the box. 
 
Warnings and precautions 
 
 Only use non-carbonated drinking water to prepare the suspension to avoid bubbles. That 

means you can use either 
 fresh tap water or 
 non-carbonated (still) mineral water 

 It is very important that the precise amount of water is added to the granules in the bottle to 
ensure the correct concentration of Xarelto. 
 Use the water syringe for measurement of 100 mL water, see below for more information. 



300 

 Measure the amount water to be provided to the bottle very carefully. 
 After preparation the suspension can be used for 14 days if stored at room temperature.  

Ensure to write the expiry date of the suspension (date of preparation plus 14 days) on the 
dedicated field on the bottle label. 

 Do not store the suspension above 30 °C. Do not freeze.  
If the suspension has been stored in the refrigerator, allow the suspension to adjust to room 
temperature before extracting the relevant dose. 

 Shake the suspension for initial preparation for at least 60 seconds.  
 Shake the suspension in the bottle for at least 10 seconds before each administration. 
 It is very important that the prescribed dose volume of Xarelto is being administered. 

 Make sure that you know the prescribed dose and frequency of administration. Ask your 
doctor or pharmacist if you do not know the prescribed dose and frequency. 

 Carefully adjust the blue syringe according the prescribed volume. 
 Administer the prescribed dose by using the blue syringe. Follow the doctor’s instructions 

on how often per day you should administer the prescribed dose.  
 Check for air bubbles in the blue syringe before administration of the oral suspension. 

 If your child repeatedly does not take all the required dose or spits some of it out, call your 
child’s doctor to find out what to do. 

 Between dosing, store the oral suspension out of sight and reach of children. 
 Keep the Instructions for Use so that you can refer to them later during the use of Xarelto. 
 
Using Xarelto  
 
 Xarelto suspension is for oral use only. 
 Volume and frequency of administration of Xarelto depend on your child’s weight, so it 

will change over time if your child will receive Xarelto for a longer time. 
 Your child's doctor will tell you the right dose volume and the frequency of 

administration. 
 Do not change the dose yourself. 
 Always use the volume prescribed by your child's doctor and have the correct dosing and 

frequency of administration written on the designated field on the outside of the box. 
If it is not written on the field, ask your child's doctor or pharmacist to provide the 
relevant information. 

 Follow the detailed Instructions for Use given in the chapters below. 
 Take care to comply with the instructions concerning administration: 
 

Intake Administration 
time point 

Time span between 
administrations 

once a day 

with feeding or with a meal 

approximately 
24 hours apart 

twice a day 
approximately 
12 hours apart 

three times a day 
approximately 
8 hours apart 

 
1. Preparing the oral suspension  
 
Step 1.1: Preparation – Get ready 
 
The preparation of the suspension is done once with every new package.  
Before preparing the suspension: 
 



301 

 

a. Thoroughly wash your hands with soap and dry them 
afterwards. 
 

 

b. Check the expiry date on the label provided on the box. 
Do not use the medicine if the medicine has expired. 
 

 c. Obtain the following additional items: 
 Container with at least 150 mL of water: 

 Either fresh tap water or non-carbonated (still) mineral 
water 

 Water should be at room temperature 
 

  Tissue for soaking up any excess water 

 
Step 1.2: Filling the required volume of water 
 
Every time you start a new pack, use only the new materials contained in the new package. 
 
 a. Unpack the water syringe. 

 

 

b. Dip the opening of the water syringe into the container with 
water. 

c. Extract a volume of more than 100 mL. 
To do this, pull the plunger rod towards you, and make sure 
that the opening of the water syringe stays below the water 
surface all the time. This will avoid air bubbles in the syringe. 

d. Take the syringe out of the water. 
 



302 

 e. Turn the water syringe in a way that the opening is facing 
upwards. 

  Any air bubbles will move to the top when holding the 
syringe upwards. 

 Tap it with your fingers to further move any air bubble to the 
top. 

 

 

f. Push the plunger rod until the upper ring of the plunger 
reaches the 100 mL mark. 
 When pressing the plunger, water can come out of the tip 
of the water syringe. This waste water can be soaked up with a 
tissue. 
 

  

 

 

Cautionary Information:  

The upper ring of the black plunger must be precisely in line 
with the 100 mL mark to be able to achieve the correct 
concentration of the suspension. 
 

 

g. Continue to hold the water syringe with the opening facing 
upwards and check the water in the syringe carefully: 
 for correct volume, 
 for air bubbles. 
Small air bubbles are uncritical, but big air bubbles are 
critical. See below for more explanation on what to do. 



303 

 
Step 1.3: Adding water to the granules 
 
 a. If the granules in the bottle appear to be clumpy: 

 Gently tap the bottle on your hand. 
 Be careful since the bottle is made of glass. 

 

 

b. Unscrew the child resistant cap of the bottle (push down and 
turn counterclockwise). 

 

 

c. Place the filled water syringe on the upper edge of the bottle 
opening 

 

d. Hold the bottle firmly. 
e. Press the plunger rod down slowly. 
 The full volume of water must be transferred to the 

bottle. 
f. Dispose of the water syringe in household waste. 
 

 

 

h. If the syringe is not loaded correctly or contains too much 
air: 
 Empty the water syringe 
 Repeat steps b. to h  

 



304 

Step 1.4: Fitting the adapter and mixing the oral suspension 
 
The adapter is used to fill the blue syringe with suspension. 

 
 a. Unpack the bottle adapter 

 

 

b. Push the adapter completely into the neck of the bottle  
 

 

c. Close the bottle tightly with the screw cap. 
 

 

d. Shake the bottle gently for at least 60 seconds. 
 This is intended to provide a well-mixed suspension. 

 

 

e. Check whether the suspension is thoroughly mixed: 
 no clumps 
 no deposit. 

 

Cautionary Information:  

To guarantee correct dose, the suspension must not contain any 
clumps or deposit. 
 



305 

 f. If there are clumps or sediment repeat steps d. to f. 
 
 When no clumps or deposits are left, the suspension is ready for 
use. 
Do not add more water to the bottle. 
The suspension has a shelf life of 14 days at room temperature. 

 

 

g. Write the date of expiry of the just prepared suspension on the label 
of the bottle. 
Date of preparation + 14 days 
The shown pictogram is only an example.  
 

 
2. Setting the prescribed dose with every new blue syringe  
 
To prevent overdosing or underdosing an exact dose of suspension is required. 
Before you take the first dose out of the bottle, the enclosed blue syringe must be set up in 
accordance with the dose prescribed by your child's doctor. This information can be found on the 
dedicated area of the box. If no information has been entered here check back with the child's 
doctor or pharmacist. 
After setting the dose the same blue syringe can be used for all administrations from the bottle of 
suspension prepared in step 1. 
Once the dose has been fixed on the blue syringe, it cannot be changed. 
 
Step 2.1: Selecting a suitable blue syringe 

 
Dosing devices with different capacities are included in this pack: 

 
 5 mL blue syringes for doses from 1 mL to 5 mL 

 
 10 mL blue syringes for doses from 5 mL to 10 mL 

 
 a. Select the suitable blue syringe based on the dose prescribed by 

your child's doctor. 
The other blue syringes are not needed. 

b. Unpack the blue syringe. 
Note: 
Do not remove the peelable label until you are prompted in 
the Instructions for Use. 
The blue syringe features a red button to adjust the volume. This 
button is initially covered by a peelable label. 
By pressing the red button the volume of the syringe is set, which 
can only be done once. Do not press the red button until the 
Instructions for Use tell you to do so. 
Once the red button has been pressed, the volume can no longer 
be adjusted. 

 
 
Step 2.2: Setting the required dose on new blue syringe 
The blue syringe features a scale (mL). 



306 

The scale of the 5 mL blue syringe starts with 1 mL. The graduation marks are in increments of 
0.2 mL. 
The scale of the 10 mL blue syringe starts with 2 mL. The graduation marks are in increments of 
0.5 mL. 
 

 

a. Review the dose provided in the respective field on the outside of 
the box. 
Note: 
Use the 10 mL blue syringe for prescribed doses larger than 
10 mL as follows: 
Dose of 15 mL: 2 x 7.5 mL blue syringe  
Dose of 20 mL: 2 x 10 mL blue syringe 

 

 b. If the information is not available: 
Ask your pharmacist or doctor to provide it. 

 
 c. Hold the blue syringe with the opening pointing upwards 

 

d. Pull the plunger rod slowly until the upper margin reaches the 
mark of the volume to be administered. 

 When moving the plunger rod, you can hear a “Click” for each 
adjustable volume step. 

 

Cautionary Information:  

The upper edge of the plunger must be exactly in line with the 
correct mark of the volume to be administered. 
 
 
The shown pictogram is only an example. Your volume might be 
different. 
Be careful, do not pull the plunger past the volume to be 
administered. 
Be careful, do not press on the label when pulling the plunger. 
 

 

  

e. Remove the label of the blue syringe completely. 
 You can now see the red button for setting the volume. 
f. Check the position of the plunger again. Ensure the upper edge of 

the plunger is exactly in line with the correct mark of the volume 
to be administered. 

g.  If the position of the blue plunger does not match the required 
volume:  
Adjust it accordingly  

 



307 

 

h. If the position of the blue plunger matches the required volume, 
push the red button to fix the adjustment. 

 The required dose is now set. 
 Pressing the red button will produce another clicking sound. 
 The clicking sound will not be audible afterwards. 

 

Cautionary Information:  

If you notice that the wrong dose has been selected (the red button 
has been pushed, when the plunger was in the wrong position) use the 
appropriate spare blue syringe. 
Repeat steps a. to h. with a new blue syringe. 
 

 

i. Push the plunger upwards in the blue syringe as far as it goes. 
The blue syringe can now be used. 

 
3. Administering the oral suspension  
 
Follow the steps described below for each required administration. 
 
 
Step 3.1: Mixing the oral suspension  
 

 

Cautionary Information:  

Allow the suspension to adjust to room temperature if it has been stored in the refrigerator. 
 

 

a. Gently shake the bottle for at least 10 seconds before each 
dose. 
 This is intended to provide a well-mixed suspension. 

 



308 

 

b. Check whether the suspension is mixed thoroughly, i.e.: 
 no clumps 
 no deposit. 
c. If there are clumps or deposit:  
Repeat steps a. and b. 

 

 d. Shaking can lead to formation of foam.  
Let the bottle stand until the foam dissolves. 
 

 

e. Unscrew the bottle cap, but keep the adapter on the top of the 
bottle. 

Note: 
The larger opening visible on the adapter is used to connect the 
blue syringe. 
The surface of the bottle adapter should be free of liquid. 

f. If there is any liquid on the adapter:  
Remove the liquid with a clean tissue  
 

 
Step 3.2: Extracting the required dose 
 

 

a. Keep the bottle in the upright position. Insert the tip of the 
blue syringe fully into the large opening of the adapter 



309 

 

b. Turn the bottle upside down. 
c. Pull the blue plunger rod slowly until it stops (i.e. until the set 

dose is reached). 

 

d. Carefully check for air in the blue syringe.  
Smaller air bubbles are not critical. 

 

 

e. If there are bigger air bubbles: 
 Return the suspension to the bottle by pushing back the 

plunger rod into the blue syringe as far as possible. 
 Repeat steps b. to e. 

f. Return the bottle to the upright position. 
g. Remove the blue syringe carefully from the adapter 
 



310 

 
Step 3.3: Administration of prescribed dose 
 

 

a. Place the blue syringe into the mouth of the patient. 
b. Direct its tip into the cheek to allow for natural swallowing. 
c. Push the plunger rod down slowly until the plunger stops (blue 

syringe is completely empty). 
d. Ensure that the patient swallows the entire dose. 

 

Cautionary Information:  

The patient must swallow the full dose of medicine. 
If the dose repeatedly is not completely swallowed or if the patient is 
vomiting, consult your doctor for further instructions. 
 

 

h. Hold the blue syringe upright and check: 
 that the tip of the blue syringe is filled 
 whether the right dose has been filled into the blue 

syringe 
 that no big air bubbles are present. 

 

 

i. If there are bigger air bubbles or air in the tip: 
 Insert the tip of the blue syringe again fully into the 

large opening of the adapter 
 Return the suspension to the bottle by pushing back the 

plunger rod into the blue syringe as far as it goes. 
 Repeat steps b. to h. until no bigger air bubbles are 

visible. 
 
j. Close the bottle with the screw cap. 
Administer the suspension immediately after filling the blue 
syringe (step 3.3) 
 



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e. Encourage the patient to drink one typical serving of liquid. 
 For an infant of 6 months, for example, this may be 20 mL. 
 This can also be breast-feeding.  
 For an adolescent it may be a volume up to 240 mL 

 

 
4. Cleaning and storage 
 
The blue syringe must be cleaned following every application. 
Follow the steps listed below to clean the device. Altogether, three cycles of cleaning are necessary to 
ensure proper cleaning. 
 
 Before you start, you will need the following equipment for step 4.1: 

 Get two containers (such as a cup or bowl) 
o one container filled with drinking water, 
o the other container empty 

 

 
Step 4.1: Cleaning 
 

 

a. Dip the tip of the blue syringe into the container of water. 
b. Withdraw water until plunger rod stops. 

 

 

c. Empty the blue syringe into the prepared empty container 
 

 d. Repeat steps a. to c. an additional two times. 
e. After cleaning, push the plunger rod back in until it stops. 
f. Dry the outer surface of the syringe with a clean tissue 



312 

 
 

 

Cautionary Information:  

 Do not clean the blue syringe in the dish washer. 
 Never boil the blue syringe. 

 
 
Step 4.2: Storage 
 
Store the blue syringe in a clean and dry place until next use, e.g. keep it in the box Xarelto 
was given to you. 
 
Keep away from sunlight. 
 

 

Cautionary Information:  

The blue syringe can be used for up to 14 days. 
 
Store the suspension below 30 °C. 
 

 

Cautionary Information:  

Do not freeze the suspension. 
The prepared suspension is stable at room teperature for up to 14 days (preparation date plus 14 days). 
Keep Xarelto out of the sight and reach of children. 
Store the prepared suspension upright. 
 
5. Disposal  
 
Any unused medicine or waste material should be disposed of in accordance with local requirements. 
 

 
 


	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