XARELTO 2.5mg tablets medication leaflet

Xarelto 2.5 mg film-coated tablets

Each film-coated tablet contains 2.5 mg rivaroxaban.

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.

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.

Xarelto, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel orticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acutecoronary syndrome (ACS) with elevated cardiac biomarkers (see sections pct. 4.3, pct. 4.4 and 5.1).

Xarelto, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention ofatherothrombotic events in adult patients with coronary artery disease (CAD) or symptomaticperipheral artery disease (PAD) at high risk of ischaemic events.

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 dailydose of 75 - 100 mg ASA in addition to either a daily dose of 75 mg clopidogrel or a standard dailydose of ticlopidine.

Treatment should be regularly evaluated in the individual patient weighing the risk for ischaemicevents against the bleeding risks. Extension of treatment beyond 12 months should be done on anindividual 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 thetime when parenteral anticoagulation therapy would normally be discontinued.

* CAD/PAD

Patients taking Xarelto 2.5 mg twice daily should also take a daily dose of 75 - 100 mg ASA.

In patients after a successful revascularisation procedure of the lower limb (surgical or endovascularincluding hybrid procedures) due to symptomatic PAD, treatment should not be started untilhaemostasis is achieved (see section 5.1).

Duration of treatment should be determined for each individual patient based on regular evaluationsand should consider the risk for thrombotic events versus the bleeding risks.

* ACS, CAD/PAD

Co-administration with antiplatelet therapy

In patients with an acute thrombotic event or vascular procedure and a need for dual antiplatelettherapy, the continuation of Xarelto 2.5 mg twice daily should be evaluated depending on the type ofevent or procedure and antiplatelet regimen.

Safety and efficacy of Xarelto 2.5 mg twice daily in combination with dual antiplatelet therapy havebeen studied in patients

* with recent ACS in combination with ASA plus clopidogrel/ticlopidine (see section 4.1), and

* after recent revascularisation procedure of the lower limb due to symptomatic PAD incombination with ASA and, if applicable, short-term clopidogrel use (see sections 4.4 and 5.1)

If a dose is missed the patient should continue with the regular dose as recommended at the nextscheduled 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 couldbe falsely elevated after the intake of Xarelto. The INR is not valid to measure the anticoagulantactivity 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 alternateanticoagulant. 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 usedfollowed 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 lastdose (see sections 4.5 and 5.2).

Converting from parenteral anticoagulants to Xarelto

For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulantand start Xarelto 0 to 2 hours before the time that the next scheduled administration of the parenteralmedicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuationof 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.

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 beused 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 clearance50 - 80 ml/min) or moderate renal impairment (creatinine clearance 30 - 49 ml/min) (see section 5.2).

Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinicallyrelevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3 and 5.2).

No dose adjustment (see sections 4.4 and 5.2)

The risk of bleeding increases with increasing age (see section 4.4).

No dose adjustment (see sections 4.4 and 5.2)

No dose adjustment (see section 5.2)

The safety and efficacy of Xarelto 2.5 mg tablets in children aged 0 to 18 years have not beenestablished. No data are available. Therefore, Xarelto 2.5 mg tablets are not recommended for use inchildren below 18 years of age.

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 withwater 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).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Lesion or condition, if considered to be a significant risk for major bleeding. This may include currentor recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recentbrain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage,known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or majorintraspinal or intracerebral vascular abnormalities.

Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), lowmolecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oralanticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances ofswitching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintainan 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 transientischaemic attack (TIA) (see section 4.4).

Concomitant treatment of CAD/PAD with ASA in patients with previous haemorrhagic or lacunarstroke, or any stroke within a month (see section 4.4).

Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhoticpatients with Child Pugh B and C (see section 5.2).

Pregnancy and breast-feeding (see section 4.6).

In ACS patients, efficacy and safety of Xarelto 2.5 mg twice daily have been investigated incombination with the antiplatelet agents ASA alone or ASA plus clopidogrel/ticlopidine.

In patients at high risk of ischaemic events with CAD/PAD, efficacy and safety of Xarelto 2.5 mgtwice daily have been investigated in combination with ASA.

In patients after recent revascularisation procedure of the lower limb due to symptomatic PAD,efficacy and safety of Xarelto 2.5 mg twice daily have been investigated in combination with theantiplatelet agent ASA alone or ASA plus short-term clopidogrel. If required, dual antiplatelet therapywith clopidogrel should be short-term; long-term dual antiplatelet therapy should be avoided (seesection 5.1).

Treatment in combination with other antiplatelet agents, e.g. prasugrel or ticagrelor, has not beenstudied and is not recommended.

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatmentperiod.

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. Xareltoadministration should be discontinued if severe haemorrhage occurs (see section 4.9).

In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinaryincluding abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequentlyduring long term rivaroxaban treatment on top of single or dual anti-platelet therapy. Thus, in additionto adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value todetect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to beappropriate.

Several sub-groups of patients, as detailed below, are at increased risk of bleeding. Therefore, the useof Xarelto in combination with dual antiplatelet therapy in patients at known increased risk forbleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. Inaddition these patients are to be carefully monitored for signs and symptoms of bleeding complicationsand 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, rivaroxabanlevels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptionalsituations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g.

overdose and emergency surgery (see sections 5.1 and 5.2).

In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levelsmay 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 notrecommended 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) concomitantlyreceiving other medicinal products which increase rivaroxaban plasma concentrations Xarelto is to beused with caution (see section 4.5).

Interaction with other medicinal products

The use of Xarelto is not recommended in patients receiving concomitant systemic treatment withazole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIVprotease 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 haemostasissuch as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) andplatelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotoninnorepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal diseasean appropriate prophylactic treatment may be considered (see sections 4.5 and 5.1).

Patients treated with Xarelto and antiplatelet agents 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 bleedingrisk such as:

* congenital or acquired bleeding disorders

* uncontrolled severe arterial hypertension

* other gastrointestinal disease without active ulceration that can potentially lead to bleedingcomplications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophagealreflux 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 plusclopidogrel or ticlopidine.

* CAD patients with severe symptomatic heart failure. Study data indicate that such patients maybenefit less from treatment with rivaroxaban (see section 5.1).

Patients with cancer

Patients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis. Theindividual benefit of antithrombotic treatment should be weighed against risk for bleeding in patientswith active cancer dependent on tumour location, antineoplastic therapy and stage of disease. Tumourslocated in the gastrointestinal or genitourinary tract have been associated with an increased risk ofbleeding during rivaroxaban therapy.

In patients with malignant neoplasms at high risk of bleeding, the use of rivaroxaban is contraindicated(see section 4.3).

Patients with prosthetic valves

Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergonetranscatheter aortic valve replacement (TAVR). Safety and efficacy of Xarelto have not been studiedin patients with prosthetic heart valves; therefore, there are no data to support that Xarelto providesadequate anticoagulation in this patient population. Treatment with Xarelto is not recommended forthese patients.

Direct acting Oral Anticoagulants (DOACs) including rivaroxaban are not recommended for patientswith a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular forpatients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, andanti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased ratesof 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 (seesection 4.3). Few ACS patients with a prior stroke or TIA have been studied but the limited efficacydata 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 strokewith in the previous month were not studied (see section 4.3).

Patients after recent revascularisation procedures of the lower limb due to symptomatic PAD with aprevious stroke or TIA were not studied. Treatment with Xarelto 2.5 mg should be avoided in thesepatients receiving dual antiplatelet therapy.

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed,patients treated with antithrombotic agents for prevention of thromboembolic complications are at riskof 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 orthe concomitant use of medicinal products affecting haemostasis. The risk may also be increased bytraumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs andsymptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladderdysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Priorto neuraxial intervention the physician should consider the potential benefit versus the risk inanticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinicalexperience with the use of Xarelto 2.5 mg and antiplatelet agents in these situations. Plateletaggregation inhibitors should be discontinued as suggested by the manufacturer’s prescribinginformation.

To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban andneuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile ofrivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed whenthe anticoagulant effect of rivaroxaban is estimated to be low (see section 5.2). However, the exacttiming to reach a sufficiently low anticoagulant effect in each patient is not known.

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 least12 hours before the intervention, if possible and based on the clinical judgement of the physician. If apatient is to undergo elective surgery and anti-platelet effect is not desired, platelet aggregationinhibitors 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 theurgency of the intervention.

Xarelto should be restarted as soon as possible after the invasive procedure or surgical interventionprovided the clinical situation allows and adequate haemostasis has been established as determined bythe treating physician (see section 5.2).

Increasing age may increase haemorrhagic risk (see sections 5.1 and 5.2).

Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESSsyndrome, have been reported during post-marketing surveillance in association with the use ofrivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in thecourse of therapy: the onset of the reaction occurring in the majority of cases within the first weeks oftreatment. 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 mucosallesions.

Xarelto contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency 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 sayessentially “sodium-free”.

CYP3A4 and P-gp inhibitors

Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice aday) led to a 2.6 fold/2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold/1.6 fold increase inmean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to anincreased bleeding risk. Therefore, the use of Xarelto is not recommended in patients receivingconcomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole,voriconazole and posaconazole or HIV protease inhibitors. These active substances are stronginhibitors 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 andmoderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in

Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can bepotentially 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 a1.3 fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely notclinically 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 foldincrease in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects withnormal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 foldincrease in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects withnormal renal function. The effect of erythromycin is additive to that of renal impairment (seesection 4.4).

Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 foldincrease in mean rivaroxaban AUC and a 1.3 fold increase in mean Cmax. The interaction withfluconazole 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 shouldbe avoided.

Anticoagulants

After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg singledose) an additive effect on anti-factor Xa activity was observed without any additional effects onclotting 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 anyother anticoagulants (see sections 4.3 and 4.4).

NSAIDs/platelet aggregation inhibitors

No clinically relevant prolongation of bleeding time was observed after concomitant administration ofrivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a morepronounced pharmacodynamic response.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed whenrivaroxaban was co-administered with 500 mg acetylsalicylic acid.

Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show apharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time wasobserved 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 bleedingrisk (see section 4.4).

SSRIs/SNRIs

As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding incase of concomitant use with SSRIs or SNRIs due to their reported effect on platelets. Whenconcomitantly used in the rivaroxaban clinical programme, numerically higher rates of major or non-major clinically relevant bleeding were observed in all treatment groups.

Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) orfrom 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 thefourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activityand ETP) reflected only the effect of rivaroxaban.

If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INRmeasurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake ofrivaroxaban) as this test is minimally affected by rivaroxaban at this time point.

No pharmacokinetic interaction was observed between warfarin and rivaroxaban.

Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate50% decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. Theconcomitant 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 rivaroxabanplasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should beavoided unless the patient is closely observed for signs and symptoms of thrombosis.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed whenrivaroxaban 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). Rivaroxabanneither inhibits nor induces any major CYP isoforms like CYP3A4.

No clinically relevant interaction with food was observed (see section 4.2).

Clotting parameters (e.g. PT, aPTT, HepTest) are affected as expected by the mode of action ofrivaroxaban (see section 5.1).

Safety and efficacy of Xarelto have not been established in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsicrisk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicatedduring pregnancy (see section 4.3).

Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.

Safety and efficacy of Xarelto have not been established in breast-feeding women. Data from animalsindicate 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 todiscontinue/abstain from therapy.

No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility. Ina study on male and female fertility in rats no effects were seen (see section 5.3).

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.

The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1).

Overall, 69,608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase IIand two phase III studies were exposed to rivaroxaban.

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

Indication Number of Total daily dose Maximumpatients* treatmentduration

Prevention of venous 6,097 10 mg 39 daysthromboembolism (VTE) in adultpatients undergoing elective hip orknee replacement surgery

Prevention of VTE in medically ill 3,997 10 mg 39 dayspatients

Treatment of deep vein thrombosis 6,790 Day 1 - 21: 30 mg 21 months(DVT), pulmonary embolism (PE) Day 22 and onwards:

and prevention of recurrence 20 mg

After at least 6 months:

10 mg or 20 mg

Treatment of VTE and prevention 329 Body weight-adjusted 12 monthsof VTE recurrence in term neonates dose to achieve a similarand children aged less than 18 years exposure as that observedfollowing initiation of standard in adults treated for DVTanticoagulation treatment with 20 mg rivaroxabanonce daily

Prevention of stroke and systemic 7,750 20 mg 41 monthsembolism in patients with non-valvular atrial fibrillation

Prevention of atherothrombotic 10,225 5 mg or 10 mg 31 monthsevents in patients after an ACS respectively, co-administered with either

ASA or ASA plusclopidogrel or ticlopidine

Prevention of atherothrombotic 18,244 5 mg co-administered 47 monthsevents in patients with CAD/PAD with ASA or 10 mg alone3,256** 5 mg co-administered 42 monthswith ASA

Indication Number of Total daily dose Maximumpatients* treatmentduration

* Patients exposed to at least one dose of rivaroxaban

** From the VOYAGER PAD study

The most commonly reported adverse reactions in patients receiving rivaroxaban were bleedings (seesection 4.4. and ‘Description of selected adverse reactions’ below) (Table 2). The most commonlyreported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %).

Table 2: Bleeding* and anaemia events rates in patients exposed to rivaroxaban across thecompleted adult and paediatric phase III studies

Indication Any bleeding Anaemia

Prevention of venous 6.8% of patients 5.9% of patientsthromboembolism (VTE) in adultpatients undergoing elective hip orknee replacement surgery

Prevention of venous 12.6% of patients 2.1% of patientsthromboembolism in medically illpatients

Treatment of DVT, PE and prevention 23% of patients 1.6% of patientsof recurrence

Treatment of VTE and prevention of 39.5% of patients 4.6% of patients

VTE recurrence in term neonates andchildren aged less than 18 yearsfollowing initiation of standardanticoagulation treatment

Prevention of stroke and systemic 28 per 100 patient 2.5 per 100 patientembolism in patients with non-valvular years yearsatrial fibrillation

Prevention of atherothrombotic events 22 per 100 patient 1.4 per 100 patientin patients after an ACS years years

Prevention of atherothrombotic events 6.7 per 100 patient 0.15 per 100 patientin patients with CAD/PAD years years**8.38 per 100 patient 0.74 per 100 patientyears # years*** #

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

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

*** A selective approach to adverse event collection was applied# From the VOYAGER PAD study

The frequencies of adverse reactions reported with Xarelto in adult and paediatric patients aresummarised 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)

Table 3: All adverse reactions reported in adult patients in phase III clinical studies or throughpost-marketing use* and in two phase II and two phase III studies in paediatric patients

Common Uncommon Rare Very rare Not known

Anaemia (incl. Thrombocytosisrespective (incl. platelet countlaboratory increased)A,parameters) thrombocytopenia

Allergic reaction, Anaphylacticdermatitis allergic, reactions includingangioedema and anaphylactic shockallergic oedema

Dizziness, Cerebral andheadache intracranialhaemorrhage,syncope

Eye haemorrhage(incl. conjunctivalhaemorrhage)

Hypotension,haematoma

Epistaxis, Eosinophilichaemoptysis pneumonia

Gingival bleeding, Dry mouthgastrointestinaltract haemorrhage(incl. rectalhaemorrhage),gastrointestinal andabdominal pains,dyspepsia, nausea,constipationA,diarrhoea,vomitingA

Increase in Hepatic Jaundice, bilirubintransaminases impairment, conjugatedincreased bilirubin, increased (with orincreased blood withoutalkaline concomitantphosphataseA, increase of ALT),increased GGTA cholestasis,hepatitis (incl.

hepatocellularinjury)

Common Uncommon Rare Very rare Not known

Pruritus (incl. Urticaria Stevens-Johnsonuncommon cases of syndrome/Toxicgeneralised Epidermalpruritus), rash, Necrolysis, DRESSecchymosis, syndromecutaneous andsubcutaneoushaemorrhage

Pain in extremityA Haemarthrosis Muscle Compartmenthaemorrhage syndromesecondary to ableeding

Urogenital tract Renal failure/acutehaemorrhage (incl. renal failurehaematuria and secondary to amenorrhagiaB), bleeding sufficientrenal impairment to cause(incl. blood hypoperfusion,creatinine Anticoagulant-increased, blood related nephropathyurea increased)

FeverA, peripheral Feeling unwell Localised oedemaAoedema, decreased (incl. malaise)general strengthand energy (incl.

fatigue andasthenia)

Increased LDHA,increased lipaseA,increased amylaseA

Postprocedural Vascularhaemorrhage (incl. pseudoaneurysmCpostoperativeanaemia, andwoundhaemorrhage),contusion, woundsecretionA

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

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 in selected phase IIIstudies. The incidence of adverse reactions did not increase and no new adverse drug reactionwas identified after analysis of these studies.

Due to the pharmacological mode of action, the use of Xarelto may be associated with an increasedrisk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagicanaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to thelocation and degree or extent of the bleeding and/or anaemia (see section 4.9 “Management ofbleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genitourinary including abnormal vaginal or increased menstrual bleeding) and anaemia were seen morefrequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition toadequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value todetect occult bleeding and quantify the clinical relevance of overt bleeding, as judged to beappropriate. The risk of bleedings may be increased in certain patient groups, e.g. those patients withuncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis (seesection 4.4 “Haemorrhagic risk”). Menstrual bleeding may be intensified and/or prolonged.

Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplainedswelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms ofcardiac ischaemia like chest pain or angina pectoris have been observed.

Known complications secondary to severe bleeding such as compartment syndrome and renal failuredue to hypoperfusion, or anticoagulant-related nephropathy have been reported for Xarelto. Therefore,the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulatedpatient.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Rare cases of overdose up to 1,960 mg have been reported. In case of overdose, the patient should beobserved carefully for bleeding complications or other adverse reactions (see section “Management ofbleeding”). Due to limited absorption a ceiling effect with no further increase in average plasmaexposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above.

A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban isavailable (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 rivaroxabanadministration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban hasa half-life of approximately 5 to 13 hours (see section 5.2). Management should be individualisedaccording to the severity and location of the haemorrhage. Appropriate symptomatic treatment couldbe used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasiswith bleeding control procedures, fluid replacement and haemodynamic support, blood products(packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) orplatelets.

If bleeding cannot be controlled by the above measures, either the administration of a specificfactor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect ofrivaroxaban, or a specific procoagulant agent, such as prothrombin complex concentrate (PCC),activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), should beconsidered. However, there is currently very limited clinical experience with the use of thesemedicinal products in individuals receiving rivaroxaban. The recommendation is also based on limitednon-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated depending onimprovement of bleeding. Depending on local availability, a consultation with a coagulation expertshould 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 andaprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit norexperience with the use of the systemic haemostatic desmopressin in individuals receivingrivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.

Pharmacotherapeutic group: Antithrombotic agents, direct factor Xa inhibitors, ATC code: B01AF01

Rivaroxaban is a highly selective direct factor Xa inhibitor with oral bioavailability. Inhibition offactor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibitingboth thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin(activated factor II) and no effects on platelets have been demonstrated.

Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) isinfluenced 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 forcoumarins and cannot be used for any other anticoagulant.

In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy adultsubjects (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 PCCreduced mean Neoplastin PT values by approximately 1.0 second within 30 minutes, compared toreductions of approximately 3.5 seconds observed with the 4-factor PCC. In contrast, the 3-factor PCChad a greater and more rapid overall effect on reversing changes in endogenous thrombin generationthan 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 noneed 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).

ACS

The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for theprevention of cardiovascular (CV) death, myocardial infarction (MI) or stroke in subjects with arecent 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). Patientswith an ACS under the age of 55 had to have either diabetes mellitus or a previous MI. The mediantime on treatment was 13 months and overall treatment duration was up to almost 3 years. 93.2% ofpatients received ASA concomitantly plus thienopyridine treatment and 6.8% ASA only. Amongpatients receiving dual anti-platelets therapy 98.8% received clopidogrel, 0.9% received ticlopidineand 0.3% received prasugrel. Patients received the first dose of rivaroxaban at a minimum of 24 hoursand up to 7 days (mean 4.7 days) after admission to the hospital, but as soon as possible afterstabilisation of the ACS event, including revascularisation procedures and when parenteralanticoagulation therapy would normally be discontinued.

Both the 2.5 mg twice daily and the 5 mg twice daily regimens of rivaroxaban were effective infurther reducing the incidence of CV events on a background of standard antiplatelet care. The 2.5 mgtwice daily regimen reduced mortality, and there is evidence that the lower dose had lower bleedingrisks, therefore rivaroxaban 2.5 mg twice daily co-administered with acetylsalicylic acid (ASA) aloneor with ASA plus clopidogrel or ticlopidine is recommended for the prevention of atherothromboticevents 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 aconstant treatment effect over the entire treatment period (see Table 4 and Figure 1). Also the firstsecondary endpoint (all-cause death, MI or stroke) was reduced significantly. An additionalretrospective analysis showed a nominally significant reduction in the incidence rates of stentthrombosis 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 patientstreated with rivaroxaban than in patients who received placebo (see Table 6). However the incidencerates were balanced between rivaroxaban and placebo for the components of fatal bleeding events,hypotension requiring treatment with intravenous inotropic agents and surgical intervention forongoing bleeding.

In Table 5 the efficacy results of patients undergoing percutaneous coronary intervention (PCI) arepresented. The safety results in this subgroup of patients undergoing PCI were comparable to theoverall safety results.

Patients with elevated biomarkers (troponin or CK-MB) and without a prior stroke/TIA constituted80% of the study population. The results of this patient population were also consistent with theoverall 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 a)

Treatment dose Rivaroxaban 2.5 mg, twice daily, Placebo

N=5,114 N=5,113n (%) n (%)

Hazard Ratio (HR) (95% CI) p-value b)

Cardiovascular death, MI or stroke 313 (6.1%) 376 (7.4%)0.84 (0.72, 0.97) p = 0.020*

All-cause death, MI or stroke 320 (6.3%) 386 (7.5%)0.83 (0.72, 0.97) p = 0.016*

Cardiovascular death 94 (1.8%) 143 (2.8%)0.66 (0.51, 0.86) p = 0.002**

All-cause death 103 (2.0%) 153 (3.0%)0.68 (0.53, 0.87) p = 0.002**

MI 205 (4.0%) 229 (4.5%)0.90 (0.75, 1.09) p = 0.270

Stroke 46 (0.9%) 41 (0.8%)1.13 (0.74, 1.73) p = 0.562

Stent thrombosis 61 (1.2%) 87 (1.7%)0.70 (0.51, 0.97) p = 0.033**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

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

Study population Patients with recent acute coronary syndromeundergoing PCI a)

Treatment dose Rivaroxaban 2.5 mg, twice daily, Placebo

N=3114 N=3096n (%) n (%)

HR (95% CI) p-value b)

Cardiovascular death, MI or stroke 153 (4.9%) 165 (5.3%)0.94 (0.75, 1.17) p = 0.572

Cardiovascular death 24 (0.8%) 45 (1.5%)0.54 (0.33, 0.89) p = 0.013**

All-cause death 31 (1.0%) 49 (1.6%)0.64 (0.41, 1.01) p = 0.053

MI 115 (3.7%) 113 (3.6%)1.03 (0.79, 1.33) p = 0.829

Stroke 27 (0.9%) 21 (0.7%)1.30 (0.74, 2.31) p = 0.360

Stent thrombosis 47 (1.5%) 71 (2.3%)0.66 (0.46, 0.95) p = 0.026**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 a)

Treatment dose Rivaroxaban 2.5 mg, twice daily, Placebo

N=5,115 N=5,125n (%) n(%)

HR (95% CI) p-value b)

Non-CABG TIMI major bleeding 65 (1.3%) 19 (0.4%)event 3.46 (2.08, 5.77) p = < 0.001*

Fatal bleeding event 6 (0.1%) 9 (0.2%)0.67 (0.24, 1.89) p = 0.450

Symptomatic intracranial 14 (0.3%) 5 (0.1%)haemorrhage 2.83 (1.02, 7.86) p = 0.037

Hypotension requiring treatment 3 (0.1%) 3 (0.1%)with intravenous inotropic agents

Surgical intervention for ongoing 7 (0.1%) 9 (0.2%)bleeding

Transfusion of 4 or more units of 19 (0.4%) 6 (0.1%)blood over a 48 hour perioda) safety population, on treatmentb) vs placebo; Log-Rank p-value

* statistically significant

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 theefficacy and safety of rivaroxaban for the prevention of a composite of CV death, MI, stroke inpatients with CAD or symptomatic PAD at high risk of ischaemic events. Patients were followed for amedian of 23 months and maximum of 3.9 years.

Subjects without a continuous need for treatment with a proton pump inhibitor were randomised topantoprazole or placebo. All patients were then randomised 1:1:1 to rivaroxaban 2.5 mg twicedaily/ASA 100 mg once daily, to rivaroxaban 5 mg twice daily, or ASA 100 mg once daily alone, andtheir matching placebos.

CAD patients had multivessel CAD and/or prior MI. For patients < 65 years of age atherosclerosisinvolving at least two vascular beds or at least two additional cardiovascular risk factors wererequired.

PAD patients had previous interventions such as bypass surgery or percutaneous transluminalangioplasty or limb or foot amputation for arterial vascular disease or intermittent claudication withankle/arm blood pressure ratio < 0.90 and/ or significant peripheral artery stenosis or previous carotidrevascularisation or asymptomatic carotid artery stenosis ≥ 50%.

Exclusion criteria included the need for dual antiplatelet or other non-ASA antiplatelet or oralanticoagulant 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 within1 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 ASA100 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 dailycompared to patients who received ASA 100 mg (see Table 8).

For the primary efficacy outcome, the observed benefit of rivaroxaban 2.5 mg twice daily plus ASA100 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% vs5.0%). 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% vs1.7%).

The use of pantoprazole 40 mg once daily in addition to antithrombotic study medication in patientswith no clinical need for a proton pump inhibitor showed no benefit in the prevention of uppergastrointestinal events (i.e. composite of upper gastrointestinal bleeding, upper gastrointestinalulceration, or upper gastrointestinal obstruction or perforation); the incidence rate of uppergastrointestinal events was 0.39/100 patient-years in the pantoprazole 40 mg once daily group and0.44/100 patient-years in the placebo once daily group.

Table 7: Efficacy results from phase III COMPASS

Study Patients with CAD/PAD a)population

Treatment dose Rivaroxaban 2.5 mg bid ASA 100 mg odin combination with

ASA 100 mg od

N=9152 N=9126

Patients with KM % Patients KM % HR p-value b)events with events (95% CI)

Stroke, MI or 0.76379 (4.1%) 5.20% 496 (5.4%) 7.17% p = 0.00004*

CV death (0.66;0.86)0.58

- Stroke 83 (0.9%) 1.17% 142 (1.6%) 2.23% p = 0.00006(0.44;0.76)0.86

- MI 178 (1.9%) 2.46% 205 (2.2%) 2.94% p = 0.14458(0.70;1.05)0.78

- CV death 160 (1.7%) 2.19% 203 (2.2%) 2.88% p = 0.02053(0.64;0.96)

All-cause 0.82313 (3.4%) 4.50% 378 (4.1%) 5.57%mortality (0.71;0.96)

Acute limb 0.5522 (0.2%) 0.27% 40 (0.4%) 0.60%ischaemia (0.32;0.92)a) intention to treat analysis set, primary analysesb) 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 incidencerisk calculated at 900 days; CV: cardiovascular; MI: myocardial infarction; od: once daily

Table 8: Safety results from phase III COMPASS

Study population Patients with CAD/PAD a)

Treatment dose Rivaroxaban 2.5 mg ASA 100 mg od Hazard Ratiobid in combination (95 % CI)with ASA 100 mgod, N=9152 N=9126 p-value b)n (Cum. risk %) n (Cum.risk %)

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 63 (0.9%) 49 (0.7%) 1.28 (0.88;1.86)critical organ (non-fatal) p = 0.19679

- Bleeding into the surgical site 10 (0.1%) 8 (0.1%) 1.24 (0.49;3.14)requiring reoperation (non-fatal, not in critical organ) p = 0.65119

- Bleeding leading to 208 (2.9%) 109 (1.6%) 1.91 (1.51;2.41)hospitalisation (non-fatal, not p < 0.00001in critical organ, not requiringreoperation)

- 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 = 0.59858a) intention-to-treat analysis set, primary analysesb) vs ASA 100 mg; Log-Rank p-valuebid: twice daily; CI: confidence interval; Cum. Risk: Cumulative incidence risk (Kaplan-Meierestimates) at 30 months; ISTH: International Society on Thrombosis and Haemostasis; od:

once daily

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

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)bid: twice daily; od: once daily; CI: confidence interval

Patients after recent revascularisation procedure of the lower limb due to symptomatic PAD

In the pivotal phase III double-blind VOYAGER PAD trial, 6,564 patients after recent successfulrevascularisation procedure of the lower limb (surgical or endovascular including hybrid procedures)due to symptomatic PAD were randomly assigned to one of two antithrombotic treatment groups:

rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily, or to ASA 100 mg oncedaily, in a 1:1 fashion. Patients were allowed to additionally receive standard dose of clopidogrel oncedaily for up to 6 months. The objective of the study was to demonstrate the efficacy and safety ofrivaroxaban plus ASA for the prevention of myocardial infarction, ischaemic stroke, CV death, acutelimb ischaemia, or major amputation of a vascular etiology in patients after recent successful lowerlimb revascularisation procedures due to symptomatic PAD. Patients aged ≥ 50 years withdocumented moderate to severe symptomatic lower extremity atherosclerotic PAD evidenced by all ofthe following: clinically (i.e. functional limitations), anatomically (i.e. imaging evidence of PAD distalto external iliac artery) and haemodynamically (ankle-brachial-index [ABI] ≤ 0.80 or toe-brachial-index [TBI] ≤ 0.60 for patients without a prior history of limb revascularisation or ABI ≤ 0.85 or

TBI ≤ 0.65 for patients with a prior history of limb revascularisation) were included. Patients in needof dual antiplatelet therapy for > 6 months, or any additional antiplatelet therapy other than ASA andclopidogrel, or oral anticoagulant therapy, as well as patients with a history of intracranialhaemorrhage, stroke, or TIA, or patients with eGFR < 15 mL/min were excluded.

The mean duration of follow-up was 24 months and the maximum follow-up was 4.1 years. The meanage of the enrolled patients was 67 years and 17% of the patient population were > 75 years. Themedian time from index revascularisation procedure to start of study treatment was 5 days in theoverall population (6 days after surgical and 4 days after endovascular revascularisation includinghybrid procedures). Overall, 53.0% of patients received short term background clopidogrel therapywith a median duration of 31 days. According to study protocol study treatment could be commencedas soon as possible but no later than 10 days after a successful qualifying revascularisation procedureand once hemostasis had been assured.

Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily was superior in thereduction of the primary composite outcome of myocardial infarction, ischaemic stroke, CV death,acute limb ischaemia and major amputation of vascular etiology compared to ASA alone (see

Table 9). The primary safety outcome of TIMI major bleeding events was increased in patients treatedwith rivaroxaban and ASA, with no increase in fatal or intracranial bleeding (see Table 10).

The secondary efficacy outcomes were tested in a prespecified, hierarchical order (see Table 9).

Table 9: Efficacy results from phase III VOYAGER PAD

Study Population Patients after recent revascularisation procedures of the lowerlimb due to symptomatic PAD a)

Treatment Dosage Rivaroxaban 2.5 mg bid ASA 100 mg od Hazard Ratioin combination with (95% CI) d)

ASA 100 mg od

N=3,286 N=3,278n (Cum. risk %)c) n (Cum. risk %)c)

Primary efficacy outcomeb) 508 (15.5%) 584 (17.8%) 0.85 (0.76;0.96)p = 0.0043 e)*

- MI 131 (4.0%) 148 (4.5%) 0.88 (0.70;1.12)

- Ischaemic stroke 71 (2.2%) 82 (2.5%) 0.87 (0.63;1.19)

- CV death 199 (6.1%) 174 (5.3%) 1.14 (0.93;1.40)

- Acute limb ischaemia f) 155 (4.7%) 227 (6.9%) 0.67 (0.55;0.82)

- Major amputation of 103 (3.1%) 115 (3.5%) 0.89 (0.68;1.16)vascular etiology

Secondary efficacyoutcome

Unplanned index limb 584 (17.8%) 655 (20.0%) 0.88 (0.79;0.99)revascularisation for p = 0.0140 e)*recurrent limb ischaemia

Hospitalisation for a 262 (8.0%) 356 (10.9%) 0.72 (0.62;0.85)coronary or peripheral p < 0.0001 e)*cause (either lower limb)of a thrombotic nature

All-cause mortality 321 (9.8%) 297 (9.1%) 1.08 (0.92;1.27)

VTE events 25 (0.8%) 41 (1.3%) 0.61 (0.37;1.00)a) intention to treat analysis set, primary analyses; ICAC adjudicatedb) composite of MI, ischaemic stroke, CV death (CV death and unknown cause of death), ALI, andmajor amputation of vascular etiologyc) only the first occurrence of the outcome event under analysis within the data scope from a subject isconsideredd) HR (95% CI) is based on the Cox proportional hazards model stratified by type of procedure andclopidogrel use with treatment as the only covariate.e) One sided p-value is based on the log-rank test stratified by type of procedure and clopidogrel usewith treatment as factor.f) acute limb ischaemia is defined as sudden significant worsening of limb perfusion, either with newpulse deficit or requiring therapeutic intervention (i.e. thrombolysis or thrombectomy, or urgentrevascularisation), and leading to hospitalisation

* The reduction in the efficacy outcome was statistically superior.

ALI: acute limb ischaemia; bid: twice daily; od: once daily; CI: confidence interval; MI: myocardialinfarction; CV: cardiovascular; ICAC: Independent Clinical Adjudication Committee

Table 10: Safety results from phase III VOYAGER PAD

Study Population Patients after recen t revascularisation procedures of the lowerlimb due to symptomatic PAD a)

Treatment Dosage Rivaroxaban 2.5 mg bid ASA 100 mg od Hazard Ratioin combination with (95% CI) c)

ASA 100 mg od

N=3,256 N=3,248n (Cum. risk %)b) n (Cum. risk %)b) p-value d)

TIMI major bleeding 62 (1.9%) 44 (1.4%) 1.43 (0.97;2.10)(CABG/non-CABG) p = 0.0695

- Fatal bleeding 6 (0.2%) 6 (0.2%) 1.02 (0.33;3.15)

- Intracranial bleeding 13 (0.4%) 17 (0.5%) 0.78 (0.38;1.61)

- Overt bleeding 46 (1.4%) 24 (0.7%) 1.94 (1.18;3.17)associated with drop Hb≥ 5g/dL/Hct ≥ 15%

ISTH major bleeding 140 (4.3%) 100 (3.1%) 1.42 (1.10;1.84)p = 0.0068

- Fatal bleeding 6 (0.2%) 8 (0.2%) 0.76 (0.26;2.19)

- Non-fatal critical organ 29 (0.9%) 26 (0.8%) 1.14 (0.67;1.93)bleeding

ISTH clinically relevant 246 (7.6%) 139 (4.3%) 1.81 (1.47;2.23)non-major bleedinga) Safety analysis set (all randomised subjects with at least one dose of study drug), ICAC:

Independent Clinical Adjudication Committeeb) n = number of subjects with events, N = number of subjects at risk, % = 100 * n/N, n/100p-yrs =ratio of number of subjects with incident events/cumulative at-risk timec) HR (95% CI) is based on the Cox proportional hazards model stratified by type of procedure andclopidogrel use with treatment as the only covariated) Two sided p-value is based on the log rank-test stratified by type of procedure and clopidogrel usewith treatment as a factor

CAD with heart failure

The COMMANDER HF study included 5,022 patients with heart failure and significant coronaryartery disease (CAD) following a hospitalisation of decompensated heart failure (HF) which wererandomly assigned into one of the two treatment groups: rivaroxaban 2.5 mg twice daily (N=2,507) ormatching 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 nostatistically significant difference between the rivaroxaban 2.5 mg twice daily group and the placebogroup with a HR=0.94 (95% CI 0.84 - 1.05), p=0.270. For all-cause mortality, there was no differencebetween rivaroxaban and placebo in the number of events (event rate per 100 patient-years; 11.41 vs11.63, 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 strokethe 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). Theprincipal safety outcome (i.e. composite of fatal bleeding or bleeding into a critical space with apotential for permanent disability), occurred in 18 (0.7%) patients in the rivaroxaban 2.5 mg twicedaily treatment group and in 23 (0.9%) patients in the placebo group, respectively (HR=0.80; 95% CI0.43 - 1.49; p=0.484). There was a statistically significant increase in ISTH major bleeding in therivaroxaban 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 studysubgroup 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 endpointadjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis,diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive forall 3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, andanti-beta 2-glycoprotein I antibodies). The study was terminated prematurely after the enrolment of120 patients due to an excess of events among patients in the rivaroxaban arm. Mean follow-up was569 days. 59 patients were randomised to rivaroxaban 20 mg (15 mg for patients with creatinineclearance (CrCl) < 50 mL/min) and 61 to warfarin (INR 2.0-3.0). Thromboembolic events occurred in12% of patients randomised to rivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). Noevents 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.

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 (seesection 4.2 for information on paediatric use).

Rivaroxaban is rapidly absorbed with maximum concentrations (Cmax) appearing 2 - 4 hours aftertablet intake.

Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100%) for the2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affectrivaroxaban AUC or Cmax at the 2.5 mg and 10 mg dose. Rivaroxaban 2.5 mg and 10 mg tablets can betaken with or without food.

Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily. At higher dosesrivaroxaban displays dissolution limited absorption with decreased bioavailability and decreasedabsorption rate with increased dose. This is more marked in fasting state than in fed state. Variabilityin rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from30% 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 Cmax compared to tablet was reported when rivaroxaban granulate isreleased in the proximal small intestine. Exposure is further reduced when rivaroxaban is released inthe distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to thestomach should be avoided since this can result in reduced absorption and related rivaroxabanexposure.

Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as acrushed tablet mixed in apple puree, or suspended in water and administered via a gastric tubefollowed by a liquid meal, compared to a whole tablet. Given the predictable, dose-proportionalpharmacokinetic profile of rivaroxaban, the bioavailability results from this study are likely applicableto lower rivaroxaban doses.

Plasma protein binding in humans is high at approximately 92% to 95%, with serum albumin beingthe main binding component. The volume of distribution is moderate with Vss being approximately50 litres.

Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with halfthen being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of theadministered dose undergoes direct renal excretion as unchanged active substance in the urine, mainlyvia active renal secretion.

Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidativedegradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites ofbiotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporterproteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein).

Unchanged rivaroxaban is the most important compound in human plasma, with no major or activecirculating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can beclassified as a low-clearance substance. After intravenous administration of a 1 mg dose theelimination half-life is about 4.5 hours. After oral administration the elimination becomes absorptionrate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours inyoung individuals, and with terminal half-lives of 11 to 13 hours in the elderly.

There were no clinically relevant differences in pharmacokinetics and pharmacodynamics betweenmale and female patients.

Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC valuesbeing approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. Nodose adjustment is necessary.

Different weight categories

Extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasmaconcentrations (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 andpharmacodynamics.

Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minorchanges in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearlycomparable to their matched healthy control group. In cirrhotic patients with moderate hepaticimpairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients alsohad 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 hepaticimpairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factorof 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in asteeper PK/PD relationship between concentration and PT.

Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy andclinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (seesection 4.3).

There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed viacreatinine 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) renalimpairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 foldrespectively. Corresponding increases in pharmacodynamic effects were more pronounced. Inindividuals with mild, moderate and severe renal impairment the overall inhibition of factor Xaactivity 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 nodata 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 usedwith 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 inpatients with ACS the geometric mean concentration (90% prediction interval) 2 - 4 h and about 12 hafter dose (roughly representing maximum and minimum concentrations during the dose interval) was47 (13 - 123) and 9.2 (4.4 - 18) mcg/l, respectively.

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasmaconcentration and several PD endpoints (factor-Xa inhibition, PT, aPTT, Heptest) has been evaluatedafter administration of a wide range of doses (5 - 30 mg twice a day). The relationship betweenrivaroxaban concentration and factor-Xa activity was best described by an Emax model. For PT, thelinear intercept model generally described the data better. Depending on the different PT reagentsused, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s andthe slope was around 3 to 4 s/(100 mcg/l). The results of the PK/PD analyses in Phase II and III wereconsistent with the data established in healthy subjects.

Safety and efficacy have not been established in the indications ACS and CAD/PAD for children andadolescents up to 18 years.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juveniletoxicity.

Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamicactivity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevantexposure levels.

In rats, no effects on male or female fertility were seen. Animal studies have shown reproductivetoxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagiccomplications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification,hepatic multiple light coloured spots) and an increased incidence of common malformations as well asplacental 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.

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)

Not applicable.

3 years

Crushed tablets

Crushed rivaroxaban tablets are stable in water and in apple puree for up to 4 hours.

This medicinal product does not require any special storage conditions.

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 doseblisters.

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.

Crushing of tablets

Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via anasogastric tube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, thetube should be flushed with water. Since rivaroxaban absorption is dependent on the site of activesubstance release, administration of rivaroxaban distal to the stomach should be avoided, as this canresult in reduced absorption and thereby, reduced active substance exposure. Enteral feeding is notrequired immediately after administration of the 2.5 mg tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bayer AG51368 Leverkusen

Germany

EU/1/08/472/025-035, EU/1/08/472/041, EU/1/08/472/046-047

Date of first authorisation: 30 September 2008

Date of latest renewal: 22 May 2018

Detailed information on this medicinal product is available on the website of the European Medicines

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