RIVAROXABAN ACCORD 2.5mg tablets medication leaflet

Rivaroxaban Accord 2.5 mg film-coated tablets

Each film-coated tablet contains 2.5 mg rivaroxaban.

Each film-coated tablet contains 27.90 mg lactose (as monohydrate), see section 4.4.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Light yellow coloured, round, biconvex, approximately 6.00 mm in diameter, film coated tablets debossedwith “IL4” on one side and plain on other side.

Rivaroxaban Accord, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrelor ticlopidine, 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).

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

The recommended dose is 2.5 mg twice daily.

* ACS

Patients taking Rivaroxaban Accord 2.5 mg twice daily should also take a daily dose of 75-100 mg ASA ora daily dose 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 ischaemic eventsagainst the bleeding risks. Extension of treatment beyond 12 months should be done on an individualpatient basis as experience up to 24 months is limited (see section 5.1).

Treatment with rivaroxaban 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 timewhen parenteral anticoagulation therapy would normally be discontinued.

* CAD/PAD

Patients taking Rivaroxaban Accord 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 until haemostasis isachieved (see section 5.1).

Duration of treatment should be determined for each individual patient based on regular evaluations andshould 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 antiplatelet therapy,the continuation of Rivaroxaban Accord 2.5 mg twice daily should be evaluated depending on the type ofevent or procedure and antiplatelet regimen.

Safety and efficacy of rivaroxaban 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 in combinationwith 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 next scheduledtime. The dose should not be doubled to make up for a missed dose.

Converting from Vitamin K Antagonists (VKA) to rivaroxaban

When converting patients from VKAs to rivaroxaban, International Normalised Ratio (INR) values couldbe falsely elevated after the intake of rivaroxaban. The INR is not valid to measure the anticoagulantactivity of rivaroxaban, and therefore should not be used (see section 4.5).

Converting from rivaroxaban to Vitamin K antagonists (VKA)

There is a potential for inadequate anticoagulation during the transition from rivaroxaban to VKA.

Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant.

It should be noted that rivaroxaban can contribute to an elevated INR.

In patients converting from rivaroxaban 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 rivaroxaban and VKA the INR shouldnot be tested earlier than 24 hours after the previous dose but prior to the next dose of rivaroxaban. Once

Rivaroxaban Accord 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 rivaroxaban

For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant andstart rivaroxaban 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 discontinuation of acontinuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin).

Converting from rivaroxaban to parenteral anticoagulants

Give the first dose of parenteral anticoagulant at the time the next rivaroxaban dose would be taken.

Limited clinical data for patients with severe renal impairment (creatinine clearance 15-29 ml/min) indicatethat rivaroxaban plasma concentrations are significantly increased. Therefore, Rivaroxaban Accord 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).

Rivaroxaban Accord is contraindicated in patients with hepatic disease associated with coagulopathy andclinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see sections 4.3and 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 rivaroxaban in children aged 0 to 18 years have not been established. No dataare available. Therefore, Rivaroxaban Accord is not recommended for use in children below 18 years ofage.

Rivaroxaban Accord 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, Rivaroxaban Accord tablet may be crushed andmixed 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).

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 current orrecent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain orspinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known orsuspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal orintracerebral vascular abnormalities.

Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), low molecularweight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants(warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances of switchinganticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an opencentral 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 lacunar stroke,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 rivaroxaban 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 rivaroxaban 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, efficacyand safety of rivaroxaban 2.5 mg twice daily have been investigated in combination with the antiplateletagent ASA alone or ASA plus short-term clopidogrel. If required, dual antiplatelet therapy with clopidogrelshould be short-term; long-term dual antiplatelet therapy should be avoided (see section 5.1).

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

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

As with other anticoagulants, patients taking Rivaroxaban Accord are to be carefully observed for signs ofbleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage.

Rivaroxaban Accord 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 includingabnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequently during longterm rivaroxaban treatment on top of single or dual anti-platelet therapy. Thus, in addition to adequateclinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occultbleeding 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 ofrivaroxaban in combination with dual antiplatelet therapy in patients at known increased risk for bleedingshould be balanced against the benefit in terms of prevention of atherothrombotic events. In addition thesepatients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia afterinitiation 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 levelsmeasured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations whereknowledge of rivaroxaban exposure may help to inform clinical decisions, e.g. overdose and emergencysurgery (see sections 5.1 and 5.2).

In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels maybe significantly increased (1.6-fold on average) which may lead to an increased bleeding risk.

Rivaroxaban Accord is to be used with caution in patients with creatinine clearance 15-29 ml/min. Use isnot 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 receivingother medicinal products which increase rivaroxaban plasma concentrations rivaroxaban is to be used withcaution (see section 4.5).

Interaction with other medicinal products

The use of Rivaroxaban Accord is not recommended in patients receiving concomitant systemic treatmentwith azole-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-gpand therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree (2.6-fold onaverage) 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 suchas non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) and plateletaggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotoninnorepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease anappropriate prophylactic treatment may be considered (see sections 4.5 and 5.1).

Patients treated with rivaroxaban 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 bleeding risksuch 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 gastroesophageal refluxdisease)

* 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 clopidogrelor 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 patients withactive cancer dependent on tumour location, antineoplastic therapy and stage of disease. Tumours locatedin the gastrointestinal or genitourinary tract have been associated with an increased risk of bleeding duringrivaroxaban therapy.

In patients with malignant neoplasms at high risk of bleeding, the use of rivaroxaban is contraindicated (seesection 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 rivaroxaban have not been studiedin patients with prosthetic heart valves; therefore, there are no data to support that rivaroxaban providesadequate anticoagulation in this patient population. Treatment with Rivaroxaban Accord is notrecommended for these patients.

Patients with prior stroke and/or TIA

Patients with ACS

Rivaroxaban 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 efficacy dataavailable 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 within 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 Rivaroxaban 2.5 mg should be avoided in thesepatients receiving dual antiplatelet therapy.

Direct acting Oral Anticoagulants (DOACs) including rivaroxaban are not recommended for patients witha history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients thatare triple positive (for lupus anticoagulant, anticardiolipin antibodies, andanti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates ofrecurrent thrombotic events compared with vitamin K antagonist therapy.

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patientstreated with antithrombotic agents for prevention of thromboembolic complications are at risk ofdeveloping an epidural or spinal haematoma which can result in long-term or permanent paralysis. The riskof these events may be increased by the post-operative use of indwelling epidural catheters or theconcomitant use of medicinal products affecting haemostasis. The risk may also be increased by traumaticor repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms ofneurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). Ifneurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxialintervention the physician should consider the potential benefit versus the risk in anticoagulated patients orin patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of

Rivaroxaban 2.5 mg and antiplatelet agents in these situations. Platelet aggregation inhibitors should bediscontinued as suggested by the manufacturer’s prescribing information.

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 anticoagulanteffect of rivaroxaban is estimated to be low (see section 5.2). However, the exact timing to reach asufficiently 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, Rivaroxaban Accord 2.5 mg should bestopped at least 12 hours before the intervention, if possible and based on the clinical judgement of thephysician. If a patient is to undergo elective surgery and anti-platelet effect is not desired, plateletaggregation 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 ofthe intervention.

Rivaroxaban Accord should be restarted as soon as possible after the invasive procedure or surgicalintervention provided the clinical situation allows and adequate haemostasis has been established asdetermined by the 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 the course oftherapy: 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, intenseand/or blistering), or any other sign of hypersensitivity in conjunction with mucosal lesions.

Rivaroxaban Accord contains lactose. Patients with rare hereditary problems of galactose intolerance, totallactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially“sodium-free”.

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 meanrivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increasedbleeding risk. Therefore, the use of rivaroxaban is not recommended in patients receiving concomitantsystemic treatment with azole-antimycotics such as ketoconazole, itraconazole, voriconazole andposaconazole or HIV protease inhibitors. These active substances are strong inhibitors of both CYP3A4and 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 Cmax. The interaction withclarithromycin is likely not clinically relevant in most patients but can be potentially significant inhigh-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-foldincrease in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely not clinicallyrelevant 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 increasein mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renalfunction. In subjects with moderate renal impairment, erythromycin led to a 2.0-fold increase in meanrivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects with normal renal function. Theeffect 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 inmean rivaroxaban AUC and a 1.3-fold increase in mean Cmax. The interaction with fluconazole is likely notclinically relevant in most patients but can be potentially significant in high-risk patients. (For patients withrenal impairment: see section 4.4).

Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should beavoided.

Anticoagulants

After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose) anadditive 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 otheranticoagulants (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 a pharmacokineticinteraction with rivaroxaban (15 mg) but a relevant increase in bleeding time was observed in a subset ofpatients 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) andplatelet aggregation inhibitors because these medicinal products typically increase the bleeding risk (seesection 4.4).

SSRIs/SNRIs

As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in caseof concomitant use with SSRIs or SNRIs due to their reported effect on platelets. When concomitantlyused in the rivaroxaban clinical programme, numerically higher rates of major or non-major clinicallyrelevant 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) morethan additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition offactor 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 dayafter 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, INRmeasurement can be used at the Ctrough of rivaroxaban (24 hours after the previous intake of rivaroxaban) asthis 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 approximate 50 %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 rivaroxaban plasmaconcentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be avoidedunless 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). Rivaroxaban neitherinhibits 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 rivaroxaban have not been established in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic riskof bleeding and the evidence that rivaroxaban passes the placenta, rivaroxaban is contraindicated duringpregnancy (see section 4.3).

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

Safety and efficacy of rivaroxaban have not been established in breast-feeding women. Data from animalsindicate that rivaroxaban is secreted into milk. Therefore, rivaroxaban is contraindicated duringbreast-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. In astudy on male and female fertility in rats no effects were seen (see section 5.3).

Rivaroxaban 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 II andtwo phase III studies were exposed to rivaroxaban.

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

Indication Number of Total daily dose Maximumpatients* treatmentduration

Prevention of venous thromboembolism (VTE) 6,097 10 mg 39 daysin adult patients undergoing elective hip orknee replacement surgery

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

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

recurrence 20 mg

After at least 6 months:

10 mg or 20 mg

Treatment of VTE and prevention of VTE 329 Body weight-adjusted 12 monthsrecurrence in term neonates and children aged dose to achieve a similarless than 18 years following initiation of exposure as thatstandard anticoagulation treatment observed in adultstreated for DVT with 20mg rivaroxaban oncedaily

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

Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 monthspatients after an ACS respectively,co-administered witheither ASA or ASA plusclopidogrel orticlopidine

Prevention of atherothrombotic events in 18,244 5 mg co-administered 47 monthspatients with CAD/PAD with ASA or 10 mgalone3,256** 5 mg co-administered 42 monthswith ASA

*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 commonly reportedbleedings 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 thromboembolism (VTE) in adult 6.8 % of patients 5.9 % of patientspatients undergoing elective hip or knee replacementsurgery

Prevention of venous thromboembolism in medically 12.6 % of patients 2.1 % of patientsill 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 39.5% of patients 4.6 % of patientsterm neonates and children aged less than 18 yearsfollowing initiation of standard anticoagulationtreatment

Prevention of stroke and systemic embolism in 28 per 100 patient 2.5 per 100 patientpatients with non-valvular atrial fibrillation years years

Prevention of atherothrombotic events in patients 22 per 100 patient 1.4 per 100 patientafter an ACS years years

Prevention of atherothrombotic events in patients 6.7 per 100 patient 0.15 per 100 patientwith 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 and adjudicated.

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

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

The frequencies of adverse reactions reported with rivaroxaban 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 through postmarketing use* and in two phase II and two phase III studies in paediatric patients

Common Uncommon Rare Very rare Not known

Anaemia (incl. respective Thrombocytosislaboratory parameters) (incl. plateletcount increased)A,

Allergic reaction, Anaphylacticdermatitis allergic, reactions

Angioedema and includingallergic oedema anaphylacticshock

Dizziness, headache Cerebral andintracranialhaemorrhage,syncope

Eye haemorrhage (incl.

conjunctival haemorrhage)

Hypotension, haematoma

Epistaxis, haemoptysis Eosinophilic

Common Uncommon Rare Very rare Not knownpneumonia

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

Increase in Hepatic Jaundice,transaminases impairment, Bilirubin

Increased conjugatedbilirubin, increased (withincreased blood or withoutalkaline concomitantphosphataseA, increase of ALT),increased GGTA Cholestasis,

Hepatitis (incl.

hepatocellularinjury)

Pruritus (incl. uncommon Urticaria Stevens-Johnsoncases of generalised syndrome/ Toxicpruritus), rash, ecchymosis, Epidermalcutaneous and Necrolysis ,subcutaneous haemorrhage DRESSsyndrome

Pain in extremityA Haemarthrosis Muscle Compartmenthaemorrhage syndromesecondary to ableeding

Urogenital tract Renalhaemorrhage (incl. failure/acutehaematuria and renal failuremenorrhagiaB), renal secondary to aimpairment (incl. blood bleedingcreatinine increased, blood sufficient tourea increased) causehypoperfusion,

Anticoagulant-relatednephropathy

FeverA, peripheral oedema, Feeling unwell Localiseddecreased general strength (incl. malaise) oedemaAand energy (incl. fatigueand asthenia)

Increased LDHA,increased lipaseA,increasedamylaseA

Common Uncommon Rare Very rare Not known

Postprocedural Vascularhaemorrhage (incl. pseudoaneurysmCpostoperative anaemia, andwound haemorrhage),contusion, woundsecretionA

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 (followingpercutaneous 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 reaction wasidentified after analysis of these studies.

Due to the pharmacological mode of action, the use of rivaroxaban may be associated with an increasedrisk 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 degreeor extent of the bleeding and/or anaemia (see section 4.9 “Management of bleeding”). In the clinicalstudies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormalvaginal or increased menstrual bleeding) and anaemia were seen more frequently during long termrivaroxaban 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 theclinical relevance of overt bleeding, as judged to be appropriate. The risk of bleedings may be increased incertain patient groups, e.g. those patients with uncontrolled severe arterial hypertension and/or onconcomitant treatment affecting haemostasis (see section 4.4 “Haemorrhagic risk”). Menstrual bleedingmay 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 aconsequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectoris have beenobserved.

Known complications secondary to severe bleeding such as compartment syndrome and renal failure due tohypoperfusion, or anticoagulant-related nephropathy have been reported for rivaroxaban. Therefore, thepossibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed 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 plasma exposureis 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 has ahalf-life of approximately 5 to 13 hours (see section 5.2). Management should be individualised accordingto the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used asneeded, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleedingcontrol procedures, fluid replacement and haemodynamic support, blood products (packed red cells orfresh 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 Xainhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of rivaroxaban, ora specific procoagulant agent, such as prothrombin complex concentrate (PCC), activated prothrombincomplex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), should be considered. However, thereis currently very limited clinical experience with the use of these medicinal products in individualsreceiving rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing ofrecombinant 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 ofmajor 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 aprotininin individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with theuse of the systemic haemostatic desmopressin in individuals receiving rivaroxaban. Due to the high plasmaprotein 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 of factor Xainterrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombinformation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated factor II) and noeffects 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 (rvalue 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 PCC hada greater and more rapid overall effect on reversing changes in endogenous thrombin generation than the4-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 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 a recent

ACS (ST-elevation myocardial infarction [STEMI], non-ST-elevation myocardial infarction [NSTEMI] orunstable angina [UA]). In the pivotal double-blind ATLAS ACS 2 TIMI 51 study, 15,526 patients wererandomly assigned in a 1:1:1 fashion to one of three treatment groups: rivaroxaban 2.5 mg orally twicedaily, 5 mg orally twice daily or to placebo twice daily co-administered with ASA alone or with ASA plusa thienopyridine (clopidogrel or ticlopidine). Patients with an ACS under the age of 55 had to have eitherdiabetes mellitus or a previous MI. The median time on treatment was 13 months and overall treatmentduration was up to almost 3 years. 93.2% of patients received ASA concomitantly plus thienopyridinetreatment and 6.8% ASA only. Among patients receiving dual antiplatelets therapy 98.8% receivedclopidogrel, 0.9% received ticlopidine and 0.3% received prasugrel. Patients received the first dose ofrivaroxaban at a minimum of 24 hours and up to 7 days (mean 4.7 days) after admission to the hospital, butas soon as possible after stabilisation of the ACS event, including revascularisation procedures and whenparenteral 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 furtherreducing the incidence of CV events on a background of standard antiplatelet care. The 2.5 mg twice dailyregimen reduced mortality, and there is evidence that the lower dose had lower bleeding risks, thereforerivaroxaban 2.5 mg twice daily co-administered with acetylsalicylic acid (ASA) alone or with ASA plusclopidogrel or ticlopidine is recommended for the prevention of atherothrombotic events in adult patientsafter an ACS with elevated cardiac biomarkers.

Relative to placebo, rivaroxaban significantly reduced the primary composite endpoint of CV death, MI orstroke. The benefit was driven by a reduction in CV death and MI and appeared early with a constanttreatment effect over the entire treatment period (see Table 4 and Figure 1). Also, the first secondaryendpoint (all-cause death, MI or stroke) was reduced significantly. An additional retrospective analysisshowed 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 whoreceived placebo (see Table 6). However, the incidence rates were balanced between rivaroxaban andplacebo for the components of fatal bleeding events, hypotension requiring treatment with intravenousinotropic agents and surgical intervention for ongoing 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 the overallsafety results.

Patients with elevated biomarkers (troponin or CK-MB) and without a prior stroke/TIA constituted 80 % ofthe study population. The results of this patient population were also consistent with the overall efficacyand 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 (%) N=5,113

Hazard ratio (HR) (95% CI) p-value b) n (%)

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

Study population Patients with a recent acute coronary syndrome a)

Treatment dose Rivaroxaban 2.5 mg, twice daily, Placebo

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

Hazard ratio (HR) (95% CI) p-value b) n (%)

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 syndrome undergoing PCIa)

Treatment dose Rivaroxaban 2.5 mg, twice daily, Placebo

N=3114 n (%) N=3096

HR (95% CI) p-value b) n (%)

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=5,125

N=5,115 n (%) 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 treatment b) 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 the efficacyand safety of Rivaroxaban for the prevention of a composite of CV death, MI, stroke in patients with CADor symptomatic PAD at high risk of ischaemic events. Patients were followed for a median of 23 monthsand 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 twice daily/ASA100 mg once daily, to rivaroxaban 5 mg twice daily, or ASA 100 mg once daily alone, and their matchingplacebos.

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 were required.

PAD patients had previous interventions such as bypass surgery or percutaneous transluminal angioplastyor limb or foot amputation for arterial vascular disease or intermittent claudication with ankle/arm bloodpressure ratio < 0.90 and/ or significant peripheral artery stenosis or previous carotid revascularization orasymptomatic 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 within 1 month or anyhistory 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) inpatients 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% 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 withno clinical need for a proton pump inhibitor showed no benefit in the prevention of upper gastrointestinalevents (i.e. composite of upper gastrointestinal bleeding, upper gastrointestinal ulceration, or uppergastrointestinal obstruction or perforation); the incidence rate of upper gastrointestinal events was0.39/100 patient-years in the pantoprazole 40 mg once daily group and 0.44/100 patient-years in theplacebo once daily group.

Table 7: Efficacy results from phase III COMPASS

Study Patients with CAD/PAD a)population

Treatment dose Rivaroxaban 2.5 mg ASA 100 mg odbid in combinationwith ASA 100 mg od

N=9152 N=9126

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

Stroke, MI or CV 379 (4.1%) 5.20% 496 (5.4%) 7.17% 0.76 p = 0.00004*death (0.66;0.86)

- Stroke 83 (0.9%) 1.17% 142 (1.6%) 2.23% 0.58 p = 0.00006(0.44;0.76)

- MI 178 (1.9%) 2.46% 205 (2.2%) 2.94% 0.86 p = 0.14458(0.70;1.05)

- CV death 160 (1.7%) 2.19% 203 (2.2%) 2.88% 0.78 p = 0.02053(0.64;0.96)

All-cause 313 (3.4%) 4.50% 378 (4.1%) 5.57% 0.82mortality (0.71;0.96)

Acute limb 22 (0.2%) 0.27% 40 (0.4%) 0.60% 0.55ischaemia (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 incidence riskcalculated 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 mg od,

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 10 (0.1%) 8 (0.1%) 1.24 (0.49;3.14)site requiring reoperation p = 0.65119(non-fatal, not in criticalorgan)

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 mg od,

N=9152 N=9126 p-value b)n (Cum. risk %) n (Cum.risk %)

- 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-Meier estimates)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 COMPASSbid: 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) dueto symptomatic PAD were randomly assigned to one of two antithrombotic treatment groups: rivaroxaban2.5 mg twice daily in combination with ASA 100 mg once daily, or to ASA 100 mg once daily, in a 1:1fashion. Patients were allowed to additionally receive standard dose of clopidogrel once daily for up to6 months. The objective of the study was to demonstrate the efficacy and safety of rivaroxaban plus ASAfor the prevention of myocardial infarction, ischaemic stroke, CV death, acute limb ischaemia, or majoramputation of a vascular etiology in patients after recent successful lower limb revascularisationprocedures due to symptomatic PAD. Patients aged ≥ 50 years with documented moderate to severesymptomatic lower extremity atherosclerotic PAD evidenced by all of the following: clinically (i.e.

functional limitations), anatomically (i.e. imaging evidence of PAD distal to external iliac artery) andhaemodynamically (ankle-brachial-index [ABI] ≤ 0.80 or toe-brachial-index [TBI] ≤ 0.60 for patientswithout a prior history of limb revascularisation or ABI ≤ 0.85 or TBI ≤ 0.65 for patients with a priorhistory of limb revascularisation) were included. Patients in need of dual antiplatelet therapy for> 6 months, or any additional antiplatelet therapy other than ASA and clopidogrel, or oral anticoagulanttherapy, as well as patients with a history of intracranial haemorrhage, stroke, or TIA, or patients witheGFR < 15 mL/min were excluded.

The mean duration of follow-up was 24 months and the maximum follow-up was 4.1 years. The mean ageof the enrolled patients was 67 years and 17% of the patient population were > 75 years. The median timefrom index revascularisation procedure to start of study treatment was 5 days in the overall population(6 days after surgical and 4 days after endovascular revascularisation including hybrid procedures).

Overall, 53.0% of patients received short term background clopidogrel therapy with a median duration of31 days. According to study protocol study treatment could be commenced as soon as possible but no laterthan 10 days after a successful qualifying revascularisation procedure and once hemostasis had beenassured.

Rivaroxaban 2.5 mg twice daily in combination with ASA 100 mg once daily was superior in the reductionof the primary composite outcome of myocardial infarction, ischaemic stroke, CV death, acute limbischaemia and major amputation of vascular etiology compared to ASA alone (see Table 9). The primarysafety outcome of TIMI major bleeding events was increased in patients treated with 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, and majoramputation 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 use withtreatment as factor.f) acute limb ischaemia is defined as sudden significant worsening of limb perfusion, either with new pulsedeficit 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 ofnumber 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 use withtreatment as a factor

CAD with heart failure

The COMMANDER HF study included 5,022 patients with heart failure and significant coronary arterydisease (CAD) following a hospitalization 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 no statisticallysignificant 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 betweenrivaroxaban 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 vsplacebo) 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 100patient-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 astatistically 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 subgroupwere 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 multicenter study with blinded endpoint adjudication,rivaroxaban was compared to warfarin in patients with a history of thrombosis, diagnosed withantiphospholipid syndrome and at high risk for thromboembolic events (positive for all 3 antiphospholipidtests: lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies). The trialwas terminated prematurely after the enrolment of 120 patients due to an excess of events among patientsin 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 3myocardial infarctions). No events were reported in patients randomised to warfarin. Major bleedingoccurred 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 thereference medicinal product containing rivaroxaban in all subsets of the paediatric population in theprevention of thromboembolic events (see section 4.2 for information on paediatric use).

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

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. Variability inrivaroxaban pharmacokinetics is moderate with inter-individual variability (CV%) ranging from 30% to40%.

Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29% and56% decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate is released inthe proximal small intestine. Exposure is further reduced when rivaroxaban is released in the distal smallintestine, or ascending colon. Therefore, administration of rivaroxaban distal to the stomach should beavoided since this can result in reduced absorption and related rivaroxaban exposure.

Bioavailability (AUC and Cmax) was comparable for 20 mg rivaroxaban administered orally as a crushedtablet mixed in apple puree, or suspended in water and administered via a gastric tube followed by a liquidmeal, compared to a whole tablet. Given the predictable, dose-proportional pharmacokinetic profile ofrivaroxaban, the bioavailability results from this study are likely applicable to lower rivaroxaban doses.

Plasma protein binding in humans is high at approximately 92% to 95%, with serum albumin being themain binding component. The volume of distribution is moderate with Vss being approximately 50 litres.

Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half thenbeing eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the administereddose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renalsecretion.

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 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 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 the eliminationhalf-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 youngindividuals, and with terminal half-lives of 11 to 13 hours in the elderly.

There were no clinically relevant differences in pharmacokinetics and pharmacodynamics between maleand 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. No doseadjustment 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 and pharmacodynamics.

Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor changesin rivaroxaban pharmacokinetics (1.2-fold increase in rivaroxaban AUC on average), nearly comparable totheir 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 healthyvolunteers. Unbound AUC was increased 2.6-fold. These patients also had reduced renal elimination ofrivaroxaban, 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 factor of2.1. 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 clinicallyrelevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 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-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 factorof 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; prolongation of PT was similarlyincreased 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 withcaution 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 h afterdose (roughly representing maximum and minimum concentrations during the dose interval) was 47(13-123) and 9.2 (4.4-18) mcg/l, respectively.

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentrationand several PD endpoints (factor Xa inhibition, PT, aPTT, Heptest) has been evaluated after administrationof a wide range of doses (5 - 30 mg twice a day). The relationship between rivaroxaban concentration andfactor Xa activity was best described by an Emax model. For PT, the linear intercept model generallydescribed 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 healthysubjects.

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 reproductive toxicityrelated to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic complications).

Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, hepatic multiple lightcoloured spots) and an increased incidence of common malformations as well as placental changes wereobserved at clinically relevant plasma concentrations. In the pre-and postnatal study in rats, reducedviability of the offspring was observed at doses that were toxic to the dams.

Lactose monohydrate

Croscarmellose sodium (E468)

Sodium laurilsulfate (E487)

Hypromellose 2910 (nominal viscosity 5.1 mPa.S) (E464)

Cellulose, microcrystalline (E460)

Silica, colloidal anhydrous (E551)

Magnesium stearate (E572)

Macrogol 4000 (E1521)

Hypromellose 2910 (nominal viscosity 5.1 mPa.S) (E464)

Titanium dioxide (E171)

Iron oxide yellow (E172)

Not applicable.

2 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.

Clear PVC/Aluminium blisters in cartons of 28, 56, 98, 100, 168 or 196 film-coated tablets or perforatedunit dose blisters of 10 x 1 or 100 x 1 tablets.

HDPE bottle fitted with white opaque child resistant polypropylene closure and induction sealing linerwad. Pack size 30 or 90 film-coated tablets.

HDPE bottle fitted with white opaque continuous thread polypropylene screw closure and inductionsealing liner wad. Pack size 500 film-coated tablets.

Not all pack sizes may be marketed.

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

Crushing of tablets

Rivaroxaban tablets may be crushed and suspended in 50 mL of water and administered via a nasogastrictube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, the tube should beflushed 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 reducedabsorption and thereby, reduced active substance exposure. Enteral feeding is not required immediatelyafter administration of the 2.5 mg tablets.

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona s/n, Edifici Est, 6a Planta,

Barcelona, 08039

Spain

EU/1/20/1488/001-011

Date of first authorisation: 16th November 2020

27/09/2023

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

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