RIVAROXABAN ACCORD 10mg tablets medication leaflet

Rivaroxaban Accord 10 mg film-coated tablets

Each film-coated tablet contains 10 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 pink to pink coloured, round, biconvex, approximately 6.00 mm in diameter, film coated tabletsdebossed with “IL1” on one side and plain on other side.

Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or kneereplacement surgery.

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

DVT and PE in adults. (See section 4.4 for haemodynamically unstable PE patients.)

Prevention of VTE in adult patients undergoing elective hip or knee replacement surgery

The recommended dose is 10 mg rivaroxaban taken orally once daily. The initial dose should be taken 6 to10 hours after surgery, provided that haemostasis has been established.

The duration of treatment depends on the individual risk of the patient for venous thromboembolism whichis determined by the type of orthopaedic surgery.

* For patients undergoing major hip surgery, a treatment duration of 5 weeks is recommended.

* For patients undergoing major knee surgery, a treatment duration of 2 weeks is recommended.

If a dose is missed the patient should take Rivaroxaban Accord immediately and then continue thefollowing day with once daily intake as before.

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE

The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first threeweeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE.

Short duration of therapy (at least 3 months) should be considered in patients with DVT or PE provoked bymajor transient risk factors (i.e. recent major surgery or trauma). Longer duration of therapy should beconsidered in patients with provoked DVT or PE not related to major transient risk factors, unprovoked

DVT or PE, or a history of recurrent DVT or PE.

When extended prevention of recurrent DVT and PE is indicated (following completion of at least6 months therapy for DVT or PE), the recommended dose is 10 mg once daily. In patients in whom the riskof recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who havedeveloped recurrent DVT or PE on extended prevention with Rivaroxaban Accord 10 mg once daily, adose of rivaroxaban 20 mg once daily should be considered.

The duration of therapy and dose selection should be individualised after careful assessment of thetreatment benefit against the risk for bleeding (see section 4.4).

Time period Dosing schedule Total daily dose

Treatment and prevention of Day 1-21 15 mg twice daily 30 mgrecurrent DVT and PE Day 22 onwards 20 mg once daily 20 mg

Prevention of recurrent DVT Following completion of 10 mg once daily 10 mgand PE at least 6 months or 20 mg once or 20 mgtherapy for DVT or PE daily

To support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment initiation pack of

Rivaroxaban Accord for treatment of DVT/PE is available.

If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take

Rivaroxaban Accord immediately to ensure intake of 30 mg rivaroxaban per day. In this case two 15 mgtablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake asrecommended on the following day.

If a dose is missed during the once daily treatment phase, the patient should take Rivaroxaban Accordimmediately, and continue on the following day with the once daily intake as recommended. The doseshould not be doubled within the same day to make up for a missed dose.

Converting from Vitamin K Antagonists (VKA) to rivaroxaban

For patients treated for DVT, PE and prevention of recurrence, VKA treatment should be stopped and

Rivaroxaban Accord therapy should be initiated once the INR is ≤ 2.5.

When converting patients from VKAs to rivaroxaban, International Normalised Ratio (INR) values will befalsely elevated after the intake of rivaroxaban. The INR is not valid to measure the anticoagulant activityof 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).

- For the prevention of VTE in adult patients undergoing elective hip or knee replacement surgery, nodose 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).

- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE, no doseadjustment from the recommended dose is necessary in patients with mild renal impairment(creatinine clearance 50-80 ml/min) (see section 5.2).

In patients with moderate (creatinine clearance 30-49 ml/min) or severe (creatinine clearance15-29 ml/min) renal impairment: patients should be treated with 15 mg twice daily for the first3 weeks. Thereafter, when the recommended dose is 20 mg once daily, a reduction of the dosefrom 20 mg once daily to 15 mg once daily should be considered if the patient’s assessed risk forbleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mgis based on PK modelling and has not been studied in this clinical setting (see sections 4.4, 5.1and 5.2).

When the recommended dose is 10 mg once daily, no dose adjustment from the recommendeddose is necessary.

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 section 5.2)

No dose adjustment (see section 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).

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

Pregnancy and breastfeeding (see section 4.6).

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 compared with VKA treatment. Thus, in addition to adequate clinicalsurveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding andquantify the clinical relevance of overt bleeding, as judged to be appropriate.

Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to becarefully monitored for signs and symptoms of bleeding complications and anaemia after initiation oftreatment (see section 4.8). In patients receiving rivaroxaban for VTE prevention following elective hip orknee replacement surgery, this may be done by regular physical examination of the patients, closeobservation of the surgical wound drainage and periodic measurements of haemoglobin. Any unexplainedfall 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 Accord is to beused with caution (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 section 4.5).

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

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.

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, and anti-beta 2-glycoprotein Iantibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic eventscompared with vitamin K antagonist therapy.

Rivaroxaban has not been studied in interventional clinical studies in patients undergoing hip fracturesurgery to evaluate efficacy and safety.

Rivaroxaban Accord is not recommended as an alternative to unfractionated heparin in patients withpulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonaryembolectomy since the safety and efficacy of rivaroxaban have not been established in these clinicalsituations.

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 risk of 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.

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).

At least 18 hours should elapse after the last administration of rivaroxaban before removal of an epiduralcatheter. Following removal of the catheter, at least 6 hours should elapse before the next rivaroxaban doseis administered.

If traumatic puncture occurs the administration of rivaroxaban is to be delayed for 24 hours.

Dosing recommendations before and after invasive procedures and surgical intervention other than electivehip or knee replacement surgery

If an invasive procedure or surgical intervention is required, Rivaroxaban Accord 10 mg should be stoppedat least 24 hours before the intervention, if possible and based on the clinical judgement of the physician.

If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency 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 section 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 aless than 18 years following initiation of similar 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 acute coronary syndrome respectively,(ACS) 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 6.8% of patients 5.9% of patients(VTE) in adult patients undergoingelective hip or knee replacement surgery

Prevention of venous thromboembolism 12.6% of patients 2.1% of patientsin medically ill patients

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 years 2.5 per 100 patientembolism in patients with non-valvular yearsatrial fibrillation

Prevention of atherothrombotic events in 22 per 100 patient years 1.4 per 100 patientpatients after an ACS years

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

* 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. Thrombocytosisrespective laboratory (incl. plateletparameters) count increased)A,

Allergic reaction, Anaphylacticdermatitis allergic, reactions

Angioedema and includingallergic oedema anaphylacticshock

Dizziness, headache Cerebral andintracranialhaemorrhage,syncope

Eye haemorrhage(incl. conjunctivalhaemorrhage)

Hypotension,haematoma

Epistaxis, haemoptysis Eosinophilicpneumonia

Gingival bleeding, Dry mouthgastrointestinal tracthaemorrhage (incl.

rectal haemorrhage),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. Urticaria Stevens-Johnsonuncommon cases of syndrome/ Toxic

Common Uncommon Rare Very rare Not knowngeneralised pruritus), Epidermalrash, ecchymosis, Necrolysis ,cutaneous and DRESS syndromesubcutaneoushaemorrhage

Pain in extremityA Haemarthrosis Muscle Compartmenthaemorrhage syndromesecondary to ableeding

Urogenital tract Renalhaemorrhage (incl. failure/acute renalhaematuria and failure secondarymenorrhagiaB), renal to a bleedingimpairment (incl. sufficient to causeblood creatinine hypoperfusion,increased, blood urea Anticoagulant-increased) relatednephropathy

FeverA, peripheral Feeling unwell Localisedoedema, decreased (incl. malaise) oedemaAgeneral strength andenergy (incl. fatigueand asthenia)

Increased LDHA,increased lipaseA,increasedamylaseA

Postprocedural Vascularhaemorrhage (incl. pseudoaneurysmCpostoperative anaemia,and woundhaemorrhage),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 III studies.

The incidence of adverse reactions did not increase and no new adverse drug reaction was identified afteranalysis 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 charcoalto 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 patients undergoing major orthopaedicsurgery, the 5/95 percentiles for PT (Neoplastin) 2 - 4 hours after tablet intake (i.e. at the time of maximumeffect) ranged from 13 to 25 s (baseline values before surgery 12 to 15 s).

In a clinical pharmacology study on the reversal of rivaroxaban pharmacodynamics in healthy 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).

Prevention of VTE in adult patients undergoing elective hip or knee replacement surgery

The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for theprevention of VTE, i.e. proximal and distal deep vein thrombosis (DVT) and pulmonary embolism (PE) inpatients undergoing major orthopaedic surgery of the lower limbs. Over 9,500 patients (7,050 in total hipreplacement surgery and 2,531 in total knee replacement surgery) were studied in controlled randomiseddouble-blind phase III clinical studies, the RECORD-programme.

Rivaroxaban 10 mg once daily (od) started no sooner than 6 hours post-operatively was compared withenoxaparin 40 mg once daily started 12 hours pre-operatively.

In all three phase III studies (see table 4), rivaroxaban significantly reduced the rate of total VTE (anyvenographically detected or symptomatic DVT, non-fatal PE and death) and major VTE (proximal DVT,non-fatal PE and VTE-related death), the pre-specified primary and major secondary efficacy endpoints.

Furthermore, in all three studies the rate of symptomatic VTE (symptomatic DVT, nonfatal PE,

VTE-related death) was lower in rivaroxaban treated patients compared to patients treated with enoxaparin.

The main safety endpoint, major bleeding, showed comparable rates for patients treated with rivaroxaban10 mg compared to enoxaparin 40 mg.

Table 4: Efficacy and safety results from phase III clinical studies

RECORD 1 RECORD 2 RECORD 3

Study 4,541 patients undergoing 2,509 patients undergoing 2,531 patients undergoing totalpopulation total hip replacement surgery total hip replacement surgery knee replacement surgery

Treatment Rivaroxaban Enoxaparin p Rivaroxaban Enoxaparin p Rivaroxaban Enoxaparin pdose and 10 mg od 40 mg od 10 mg od 40 mg od 10 mg od 40 mg odduration 35 ± 4 days 35 ± 4 days 35 ± 4 days 12 ± 2 days 12 ± 2 days 12 ± 2after dayssurgery

Total VTE 18 (1.1 %) 58 (3.7 %) < 0.001 17 (2.0 %) 81 (9.3 %) < 0.001 79 (9.6 %) 166 < 0.001(18.9 %)

Major VTE 4 (0.2 %) 33 (2.0 %) < 0.001 6 (0.6 %) 49 (5.1 %) < 0.001 9 (1.0 %) 24 0.01(2.6 %)

Symptomatic 6 (0.4 %) 11 (0.7 %) 3 (0.4 %) 15 (1.7 %) 8 (1.0 %) 24 (2.7 %)

VTE

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

The analysis of the pooled results of the phase III studies corroborated the data obtained in the individualstudies regarding reduction of total VTE, major VTE and symptomatic VTE with rivaroxaban 10 mg oncedaily compared to enoxaparin 40 mg once daily.

In addition to the phase III RECORD programme, a post-authorization, non-interventional, open-labelcohort study (XAMOS) has been conducted in 17,413 patients undergoing major orthopaedic surgery ofthe hip or knee, to compare rivaroxaban with other pharmacological thromboprophylaxis (standard-of-care)under real-life setting. Symptomatic VTE occurred in 57 (0.6 %) patients in the rivaroxaban group(n=8,778) and 88 (1.0 %) of patients in the standard-of-care group (n=8,635; HR 0.63; 95% CI 0.43-0.91);safety population). Major bleeding occurred in 35 (0.4%) and 29 (0.3%) of patients in the rivaroxaban andstandard-of-care groups (HR 1.10; 95% CI 0.67-1.80). Thus, the results were consistent with the results ofthe pivotal randomised studies.

Treatment of DVT, PE and prevention of recurrent DVT and PE

The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban in the initialand continued treatment of acute DVT and PE and prevention of recurrence.

Over 12,800 patients were studied in four randomised controlled phase III clinical studies (Einstein DVT,

Einstein PE, Einstein Extension and Einstein Choice) and additionally a predefined pooled analysis of the

Einstein DVT and Einstein PE studies was conducted. The overall combined treatment duration in allstudies was up to 21 months.

In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and the preventionof recurrent DVT and PE (patients who presented with symptomatic PE were excluded from this study).

The treatment duration was for 3, 6 or 12 months depending on the clinical judgement of the investigator.

For the initial 3 week treatment of acute DVT 15 mg rivaroxaban was administered twice daily. This wasfollowed by 20 mg rivaroxaban once daily.

In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention ofrecurrent DVT and PE. The treatment duration was for 3, 6 or 12 months depending on the clinicaljudgement of the investigator.

For the initial treatment of acute PE 15 mg rivaroxaban was administered twice daily for three weeks. Thiswas followed by 20 mg rivaroxaban once daily.

In both the Einstein DVT and the Einstein PE study, the comparator treatment regimen consisted ofenoxaparin administered for at least 5 days in combination with vitamin K antagonist treatment until the

PT/INR was in therapeutic range (≥ 2.0). Treatment was continued with a vitamin K antagonistdose-adjusted to maintain the PT/INR values within the therapeutic range of 2.0 to 3.0.

In Einstein Extension 1,197 patients with DVT or PE were studied for the prevention of recurrent DVT and

PE. The treatment duration was for an additional 6 or 12 months in patients who had completed 6 to12 months of treatment for venous thromboembolism depending on the clinical judgment of theinvestigator. Rivaroxaban 20 mg once daily was compared with placebo.

Einstein DVT, PE and Extension used the same pre-defined primary and secondary efficacy outcomes. Theprimary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent DVT orfatal or non-fatal PE. The secondary efficacy outcome was defined as the composite of recurrent DVT,non-fatal PE and all-cause mortality.

In Einstein Choice, 3,396 patients with confirmed symptomatic DVT and/or PE who completed6-12 months of anticoagulant treatment were studied for the prevention of fatal PE or non-fatalsymptomatic recurrent DVT or PE. Patients with an indication for continued therapeutic-dosedanticoagulation were excluded from the study. The treatment duration was up to 12 months depending onthe individual randomisation date (median: 351 days). rivaroxaban 20 mg once daily and rivaroxaban10 mg once daily were compared with 100 mg acetylsalicylic acid once daily.

The primary efficacy outcome was symptomatic recurrent VTE defined as the composite of recurrent

DVT or fatal or non-fatal PE.

In the Einstein DVT study (see Table 5) rivaroxaban was demonstrated to be non-inferior toenoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); Hazard Ratio HR:

0.680 (0.443 - 1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primaryefficacy outcome plus major bleeding events) was reported with a HR of 0.67 ((95 % CI: 0.47 - 0.95),nominal p value p=0.027) in favour of rivaroxaban. INR values were within the therapeutic range a meanof 60.3 % of the time for the mean treatment duration of 189 days, and 55.4 %, 60.1 %, and 62.8 % of thetime in the 3-, 6-, and 12-month intended treatment duration groups, respectively. In the enoxaparin/VKAgroup, there was no clear relation between the level of mean centre TTR (Time in Target INR Range of2.0 - 3.0) in the equally sized tertiles and the incidence of the recurrent VTE (P=0.932 for interaction).

Within the highest tertile according to centre, the HR with rivaroxaban versus warfarin was 0.69 (95 % CI:

0.35 - 1.35).

The incidence rates for the primary safety outcome (major or clinically relevant non-major bleedingevents) as well as the secondary safety outcome (major bleeding events) were similar for both treatmentgroups.

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

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

Treatment dose and duration Rivaroxabana) Enoxaparin/VKAb)3, 6 or 12 months 3, 6 or 12 months

N=1,731 N=1,718

Symptomatic recurrent VTE* 36 51(2.1 %) (3.0 %)

Symptomatic recurrent PE 20 18(1.2 %) (1.0 %)

Symptomatic recurrent DVT 14 28(0.8 %) (1.6 %)

Symptomatic PE and DVT 1 0(0.1 %)

Fatal PE/death where PE cannot 4 6be ruled out (0.2 %) (0.3 %)

Major or clinically relevant 139 138non-major bleeding (8.1 %) (8.1 %)

Major bleeding events 14 20(0.8 %) (1.2 %)a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once dailyb) Enoxaparin for at least 5 days, overlapped with and followed by VKA

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

In the Einstein PE study (see Table 6) rivaroxaban was demonstrated to be non-inferior toenoxaparin/VKA for the primary efficacy outcome (p=0.0026 (test for non-inferiority); HR: 1.123 (0.749 -1.684)). The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) wasreported with a HR of 0.849 ((95% CI: 0.633 - 1.139), nominal p value p= 0.275). INR values were withinthe therapeutic range a mean of 63 % of the time for the mean treatment duration of 215 days, and 57 %,62 %, and 65 % of the time in the 3-, 6-, and 12-month intended treatment duration groups, respectively. Inthe enoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in

Target INR Range of 2.0 - 3.0) in the equally sized tertiles and the incidence of the recurrent VTE(p=0.082 for interaction). Within the highest tertile according to centre, the HR with rivaroxaban versuswarfarin was 0.642 (95% CI: 0.277 - 1.484).

The incidence rates for the primary safety outcome (major or clinically relevant non-major bleedingevents) were slightly lower in the rivaroxaban treatment group (10.3 % (249/2412)) than in theenoxaparin/VKA treatment group (11.4 % (274/2405)). The incidence of the secondary safety outcome(major bleeding events) was lower in the rivaroxaban group (1.1 % (26/2412)) than in the enoxaparin/VKAgroup (2.2 % (52/2405)) with a HR 0.493 (95 % CI: 0.308 - 0.789).

Table 6: Efficacy and safety results from phase III Einstein PE

Study population 4,832 patients with an acute symptomatic PE

Treatment dose and duration Rivaroxabana) Enoxaparin/VKAb)3, 6 or 12 months 3, 6 or 12 months

N=2,419 N=2,413

Symptomatic recurrent VTE* 50 44(2.1 %) (1.8 %)

Symptomatic recurrent PE 23 20(1.0 %) (0.8 %)

Symptomatic recurrent DVT 18 17(0.7 %) (0.7 %)

Symptomatic PE and DVT 0 2(< 0.1 %)

Fatal PE/death where PE cannot 11 7be ruled out (0.5 %) (0.3 %)

Major or clinically relevant 249 274non-major bleeding (10.3 %) (11.4 %)

Major bleeding events 26 52(1.1 %) (2.2 %)a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once dailyb) Enoxaparin for at least 5 days, overlapped with and followed by VKA

* p < 0.0026 (non-inferiority to a prespecified HR of 2.0); HR: 1.123 (0.749-1.684)

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

Table 7).

Table 7: Efficacy and safety results from pooled analysis of phase III Einstein DVT and

Einstein PE

Study population 8,281 patients with an acute symptomatic DVT or PE

Treatment dose and duration Rivaroxabana) Enoxaparin/VKAb)3, 6 or 12 months 3, 6 or 12 months

N=4,150 N=4,131

Symptomatic recurrent VTE* 86 95(2.1 %) (2.3 %)

Symptomatic recurrent PE 43 38(1.0 %) (0.9 %)

Symptomatic recurrent DVT 32 45(0.8 %) (1.1 %)

Symptomatic PE and DVT 1 2(< 0.1 %) (< 0.1 %)

Fatal PE/death where PE 15 13cannot be ruled out (0.4 %) (0.3 %)

Study population 8,281 patients with an acute symptomatic DVT or PE

Treatment dose and duration Rivaroxabana) Enoxaparin/VKAb)3, 6 or 12 months 3, 6 or 12 months

N=4,150 N=4,131

Major or clinically relevant 388 412non-major bleeding (9.4 %) (10.0 %)

Major bleeding events 40 72(1.0 %) (1.7 %)a) Rivaroxaban 15 mg twice daily for 3 weeks followed by 20 mg once dailyb) Enoxaparin for at least 5 days, overlapped with and followed by VKA

* p < 0.0001 (non-inferiority to a prespecified HR of 1.75); HR: 0.886 (0.661-1.186)

The prespecified net clinical benefit (primary efficacy outcome plus major bleeding events) of the pooledanalysis was reported with a HR of 0.771 ((95% CI: 0.614-0.967), nominal p value p= 0.0244).

In the Einstein Extension study (see Table 8) rivaroxaban was superior to placebo for the primary andsecondary efficacy outcomes. For the primary safety outcome (major bleeding events) there was anon-significant numerically higher incidence rate for patients treated with rivaroxaban 20 mg once dailycompared to placebo. The secondary safety outcome (major or clinically relevant non-major bleedingevents) showed higher rates for patients treated with rivaroxaban 20 mg once daily compared to placebo.

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

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

Treatment dose and duration Rivaroxabana) Placebo6 or 12 months 6 or 12 months

N=602 N=594

Symptomatic recurrent VTE* 8 42(1.3 %) (7.1 %)

Symptomatic recurrent PE 2 13(0.3 %) (2.2 %)

Symptomatic recurrent DVT 5 31(0.8 %) (5.2 %)

Fatal PE/death where PE 1 1cannot be ruled out (0.2 %) (0.2 %)

Major bleeding events 4 0(0.7 %) (0.0 %)

Clinically relevant non-major 32 7bleeding (5.4 %) (1.2 %)a) Rivaroxaban 20 mg once daily

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

In the Einstein Choice study (see Table 9) rivaroxaban 20 mg and 10 mg were both superior to 100 mgacetylsalicylic acid for the primary efficacy outcome. The principal safety outcome (major bleeding events)was similar for patients treated with rivaroxaban 20 mg and 10 mg once daily compared to 100 mgacetylsalicylic acid.

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

Study population 3,396 patients continued prevention of recurrent venousthromboembolism

Treatment dose Rivaroxaban Rivaroxaban ASA 100 mg20 mg once 10 mg once once dailydaily daily N=1,131

N=1,107 N=1,127

Treatment duration 349 [189-362] days 353 [190-362] days 350 [186-362] daysmedian [interquartilerange]

Symptomatic recurrent 17 13 50

VTE (1.5 %) (1.2 %)* (4.4 %)

* *

Symptomatic recurrent 6 6 19

PE (0.5 %) (0.5 %) (1.7 %)

Symptomatic recurrent 9 8 30

DVT (0.8 %) (0.7 %) (2.7 %)

Fatal PE/death where PE 2 0 2cannot be ruled out (0.2 %) (0.0 %) (0.2 %)

Symptomatic recurrent 19 18 56

VTE, MI, stroke, or (1.7 %) (1.6 %) (5.0 %)non-CNS systemicembolism

Major bleeding events 6 5 3(0.5 %) (0.4 %) (0.3 %)

Clinically relevant 30 22 20non-major bleeding (2.7 %) (2.0 %) (1.8 %)

Symptomatic recurrent 23 17 53

VTE or major bleeding (2.1 %)+ (1.5 %)++ (4.7 %)(net clinical benefit)

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

** p < 0.001 (superiority) rivaroxaban 10 mg od vs ASA 100 mg od; HR=0.26 (0.14-0.47)+ Rivaroxaban 20 mg od vs. ASA 100 mg od; HR=0.44 (0.27-0.71), p=0.0009 (nominal)++ Rivaroxaban 10 mg od vs. ASA 100 mg od; HR=0.32 (0.18-0.55), p < 0.0001 (nominal)

In addition to the phase III EINSTEIN programme, a prospective, non-interventional, open-label cohortstudy (XALIA) with central outcome adjudication including recurrent VTE, major bleeding and death hasbeen conducted. 5,142 patients with acute DVT were enrolled to investigate the long-term safety ofrivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice.

Rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7 %, 1.4 % and0.5 %, respectively. There were differences in patient baseline characteristics including age, cancer andrenal impairment. A pre-specified propensity score stratified analysis was used to adjust for measuredbaseline differences but residual confounding may, in spite of this, influence the results. Adjusted HRscomparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE and all-cause mortalitywere 0.77 (95 % CI 0.40-1.50), 0.91 (95 % CI 0.54-1.54) and 0.51 (95 % CI 0.24-1.07), respectively.

These results in clinical practice are consistent with the established safety profile in this indication.

In a post-authorisation, non-interventional study, in more than 40,000 patients without a history of cancerfrom four countries, rivaroxaban was prescribed for the treatment or prevention of DVT and PE. The eventrates per 100 patient-years for symptomatic/clinically apparent VTE/thromboembolic events leading tohospitalisation ranged from 0.64 (95% CI 0.40 - 0.97) in the UK to 2.30 (95% CI 2.11 - 2.51) for Germany.

Bleeding resulting in hospitalisation occurred at event rates per 100 patient-years of 0.31 (95% CI 0.23 -0.42) for intracranial bleeding, 0.89 (95% CI 0.67 - 1.17) for gastrointestinal bleeding, 0.44 (95% CI 0.26 -0.74) for urogenital bleeding and 0.41 (95% CI 0.31 - 0.54) for other bleeding.

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 mgonce daily. At higher doses rivaroxaban displays dissolution limited absorption with decreasedbioavailability and decreased absorption rate with increased dose. This is more marked in fasting state thanin fed state. Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability(CV %) ranging from 30 % to 40 %, apart from on the day of surgery and the following day whenvariability in exposure is high (70 %).

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) renal impairment,rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6-fold respectively.

Corresponding increases in pharmacodynamic effects were more pronounced. In individuals with mild,moderate and severe renal impairment the overall inhibition of factor Xa activity was increased by a 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 for prevention of VTE 10 mg once daily the geometric meanconcentration (90 % prediction interval) 2-4 h and about 24 h after dose (roughly representing maximumand minimum concentrations during the dose interval) was 101 (7-273) and 14 (4-51) 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. In patients, baseline factor Xa and PT were influenced by the surgery resulting in a difference inthe concentration-PT slope between the day postsurgery and steady state.

Safety and efficacy have not been established in the indication primary prevention of VTE 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 red (E172)

Not applicable.

2 years.

Crushed tablets

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

This medicinal product does not require any special storage conditions.

Clear PVC/Aluminium blisters in cartons of 5, 10, 14, 28, 30, 98 or 100 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 10 mg tablets.

Accord Healthcare S.L.U.

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

Barcelona, 08039

Spain

EU/1/20/1488/012-023

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.