RIVAROXABAN ACCORD 15mg tablets medication leaflet

Rivaroxaban Accord 15 mg film-coated tablets

Each film-coated tablet contains 15 mg rivaroxaban.

Each film-coated tablet contains 20.920 mg lactose (as monohydrate), see section 4.4.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Red coloured, round, biconvex, approximately 5.00 mm in diameter, film coated tablets debossed with‘‘IL’’ on one side and ‘‘2’’ on other side.

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with oneor more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, priorstroke or transient ischaemic attack.

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

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

Treatment of venous thromboembolism (VTE) and prevention of VTE recurrence in children andadolescents aged less than 18 years and weighing from 30 kg to 50 kg after at least 5 days of initialparenteral anticoagulation treatment.

Prevention of stroke and systemic embolism in adults

The recommended dose is 20 mg once daily, which is also the recommended maximum dose.

Therapy with Rivaroxaban Accord should be continued long term provided the benefit of prevention ofstroke and systemic embolism outweighs the risk of bleeding (see section 4.4).

If a dose is missed the patient should take Rivaroxaban Accord immediately and continue on the followingday with the once daily intake as recommended. The dose should not be doubled within the same day tomake up for a missed dose.

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

The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first 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 10 mg once daily, a dose ofrivaroxaban 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 Day 1-21 15 mg twice daily 30 mgprevention of recurrent Day 22 onwards 20 mg once daily 20 mg

DVT and PE

Prevention of recurrent Following 10 mg once daily 10 mg

DVT and PE completion of at or 20 mg once or 20 mgleast 6 months dailytherapy for DVT or

PE

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.

Treatment of VTE and prevention of VTE recurrence in children and adolescents

Rivaroxaban Accord treatment in children and adolescents aged less than 18 years should be initiatedfollowing at least 5 days of initial parenteral anticoagulation treatment (see section 5.1).

The dose for children and adolescent is calculated based on body weight.

- Body weight from 30 to 50 kg:

a once daily dose of 15 mg rivaroxaban is recommended. This is the maximum daily dose.

- Body weight of 50 kg or more:

a once daily dose of 20 mg rivaroxaban is recommended. This is the maximum daily dose.

- For patients with body weight less 30 kg refer to the Summary of Product Characteristics of othermedicinal products that contain rivaroxaban granules for oral suspension available on the market.

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

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

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

Converting from Vitamin K Antagonists (VKA) to rivaroxaban

- Prevention of stroke and systemic embolism, VKA treatment should be stopped and Rivaroxaban

Accord therapy should be initiated when the International Normalised Ratio (INR) is ≤ 3.0.

- Treatment of DVT, PE and prevention of recurrence in adults and treatment of VTE andprevention of recurrence in paediatric patients:

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, INR values will be falsely elevated after theintake of rivaroxaban. The INR is not valid to measure the anticoagulant activity of rivaroxaban, andtherefore 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 alternateanticoagulant. 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 usedfollowed by VKA dosing, as guided by INR testing. While patients are on both rivaroxaban and VKAthe INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose ofrivaroxaban. Once Rivaroxaban Accord is discontinued INR testing may be done reliably at least24 hours after the last dose (see sections 4.5 and 5.2).

Children who convert from Rivaroxaban Accord to VKA need to continue Rivaroxaban Accord for 48hours after the first dose of VKA. After 2 days of co-administration an INR should be obtained priorto the next scheduled dose of Rivaroxaban Accord. Co-administration of Rivaroxaban Accord and

VKA is advised to continue until the INR is ≥ 2.0. Once Rivaroxaban Accord is discontinued INRtesting may be done reliably 24 hours after the last dose (see above and section 4.5).

Converting from parenteral anticoagulants to rivaroxaban

For adult and paediatric patients currently receiving a parenteral anticoagulant, discontinue theparenteral anticoagulant and start rivaroxaban 0 to 2 hours before the time that the next scheduledadministration of the parenteral medicinal product (e.g. low molecular weight heparins) would be dueor at the time of discontinuation of a continuously administered parenteral medicinal product (e.g.

intravenous unfractionated heparin).

Converting from rivaroxaban to parenteral anticoagulants

Discontinue Rivaroxaban Accord and give the first dose of parenteral anticoagulant at the time thenext rivaroxaban dose would be taken.

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

Accord is to be used with caution in these patients. Use is not recommended in patients with creatinineclearance < 15 ml/min (see sections 4.4 and 5.2).

In patients with moderate (creatinine clearance 30-49 ml/min) or severe (creatinine clearance15-29 ml/min) renal impairment the following dose recommendations apply:

- For the prevention of stroke and systemic embolism in patients with non-valvular atrialfibrillation, the recommended dose is 15 mg once daily (see section 5.2).

- For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE, patientsshould be treated with 15 mg twice daily for the first 3 weeks. Thereafter, when therecommended dose is 20 mg once daily, a reduction of the dose from 20 mg once daily to15 mg once daily should be considered if the patient’s assessed risk for bleeding outweighsthe risk for recurrent DVT and PE. The recommendation for the use of 15 mg is based on PKmodelling and has not been studied in this clinical setting (see sections 4.4, 5.1 and 5.2).

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

No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance50-80 ml/min) (see section 5.2).

- Children and adolescents with mild renal impairment (glomerular filtration rate 50 - 80mL/min/1.73 m2): no dP Pose adjustment is required, based on data in adults and limited data inpaediatric patients (see section 5.2).

- Children and adolescents with moderate or severe renal impairment (glomerular filtration rate< 50 mL/min/1.73 mPP 2): Rivaroxaban Accord is not recommended as no clinical data is available(see section 4.4).

Rivaroxaban Accord is contraindicated in patients with hepatic disease associated with coagulopathyand clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (seesections 4.3 and 5.2). No clinical data is available in children with hepatic impairment.

No dose adjustment (see section 5.2)

No dose adjustment for adults (see section 5.2)

For paediatric patients the dose is determined based on body weight.

No dose adjustment (see section 5.2)

Rivaroxaban Accord can be initiated or continued in patients who may require cardioversion.

For transesophageal echocardiogram (TEE) guided cardioversion in patients not previously treatedwith anticoagulants, Rivaroxaban Accord treatment should be started at least 4 hours beforecardioversion to ensure adequate anticoagulation (see sections 5.1 and 5.2). For all patients,confirmation should be sought prior to cardioversion that the patient has taken Rivaroxaban Accord asprescribed. Decisions on initiation and duration of treatment should take established guidelinerecommendations for anticoagulant treatment in patients undergoing cardioversion into account.

Patients with non-valvular atrial fibrillation who undergo PCI (percutaneous coronary intervention)with stent placement

There is limited experience of a reduced dose of 15 mg rivaroxaban once daily (or 10 mg rivaroxabanonce daily for patients with moderate renal impairment [creatinine clearance 30-49 ml/min]) inaddition to a P2Y12 inhibitor for a maximum of 12 months in patients with non-valvular atrialfibrillation who require oral anticoagulation and undergo PCI with stent placement (see sections 4.4and 5.1).

The safety and efficacy of Rivaroxaban Accord in children aged 0 to < 18 years have not beenestablished in the indication prevention of stroke and systemic embolism in patients with non-valvularatrial fibrillation. No data are available. Therefore, it is not recommended for use in children below 18years of age in indications other than the treatment of VTE and prevention of VTE recurrence.

Rivaroxaban Accord is for oral use.

The tablets are to be taken with food (see section 5.2).

Crushing of tablets

For patients who are unable to swallow whole tablets, Rivaroxaban Accord tablet may be crushed andmixed with water or apple puree immediately prior to use and administered orally. After theadministration of crushed Rivaroxaban Accord 15 mg or 20 mg film-coated tablets, the dose should beimmediately followed by food.

The crushed Rivaroxaban Accord tablet may also be given through gastric tubes (see sections 5.2 and6.6).

Children and adolescents weighing 30 kg to 50 kg

Rivaroxaban Accord is for oral use.

The patient should be advised to swallow the tablet with liquid. It should also be taken with food (seesection 5.2). The tablets should be taken approximately 24 hours apart.

In case the patient immediately spits up the dose or vomits within 30 minutes after receiving the dose,a new dose should be given. However, if the patient vomits more than 30 minutes after the dose, thedose should not be re-administered and the next dose should be taken as scheduled.

The tablet must not be split in an attempt to provide a fraction of a tablet dose.

Crushing of tablets

For patients who are unable to swallow whole tablets, other medicinal products that containrivaroxaban granules for oral suspension available on the market should be used.

If the oral suspension is not immediately available, when doses of 15 mg or 20 mg rivaroxaban areprescribed, these could be provided by crushing the 15 mg or 20 mg tablet and mixing it with water orapple puree immediately prior to use and administering orally.

The crushed tablet may be given through a nasogastric or gastric feeding tube (see sections 5.2 and6.6).

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

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

Concomitant treatment with any other anticoagulants, e.g. unfractionated heparin (UFH), lowmolecular weight heparins (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oralanticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under specific circumstances ofswitching anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintainan open central venous or arterial catheter (see section 4.5).

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).

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

As with other anticoagulants, patients taking Rivaroxaban Accord are to be carefully observed forsigns of bleeding. It is recommended to be used with caution in conditions with increased risk ofhaemorrhage. Rivaroxaban Accord administration should be discontinued if severe haemorrhageoccurs (see section 4.9).

In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinaryincluding abnormal vaginal or increased menstrual bleeding) and anaemia were seen more frequentlyduring long term rivaroxaban treatment compared with VKA treatment. 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. These patients areto 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, rivaroxabanlevels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptionalsituations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g.

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

There is limited data in children with cerebral vein and sinus thrombosis who have a CNS infection(see section 5.1). The risk of bleeding should be carefully evaluated before and during therapy withrivaroxaban.

In adult patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasmalevels may be significantly increased (1.6-fold on average) which may lead to an increased bleedingrisk.

Rivaroxaban Accord is to be used with caution in patients with creatinine clearance 15-29 ml/min. Useis not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2).

Rivaroxaban Accord should be used with caution in patients with renal impairment concomitantlyreceiving other medicinal products which increase rivaroxaban plasma concentrations (seesection 4.5).

Rivaroxaban Accord is not recommended in children and adolescents with moderate or severe renalimpairment (glomerular filtration rate < 50 mL/min/1.73 m2), as no clinical data is available.

Interaction with other medicinal products

The use of Rivaroxaban Accord is not recommended in patients receiving concomitant systemictreatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole andposaconazole) or HIV protease inhibitors (e.g. ritonavir). These active substances are strong inhibitorsof both CYP3A4 and P-gp and therefore may increase rivaroxaban plasma concentrations to aclinically relevant degree (2.6-fold on average) which may lead to an increased bleeding risk. Noclinical data is available in children receiving concomitant systemic treatment with strong inhibitors ofboth CYP 3A4 and P-gp (see section 4.5).

Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasissuch as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid andplatelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs), and serotoninnorepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal diseasean appropriate prophylactic treatment may be considered (see section 4.5).

Other haemorrhagic risk factors

As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleedingrisk such as:

* congenital or acquired bleeding disorders

* uncontrolled severe arterial hypertension

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

* vascular retinopathy

* bronchiectasis or history of pulmonary bleeding

Patients with cancer

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

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

Patients with prosthetic valves

Rivaroxaban should not be used for thromboprophylaxis in patients having recently undergonetranscatheter aortic valve replacement (TAVR). Safety and efficacy of rivaroxaban have not beenstudied in patients with prosthetic heart valves; therefore, there are no data to support that rivaroxabanprovides adequate anticoagulation in this patient population. Treatment with Rivaroxaban Accord isnot recommended for these patients.

Patients with non-valvular atrial fibrillation who undergo PCI with stent placement

Clinical data are available from an interventional study with the primary objective to assess safety inpatients with non-valvular atrial fibrillation who undergo PCI with stent placement. Data on efficacyin this population are limited (see sections 4.2 and 5.1). No data are available for such patients with ahistory of stroke/ transient ischaemic attack (TIA).

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonaryembolectomy

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.

Direct acting Oral Anticoagulants (DOACs) including rivaroxaban are not recommended for patientswith a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular forpatients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta2-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,patients treated with antithrombotic agents for prevention of thromboembolic complications are at riskof developing an epidural or spinal haematoma which can result in long-term or permanent paralysis.

The risk of these events may be increased by the post-operative use of indwelling epidural catheters orthe concomitant use of medicinal products affecting haemostasis. The risk may also be increased bytraumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs andsymptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladderdysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Priorto neuraxial intervention the physician should consider the potential benefit versus the risk inanticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinicalexperience with the use of 15 mg rivaroxaban in these situations.

To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban andneuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile ofrivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed whenthe anticoagulant effect of rivaroxaban is estimated to be low. However, the exact timing to reach asufficiently low anticoagulant effect in each patient is not known and should be weighed against theurgency of a diagnostic procedure.

For the removal of an epidural catheter and based on the general PK characteristics at least 2xhalf-life, i.e. at least 18 hours in young adult patients and 26 hours in elderly patients should elapseafter the last administration of rivaroxaban (see section 5.2). Following removal of the catheter, atleast 6 hours should elapse before the next rivaroxaban dose is administered.

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

No data is available on the timing of the placement or removal of neuraxial catheter in children whileon Rivaroxaban Accord. In such cases, discontinue rivaroxaban and consider a short acting parenteralanticoagulant.

Dosing recommendations before and after invasive procedures and surgical intervention

If an invasive procedure or surgical intervention is required, Rivaroxaban Accord 15 mg should bestopped at least 24 hours before the intervention, if possible and based on the clinical judgement of thephysician.

If the procedure cannot be delayed the increased risk of bleeding should be assessed against theurgency of the 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 thecourse of therapy: the onset of the reaction occurring in the majority of cases within the first weeks oftreatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g.

spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosallesions.

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

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

The extent of interactions in the paediatric population is not known. The below mentioned interactiondata was obtained in adults and the warnings in section 4.4 should be taken into account for thepaediatric population.

CYP3A4 and P-gp inhibitors

Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice aday) led to a 2.6-fold/2.5-fold increase in mean rivaroxaban AUC and a 1.7-fold/1.6-fold increase inmean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to anincreased bleeding risk. Therefore, the use of rivaroxaban is not recommended in patients receivingconcomitant systemic treatment with azole-antimycotics such as ketoconazole, itraconazole,voriconazole and posaconazole or HIV protease inhibitors. These active substances are stronginhibitors of both CYP3A4 and P-gp (see section 4.4).

Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either

CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent.

Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor andmoderate P-gp inhibitor, led to a 1.5-fold increase in mean rivaroxaban AUC and a 1.4-fold increase in

Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can bepotentially significant in high-risk patients. (For patients with renal impairment: see section 4.4).

Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a1.3-fold increase in mean rivaroxaban AUC and Cmax. The interaction with erythromycin is likely notclinically relevant in most patients but can be potentially significant in high-risk patients.

In subjects with mild renal impairment erythromycin (500 mg three times a day) led to a 1.8-foldincrease in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects withnormal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0-foldincrease in mean rivaroxaban AUC and 1.6-fold increase in Cmax when compared to subjects withnormal renal function. The effect of erythromycin is additive to that of renal impairment (seesection 4.4).

Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4-foldincrease in mean rivaroxaban AUC and a 1.3-fold increase in mean Cmax. The interaction withfluconazole is likely not clinically relevant in most patients but can be potentially significant inhigh-risk patients. (For patients with renal impairment: see section 4.4).

Given the limited clinical data available with dronedarone, co-administration with rivaroxaban shouldbe avoided.

Anticoagulants

After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg singledose) an additive effect on anti-factor Xa activity was observed without any additional effects onclotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban.

Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with anyother anticoagulants (see sections 4.3 and 4.4).

NSAIDs/platelet aggregation inhibitors

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

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

Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show apharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time wasobserved in a subset of patients which was not correlated to platelet aggregation, P-selectin or

GPIIb/IIIa receptor levels.

Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid)and platelet aggregation inhibitors because these medicinal products typically increase the bleedingrisk (see section 4.4).

SSRIs/SNRIs

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

Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) orfrom rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin)more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT,inhibition of factor Xa activity and endogenous thrombin potential were additive.

If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period,anti-factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. Onthe fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xaactivity 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 ofrivaroxaban) as this test is minimally affected by rivaroxaban at this time point.

No pharmacokinetic interaction was observed between warfarin and rivaroxaban.

Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. Theconcomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine,phenobarbital or St. John’s Wort (Hypericum perforatum)) may also lead to reduced rivaroxabanplasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should beavoided unless the patient is closely observed for signs and symptoms of thrombosis.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed whenrivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp),atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxabanneither inhibits nor induces any major CYP isoforms like CYP3A4.

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 animalshave shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, theintrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, Rivaroxaban Accord iscontraindicated during pregnancy (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 fromanimals indicate that rivaroxaban is secreted into milk. Therefore, Rivaroxaban Accord iscontraindicated during breast-feeding (see section 4.3). A decision must be made whether todiscontinue breast-feeding or to discontinue/abstain from therapy.

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

Rivaroxaban has minor influence on the ability to drive and use machines. Adverse reactions likesyncope (frequency: uncommon) and dizziness (frequency: common) have been reported (seesection 4.8).

Patients experiencing these adverse reactions should not drive or use machines.

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

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

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

Indication Number of Total daily dose Maximumpatients* treatmentduration

Prevention of venous thromboembolism 6,097 10 mg 39 days(VTE) in adult patients undergoing electivehip or knee 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 least6 months: 10 mg or20 mg

Treatment of VTE and prevention of VTE 329 Body weight-adjusted 12 monthsrecurrence in term neonates and children dose to achieve aaged less than 18 years following initiation similar exposure asof standard anticoagulation treatment that observed in adultstreated for DVT with20 mg rivaroxabanonce daily

Prevention of stroke and systemic embolism 7,750 20 mg 41 monthsin patients with non-valvular atrialfibrillation

Prevention of atherothrombotic events in 10,225 5 mg or 10 mg 31 monthspatients after an ACS respectively,co-administered witheither ASA or ASAplus clopidogrel 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 commonlyreported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %).

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

Indication Any bleeding Anaemia

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

Prevention of venous 12.6 % of 2.1 % of patientsthromboembolism in medically ill patientspatients

Treatment of DVT, PE and 23 % of patients 1.6 % of patientsprevention of 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 2.5 per 100 patientembolism in patients with patient years yearsnon-valvular atrial fibrillation

Prevention of atherothrombotic 22 per 100 1.4 per 100 patientevents in patients after an ACS patient years years

Prevention of atherothrombotic 6.7 per 100 0.15 per 100events in patients with CAD/PAD patient years patient years**8.38 per 100 0.74 per 100 patientpatient years # 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 throughpost marketing use* and in two phase II and two phase III studies in paediatric patients

Common Uncommon Rare Very rare Not known

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

Allergic reaction, Anaphylacticdermatitis allergic, reactions

Angioedema and includingallergic oedema anaphylactic

Common Uncommon Rare Very rare Not knownshock

Dizziness, headache Cerebral andintracranialhaemorrhage,syncope

Eye haemorrhage(incl. conjunctivalhaemorrhage)

Hypotension,haematoma

Epistaxis, Eosinophilichaemoptysis pneumonia

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/ Toxicgeneralised pruritus), Epidermalrash, ecchymosis, Necrolysis ,cutaneous and DRESSsubcutaneous syndromehaemorrhage

Pain in extremityA Haemarthrosis Muscle Compartmenthaemorrhage syndromesecondary to ableeding

Common Uncommon Rare Very rare Not known

Urogenital tract Renalhaemorrhage (incl. failure/acutehaematuria and renal failuremenorrhagiaB), renal secondary to aimpairment (incl. bleedingblood creatinine sufficient toincreased, blood urea causeincreased) hypoperfusion,

Anticoagulant-relatednephropathy

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

Increased LDHA,increased lipaseA,increasedamylaseA

Postprocedural Vascularhaemorrhage (incl. pseudoaneurysmCpostoperativeanaemia, and woundhaemorrhage),contusion, woundsecretionA

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

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

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

* A pre-specified selective approach to adverse event collection was applied in selected phase IIIstudies. The incidence of adverse reactions did not increase and no new adverse drug reaction wasidentified after analysis of these studies.

Due to the pharmacological mode of action, the use of rivaroxaban may be associated with anincreased risk of occult or overt bleeding from any tissue or organ which may result in posthaemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will varyaccording to the location and degree or extent of the bleeding and/or anaemia (see section 4.9“Management of bleeding”). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival,gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) andanaemia were seen more frequently during long term rivaroxaban treatment compared with VKAtreatment. Thus, in addition to adequate clinical surveillance, laboratory testing ofhaemoglobin/haematocrit could be of value to detect occult bleeding and quantify the clinicalrelevance 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”). Menstrualbleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness,paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In somecases as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectorishave been observed.

Known complications secondary to severe bleeding such as compartment syndrome and renal failuredue to hypoperfusion, or anticoagulant-related nephropathy have been reported for rivaroxaban.

Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in anyanticoagulated patient.

Treatment of VTE and prevention of VTE recurrence

The safety assessment in children and adolescents is based on the safety data from two phase II andone phase III open-label active controlled studies in paediatric patients aged birth to less than 18 years.

The safety findings were generally similar between rivaroxaban and comparator in the variouspaediatric age groups. Overall, the safety profile in the 412 children and adolescents treated withrivaroxaban was similar to that observed in the adult population and consistent across age subgroups,although assessment is limited by the small number of patients.

In paediatric patients, headache (very common, 16.7%), fever (very common, 11.7%), epistaxis (verycommon, 11.2%), vomiting (very common, 10.7%), tachycardia (common, 1.5%), increase in bilirubin(common, 1.5%) and bilirubin conjugated increased (uncommon, 0.7%) were reported morefrequently as compared to adults. Consistent with adult population, menorrhagia was observed in 6.6%(common) of female adolescents after menarche. Thrombocytopenia as observed in the post-marketingexperience in adult population was common (4.6%) in paediatric clinical studies. The adverse drugreactions in paediatric patients were primarily mild to moderate in severity.

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

In adults, rare cases of overdose up to 1,960 mg have been reported. In case of overdose, the patientshould be observed carefully for bleeding complications or other adverse reactions (see section“Management of bleeding”). There is limited data available in children. Due to limited absorption aceiling effect with no further increase in average plasma exposure is expected at supratherapeuticdoses of 50 mg rivaroxaban or above in adults, however, no data is available at supratherapeutic dosesin children.

A specific reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban isavailable for adults, but not established in children (refer to the Summary of Product Characteristics ofandexanet alfa). The use of activated charcoal to reduce absorption in case of rivaroxaban overdosemay be considered.

Management of bleeding

Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxabanadministration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban hasa half-life of approximately 5 to 13 hours in adults. The half life in children estimated using populationpharmacokinetic (popPK) modelling approaches is shorter (see section 5.2). Management should beindividualised according to the severity and location of the haemorrhage. Appropriate symptomatictreatment could be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgicalhaemostasis with bleeding control procedures, fluid replacement and haemodynamic support, bloodproducts (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy)or platelets.

If bleeding cannot be controlled by the above measures, either the administration of a specific factor

Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect ofrivaroxaban, or a specific procoagulant agent, such as prothrombin complex concentrate (PCC),activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), should beconsidered. However, there is currently very limited clinical experience with the use of thesemedicinal products in adults and in children receiving rivaroxaban. The recommendation is also basedon limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrateddepending on improvement of bleeding.

Depending on local availability, a consultation with a coagulation expert should be considered in caseof major bleedings (see section 5.1).

Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban.

There is limited experience with tranexamic acid and no experience with aminocaproic acid andaprotinin in adults receiving rivaroxaban. There is no experience on the use of these agents in childrenreceiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use ofthe 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 offactor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibitingboth thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin(activated factor II) and no effects on platelets have been demonstrated.

Dose-dependent inhibition of factor Xa activity was observed in humans. Prothrombin time (PT) isinfluenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations(r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results.

The readout for PT is to be done in seconds, because the INR is only calibrated and validated forcoumarins and cannot be used for any other anticoagulant.

In patients receiving rivaroxaban for treatment of DVT and PE and prevention of recurrence, the 5/95percentiles for PT (Neoplastin) 2-4 hours after tablet intake (i.e. at the time of maximum effect) for15 mg rivaroxaban twice daily ranged from 17 to 32 s and for 20 mg rivaroxaban once daily from 15to 30 s. At trough (8-16 h after tablet intake) the 5/95 percentiles for 15 mg twice daily ranged from 14to 24 s and for 20 mg once daily (18-30 h after tablet intake) from 13 to 20 s.

In patients with non-valvular atrial fibrillation receiving rivaroxaban for the prevention of stroke andsystemic embolism, the 5/95 percentiles for PT (Neoplastin) 1-4 hours after tablet intake (i.e. at thetime of maximum effect) in patients treated with 20 mg once daily ranged from 14 to 40 s and inpatients with moderate renal impairment treated with 15 mg once daily from 10 to 50 s. At trough(16-36 h after tablet intake) the 5/95 percentiles in patients treated with 20 mg once daily ranged from12 to 26 s and in patients with moderate renal impairment treated with 15 mg once daily from 12 to26 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 PCChad a greater and more rapid overall effect on reversing changes in endogenous thrombin generationthan the 4-factor PCC (see section 4.9).

The activated partial 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 quantitativeanti-factor Xa tests (see section 5.2).

PT (neoplastin reagent), aPTT, and anti-Xa assay (with a calibrated quantitative test) display a closecorrelation to plasma concentrations in children. The correlation between anti-Xa to plasmaconcentrations is linear with a slope close to 1. Individual discrepancies with higher or lower anti-Xavalues as compared to the corresponding plasma concentrations may occur. There is no need forroutine monitoring of coagulation parameters during clinical treatment with rivaroxaban. However, ifclinically indicated, rivaroxaban concentrations can be measured by calibrated quantitative anti- Factor

Xa tests in mcg/L (see table 13 in section 5.2 for ranges of observed rivaroxaban plasmaconcentrations in children). The lower limit of quantifications must be considered when the anti-Xatest is used to quantify plasma concentrations of rivaroxaban in children. No threshold for efficacy orsafety events has been established.

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

The rivaroxaban clinical programme was designed to demonstrate the efficacy of rivaroxaban for theprevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation.

In the pivotal double-blind ROCKET AF study, 14,264 patients were assigned either to rivaroxaban20 mg once daily (15 mg once daily in patients with creatinine clearance 30-49 ml/min) or to warfarintitrated to a target INR of 2.5 (therapeutic range 2.0 to 3.0). The median time on treatment was19 months and overall treatment duration was up to 41 months.

34.9 % of patients were treated with acetylsalicylic acid and 11.4 % were treated with class IIIantiarrhythmic including amiodarone.

Rivaroxaban was non-inferior to warfarin for the primary composite endpoint of stroke and non-CNSsystemic embolism. In the per-protocol population on treatment, stroke or systemic embolism occurredin 188 patients on rivaroxaban (1.71 % per year) and 241 on warfarin (2.16 % per year) (HR 0.79;95 % CI, 0.66-0.96; P < 0.001 for non-inferiority). Among all randomised patients analysed accordingto ITT, primary events occurred in 269 on rivaroxaban (2.12 % per year) and 306 on warfarin (2.42 %per year) (HR 0.88; 95 % CI, 0.74-1.03; P < 0.001 for non-inferiority; P=0.117 for superiority).

Results for secondary endpoints as tested in hierarchical order in the ITT analysis are displayed in

Table 4.

Among patients in the warfarin group, INR values were within the therapeutic range (2.0 to 3.0) amean of 55 % of the time (median, 58%; interquartile range, 43 to 71). The effect of rivaroxaban didnot differ across the level of centre TTR (Time in Target INR Range of 2.0-3.0) in the equally sizedquartiles (P=0.74 for interaction). Within the highest quartile according to centre, the Hazard Ration(HR) with rivaroxaban versus warfarin was 0.74 (95 % CI, 0.49-1.12).

The incidence rates for the principal safety outcome (major and non-major clinically relevant bleedingevents) were similar for both treatment groups (see Table 5).

Table 4: Efficacy results from phase III ROCKET AF

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

Treatment dose Rivaroxaban 20 mg Warfarin titrated to a HR (95 % CI)once daily (15 mg once target INR of 2.5 p-value, test fordaily in patients with (therapeutic range 2.0 superioritymoderate renal to 3.0)impairment) Event rate (100 pt-yr)

Event rate (100 pt-yr)

Stroke and non-CNS 269 306 0.88systemic embolism (2.12) (2.42) (0.74-1.03)0.117

Stroke, non-CNS 572 609 0.94systemic embolism (4.51) (4.81) (0.84-1.05)and vascular death 0.265

Stroke, non-CNS 659 709 0.93systemic embolism, (5.24) (5.65) (0.83-1.03)vascular death and 0.158myocardial infarction

Stroke 253 281 0.90(1.99) (2.22) (0.76-1.07)0.221

Non-CNS systemic 20 27 0.74embolism (0.16) (0.21) (0.42-1.32)0.308

Myocardial infarction 130 142 0.91(1.02) (1.11) (0.72-1.16)0.464

Table 5: Safety results from phase III ROCKET AF

Study population Patients with non-valvular atrial fibrillationa)

Treatment dose Rivaroxaban 20 mg Warfarin titrated to aonce daily (15 mg once target INR of 2.5dailyin patients with (therapeutic range HR (95% CI)moderate renal 2.0 to 3.0) p-valueimpairment)

Event rate (100 pt-yr) Event rate (100 pt-yr)

Major and non-major 1,475 1,449 1.03 (0.96-1.11)clinically relevant bleeding (14.91) (14.52) 0.442events

Major bleeding events 395 386 1.04 (0.90-1.20)(3.60) (3.45) 0.576

Death due to bleeding* 27 55 0.50 (0.31-0.79)(0.24) (0.48) 0.003

Critical organ bleeding* 91 133 0.69 (0.53-0.91)(0.82) (1.18) 0.007

Intracranial 55 84 0.67 (0.47-0.93)haemorrhage* (0.49) (0.74) 0.019

Haemoglobin drop* 305 254 1.22 (1.03-1.44)(2.77) (2.26) 0.019

Transfusion of 2 or 183 149 1.25 (1.01-1.55)more units of packed (1.65) (1.32) 0.044red blood cells or wholeblood*

Non-major clinically 1,185 1,151 1.04 (0.96-1.13)relevant bleeding events (11.80) (11.37) 0.345

All-cause mortality 208 250 0.85 (0.70-1.02)(1.87) (2.21) 0.073a) Safety population, on treatment

* Nominally significant

In addition to the phase III ROCKET AF study, a prospective, single-arm, post-authorization,noninterventional, open label cohort study (XANTUS) with central outcome adjudication includingthromboembolic events and major bleeding has been conducted. 6,704 patients with non-valvularatrial fibrillation were enrolled for prevention of stroke and non-central nervous system (CNS)systemic embolism in clinical practice. The mean CHADS2 score was 1.9 and HAS-BLED score was2.0 in XANTUS, compared to a mean CHADS2 and HAS-BLED score of 3.5 and 2.8 in ROCKET

AF, respectively. Major bleeding occurred in 2.1 per 100 patient years. Fatal haemorrhage wasreported in 0.2 per 100 patient years and intracranial haemorrhage in 0.4 per 100 patient years. Strokeor non-CNS systemic embolism was recorded in 0.8 per 100 patient years.

These observations in clinical practice are consistent with the established safety profile in thisindication.

In a post-authorisation, non-interventional study, in more than 162,000 patients from four countries,rivaroxaban was prescribed for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. The event rate for ischaemic stroke was 0.70 (95% CI 0.44 - 1.13) per 100patient-years. Bleeding resulting in hospitalisation occurred at event rates per 100 patient-years of 0.43(95% CI 0.31 - 0.59) for intracranial bleeding, 1.04 (95% CI 0.65 - 1.66) for gastrointestinal bleeding,0.41 (95% CI 0.31 - 0.53) for urogenital bleeding and 0.40 (95% CI 0.25 - 0.65) for other bleeding.

A prospective, randomised, open-label, multicentre, exploratory study with blinded endpointevaluation (X-VERT) was conducted in 1504 patients (oral anticoagulant naive and pre-treated) withnon-valvular atrial fibrillation scheduled for cardioversion to compare rivaroxaban with dose-adjusted

VKA (randomised 2:1), for the prevention of cardiovascular events. TEE- guided (1-5 days ofpretreatment) or conventional cardioversion (at least three weeks of pre-treatment) strategies wereemployed. The primary efficacy outcome (all stroke, transient ischaemic attack, non-CNS systemicembolism, myocardial infarction (MI) and cardiovascular death) occurred in 5 (0.5 %) patients in therivaroxaban group (n = 978) and 5 (1.0 %) patients in the VKA group (n = 492; RR 0.50; 95 % CI0.15-1.73; modified ITT population). The principal safety outcome (major bleeding) occurred in 6(0.6 %) and 4 (0.8 %) patients in the rivaroxaban (n = 988) and VKA (n = 499) groups, respectively(RR 0.76; 95 % CI 0.21-2.67; safety population). This exploratory study showed comparable efficacyand safety between rivaroxaban and VKA treatment groups in the setting of cardioversion.

Patients with non-valvular atrial fibrillation who undergo PCI with stent placement

A randomised, open-label, multicentre study (PIONEER AF-PCI) was conducted in 2,124 patientswith non-valvular atrial fibrillation who underwent PCI with stent placement for primaryatherosclerotic disease to compare safety of two rivaroxaban regimens and one VKA regimen. Patientswere randomly assigned in a 1:1:1 fashion for an overall 12-month-therapy. Patients with a history ofstroke or TIA were excluded.

Group 1 received rivaroxaban 15 mg once daily (10 mg once daily in patients with creatinineclearance 30-49 ml/min) plus P2Y12 inhibitor. Group 2 received rivaroxaban 2.5 mg twice daily plus

DAPT (dual antiplatelet therapy i.e. clopidogrel 75 mg [or alternate P2Y12 inhibitor] plus low-doseacetylsalicylic acid [ASA]) for 1, 6 or 12 months followed by rivaroxaban 15 mg (or 10 mg forsubjects with creatinine clearance 30-49 ml/min) once daily plus low-dose ASA. Group 3 receiveddose-adjusted VKA plus DAPT for 1, 6 or 12 months followed by dose adjusted VKA plus low-dose

ASA.

The primary safety endpoint, clinically significant bleeding events, occurred in 109 (15.7 %), 117(16.6 %), and 167 (24.0 %) subjects in group 1, group 2 and group 3, respectively (HR 0.59; 95 % CI0.47-0.76; p < 0.001, and HR 0.63; 95 % CI 0.50-0.80; p < 0.001, respectively). The secondaryendpoint (composite of cardiovascular events CV death, MI, or stroke) occurred in 41 (5.9 %), 36(5.1 %), and 36 (5.2 %) subjects in the group 1, group 2 and group 3, respectively. Each of therivaroxaban regimens showed a significant reduction in clinically significant bleeding eventscompared to the VKA regimen in patients with non-valvular atrial fibrillation who underwent a PCIwith stent placement.

The primary objective of PIONEER AF-PCI was to assess safety. Data on efficacy (includingthromboembolic events) in this population are limited.

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

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

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

DVT, Einstein PE, Einstein Extension and Einstein Choice) and additionally a predefined pooledanalysis of the Einstein DVT and Einstein PE studies was conducted. The overall combined treatmentduration in all studies was up to 21 months.

In Einstein DVT 3,449 patients with acute DVT were studied for the treatment of DVT and theprevention of recurrent DVT and PE (patients who presented with symptomatic PE were excludedfrom this study). The treatment duration was for 3, 6 or 12 months depending on the clinicaljudgement of the investigator.

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

In Einstein PE, 4,832 patients with acute PE were studied for the treatment of PE and the prevention 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.

This was 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 untilthe 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 hadcompleted 6 to 12 months of treatment for venous thromboembolism depending on the clinicaljudgment of the investigator. Rivaroxaban 20 mg once daily was compared with placebo.

Einstein DVT, PE and Extension used the same pre-defined primary and secondary efficacy outcomes.

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

DVT or fatal or non-fatal PE. The secondary efficacy outcome was defined as the composite ofrecurrent DVT, non-fatal PE and all-cause mortality.

In Einstein Choice, 3,396 patients with confirmed symptomatic DVT and/or PE who completed 6-12months 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 dependingon the individual randomisation date (median: 351 days). Rivaroxaban 20 mg once daily andrivaroxaban 10 mg once daily were compared with 100 mg acetylsalicylic acid once daily.

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

DVT or fatal or non-fatal PE.

In the Einstein DVT study (see Table 6) rivaroxaban was demonstrated to be non-inferior toenoxaparin/VKA for the primary efficacy outcome (p < 0.0001 (test for non-inferiority); HR: 0.680(0.443-1.042), p=0.076 (test for superiority)). The prespecified net clinical benefit (primary efficacyoutcome plus major bleeding events) was reported with a HR of 0.67 ((95 % CI: 0.47 - 0.95), nominalp value p=0.027) in favour of rivaroxaban. INR values were within the therapeutic range a mean of60.3 % 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 theenoxaparin/VKA group, there was no clear relation between the level of mean centre TTR (Time in

Target INR Range of 2.0-3.0) in the equally sized tertiles and the incidence of the recurrent VTE(P=0.932 for interaction). Within the highest tertile according to centre, the HR with rivaroxabanversus 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 bothtreatment groups.

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

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

Treatment dose and duration 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 7) 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 bleedingevents) was reported with a HR of 0.849 ((95 % CI: 0.633-1.139), nominal p value p= 0.275). INRvalues were within the therapeutic range a mean of 63 % of the time for the mean treatment durationof 215 days, and 57 %, 62 %, and 65 % of the time in the 3-, 6-, and 12-month intended treatmentduration groups, respectively. In the enoxaparin/VKA group, there was no clear relation between thelevel of mean centre TTR (Time in Target INR Range of 2.0-3.0) in the equally sized tertiles and theincidence of the recurrent VTE (p=0.082 for interaction). Within the highest tertile according tocentre, the HR with rivaroxaban versus warfarin was 0.642 (95% CI: 0.277-1.484).

The incidence rates for the primary safety outcome (major or clinically relevant non-major 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 safetyoutcome (major bleeding events) was lower in the rivaroxaban group (1.1 % (26/2412)) than in theenoxaparin/VKA group (2.2 % (52/2405)) with a HR 0.493 (95% CI: 0.308-0.789).

Table 7: Efficacy and safety results from phase III Einstein PE

Study population 4,832 patients with an acute symptomatic PE

Treatment dose and duration 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 11 7cannot be 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 8).

Table 8: Efficacy and safety results from pooled analysis of phase III Einstein DVT and

Einstein PE

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

Treatment dose and duration 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 %)

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 thepooled analysis was reported with a HR of 0.771 ((95 % CI: 0.614-0.967), nominal p value p=0.0244).

In the Einstein Extension study (see Table 9) rivaroxaban was superior to placebo for the primary 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 oncedaily compared to placebo. The secondary safety outcome (major or clinically relevant non-majorbleeding events) showed higher rates for patients treated with rivaroxaban 20 mg once daily comparedto placebo.

Table 9: 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 10) rivaroxaban 20 mg and 10 mg were both superior to100 mg acetylsalicylic acid for the primary efficacy outcome. The principal safety outcome (majorbleeding events) was similar for patients treated with rivaroxaban 20 mg and 10 mg once dailycompared to 100 mg acetylsalicylic acid.

Table 10: Efficacy and safety results from phase III Einstein Choice

Study population 3,396 patients continued prevention of recurrent venousthromboembolism

Treatment dose Rivaroxaban Rivaroxaban ASA 100 mg once20 mg once daily 10 mg once daily daily

N=1,107 N=1,127 N=1,131

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 2 0 2

PE

Study population 3,396 patients continued prevention of recurrent venousthromboembolism

Treatment dose Rivaroxaban Rivaroxaban ASA 100 mg once20 mg once daily 10 mg once daily daily

N=1,107 N=1,127 N=1,131cannot 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 (2.1 %)+ (1.5 %)++ (4.7 %)or major bleeding(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-labelcohort study (XALIA) with central outcome adjudication including recurrent VTE, major bleeding anddeath has been conducted. 5,142 patients with acute DVT were enrolled to investigate the long-termsafety of rivaroxaban compared with standard-of-care anticoagulation therapy in clinical practice.

Rates of major bleeding, recurrent VTE and all-cause mortality for rivaroxaban were 0.7 %, 1.4 % and0.5 %, respectively. There were differences in patient baseline characteristics including age, cancerand renal impairment. A pre-specified propensity score stratified analysis was used to adjust formeasured baseline differences but residual confounding may, in spite of this, influence the results.

Adjusted HRs comparing rivaroxaban and standard-of-care for major bleeding, recurrent VTE andall-cause mortality were 0.77 (95 % CI 0.40-1.50), 0.91 (95 % CI 0.54-1.54) and 0.51 (95 % CI0.24-1.07), respectively. These results in clinical practice are consistent with the established safetyprofile in this indication.

In a post-authorisation, non-interventional study, in more than 40,000 patients without a history ofcancer from four countries, rivaroxaban was prescribed for the treatment or prevention of DVT and

PE. The event rates per 100 patient-years for symptomatic/clinically apparent VTE/thromboembolicevents leading to hospitalisation ranged from 0.64 (95% CI 0.40 - 0.97) in the UK to 2.30 (95% CI2.11 - 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) forgastrointestinal bleeding, 0.44 (95% CI 0.26 - 0.74) for urogenital bleeding and 0.41 (95% CI 0.31 -0.54) for other bleeding.

Treatment of VTE and prevention of VTE recurrence in paediatric patients

A total of 727 children with confirmed acute VTE, of whom 528 received rivaroxaban, were studied in6 open-label, multicentre paediatric studies. Body weight-adjusted dosing in patients from birth to lessthan 18 years resulted in rivaroxaban exposure similar to that observed in adult DVT patients treatedwith rivaroxaban 20 mg once daily as confirmed in the phase III study (see section 5.2).

The EINSTEIN Junior phase III study was a randomised, active-controlled, open-label multicentreclinical study in 500 paediatric patients (aged from birth to < 18 years) with confirmed acute VTE.

There were 276 children aged 12 to < 18 years, 101 children aged 6 to < 12 years, 69 children aged2 to < 6 years, and 54 children aged < 2 years.

Index VTE was classified as either central venous catheter-related VTE (CVC-VTE; 90/335 patientsin the rivaroxaban group, 37/165 patients in the comparator group), cerebral vein and sinus thrombosis(CVST; 74/335 patients in the rivaroxaban group, 43/165 patients in the comparator group), and allothers including DVT and PE (non-CVC-VTE; 171/335 patients in the rivaroxaban group,85/165 patients in the comparator group). The most common presentation of index thrombosis inchildren aged 12 to < 18 years was non-CVC-VTE in 211 (76.4%); in children aged 6 to < 12 yearsand aged 2 to < 6 years was CVST in 48 (47.5%) and 35 (50.7%), respectively; and in children aged< 2 years was CVC-VTE in 37 (68.5%). There were no children < 6 months with CVST in therivaroxaban group. 22 of the patients with CVST had a CNS infection (13 patients in the rivaroxabangroup and 9 patients in comparator group).

VTE was provoked by persistent, transient, or both persistent and transient risk factors in 438 (87.6%)children.

Patients received initial treatment with therapeutic doses of UFH, LMWH, or fondaparinux for at least5 days, and were randomised 2:1 to receive either body weight-adjusted doses of rivaroxaban orcomparator group (heparins, VKA) for a main study treatment period of 3 months (1 month forchildren < 2 years with CVC-VTE). At the end of the main study treatment period, the diagnosticimaging test, which was obtained at baseline, was repeated, if clinically feasible. The study treatmentcould be stopped at this point, or at the discretion of the Investigator continued for up to 12 months(for children < 2 years with CVC-VTE up to 3 months) in total.

The primary efficacy outcome was symptomatic recurrent VTE. The primary safety outcome was thecomposite of major bleeding and clinically relevant non-major bleeding (CRNMB). All efficacy andsafety outcomes were centrally adjudicated by an independent committee blinded for treatmentallocation. The efficacy and safety results are shown in Tables 11 and 12 below.

Recurrent VTEs occurred in the rivaroxaban group in 4 of 335 patients and in the comparator group in5 of 165 patients. The composite of major bleeding and CRNMB was reported in 10 of 329 patients(3%) treated with rivaroxaban and in 3 of 162 patients (1.9%) treated with comparator. Net clinicalbenefit (symptomatic recurrent VTE plus major bleeding events) was reported in the rivaroxabangroup in 4 of 335 patients and in the comparator group in 7 of 165 patients. Normalisation of thethrombus burden on repeat imaging occurred in 128 of 335 patients with rivaroxaban treatment and in43 of 165 patients in the comparator group. These findings were generally similar among age groups.

There were 119 (36.2%) children with any treatment-emergent bleeding in the rivaroxaban group and45 (27.8%) children in the comparator group.

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

Event Rivaroxaban N=335* Comparator N=165*

Recurrent VTE (primary efficacy outcome) 4 5(1.2%, 95% CI (3.0%, 95% CI0.4% - 3.0%) 1.2% - 6.6%)

Composite: Symptomatic recurrent VTE + 5 6asymptomatic deterioration on repeat imaging (1.5%, 95% CI (3.6%, 95% CI0.6% - 3.4%) 1.6% - 7.6%)

Composite: Symptomatic recurrent VTE + 21 19asymptomatic deterioration + no change on repeat (6.3%, 95% CI (11.5%, 95% CIimaging 4.0% - 9.2%) 7.3% - 17.4%)

Normalisation on repeat imaging 128 43(38.2%, 95% CI (26.1%, 95% CI33.0% - 43.5%) 19.8% - 33.0%)

Composite: Symptomatic recurrent VTE + major 4 7bleeding (net clinical benefit) (1.2%, 95% CI (4.2%, 95% CI0.4% - 3.0%) 2.0% - 8.4%)

Fatal or non-fatal pulmonary embolism 1 1(0.3%, 95% CI (0.6%, 95% CI0.0% - 1.6%) 0.0% - 3.1%)

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

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

Rivaroxaban N=329* Comparator N=162*

Composite: Major bleeding + CRNMB (primary safety 10 3outcome) (3.0%, 95% CI (1.9%, 95% CI1.6% - 5.5%) 0.5% - 5.3%)

Major bleeding 0 2(0.0%, 95% CI (1.2%, 95% CI0.0% - 1.1%) 0.2% - 4.3%)

Any treatment-emergent bleedings 119 (36.2%) 45 (27.8%)

* SAF= safety analysis set, all children who were randomised and received at least 1 dose ofstudy medicinal product.

The efficacy and safety profile of rivaroxaban was largely similar between the paediatric VTEpopulation and the DVT/PE adult population, however, the proportion of subjects with any bleedingwas higher in the paediatric VTE population as compared to the DVT/PE adult population.

Patients with high risk triple positive antiphospholipid syndrome

In an investigator sponsored, randomised open-label multicenter study with blinded endpointadjudication, rivaroxaban was compared to warfarin in patients with a history of thrombosis,diagnosed with antiphospholipid syndrome and at high risk for thromboembolic events (positive for all3 antiphospholipid tests: lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein Iantibodies). The trial was terminated prematurely after the enrolment of 120 patients due to an excessof events among patients in the rivaroxaban arm. Mean follow-up was 569 days. 59 patients wererandomised 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 torivaroxaban (4 ischaemic strokes and 3 myocardial infarctions). No events were reported in patientsrandomised to warfarin. Major bleeding occurred in 4 patients (7%) of the rivaroxaban group and 2patients (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).

The following information is based on the data obtained in adults.

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.

Due to a reduced extent of absorption an oral bioavailability of 66 % was determined for the 20 mgtablet under fasting conditions. When rivaroxaban 20 mg tablets are taken together with food increasesin mean AUC by 39 % were observed when compared to tablet intake under fasting conditions,indicating almost complete absorption and high oral bioavailability. Rivaroxaban 15 mg and 20 mg areto be taken with food (see section 4.2).

Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily in fasting state.

Under fed conditions rivaroxaban 10 mg, 15 mg and 20 mg tablets demonstrated dose-proportionality.

At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability anddecreased absorption rate with increased dose.

Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV %)ranging from 30 % to 40 %.

Absorption of rivaroxaban is dependent on the site of its release in the gastrointestinal tract. A 29 %and 56 % decrease in AUC and Cmax compared to tablet was reported when rivaroxaban granulate isreleased in the proximal small intestine. Exposure is further reduced when rivaroxaban is released inthe distal small intestine, or ascending colon. Therefore, administration of rivaroxaban distal to thestomach should be avoided since this can result in reduced absorption and related rivaroxabanexposure.

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

Children received rivaroxaban tablet or oral suspension during or closely after feeding or food intakeand with a typical serving of liquid to ensure reliable dosing in children. As in adults, rivaroxaban isreadily absorbed after oral administration as tablet or granules for oral suspension formulation inchildren. No difference in the absorption rate nor in the extent of absorption between the tablet andgranules for oral suspension formulation was observed. No PK data following intravenousadministration to children are available so that the absolute bioavailability of rivaroxaban in children isunknown. A decrease in the relative bioavailability for increasing doses (in mg/kg bodyweight) wasfound, suggesting absorption limitations for higher doses, even when taken together with food.

Rivaroxaban 15 mg tablets should be taken with feeding or with food (see section 4.2).

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

No data on rivaroxaban plasma protein binding specific to children is available. No PK data followingintravenous administration of rivaroxaban to children is available. Vss estimated via population PKmodelling in children (age range 0 to < 18 years) following oral administration of rivaroxaban isdependent on body weight and can be described with an allometric function, with an average of 113 Lfor a subject with a body weight of 82.8 kg.

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

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

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

No metabolism data specific to children is available. No PK data following intravenous administrationof rivaroxaban to children is available. CL estimated via population PK modelling in children (agerange 0 to < 18 years) following oral administration of rivaroxaban is dependent on body weight andcan be described with an allometric function, with an average of 8 L/h for a subject with body weightof 82.8 kg. The geometric mean values for disposition half-lives (t1/2) estimated via population PKmodelling decrease with decreasing age and ranged from 4.2 h in adolescents to approximately 3 h inchildren aged 2-12 years down to 1.9 and 1.6 h in children aged 0.5-< 2 years and less than 0.5 years,respectively.

In adults, there were no clinically relevant differences in pharmacokinetics and pharmacodynamicsbetween male and female patients. An exploratory analysis did not reveal relevant differences inrivaroxaban exposure between male and female children.

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

Different weight categories

In adults, extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxabanplasma concentrations (less than 25 %). No dose adjustment is necessary.

In children, rivaroxaban is dosed based on body weight. An exploratory analysis did not reveal arelevant impact of underweight or obesity on rivaroxaban exposure in children.

Inter-ethnic differences

In adults, no clinically relevant inter-ethnic differences among Caucasian, African-American,

Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics andpharmacodynamics.

An exploratory analysis did not reveal relevant inter-ethnic differences in rivaroxaban exposure among

Japanese, Chinese or Asian children outside Japan and China compared to the respective overallpaediatric population.

Cirrhotic adult patients with mild hepatic impairment (classified as Child Pugh A) exhibited onlyminor changes in rivaroxaban pharmacokinetics (1.2-fold increase in rivaroxaban AUC on average),nearly comparable to their matched healthy control group. In cirrhotic patients with moderate hepaticimpairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by2.3-fold compared to healthy volunteers. Unbound AUC was increased 2.6-fold. These patients alsohad reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment.

There are no data in patients with severe hepatic impairment.

The inhibition of factor Xa activity was increased by a factor of 2.6 in patients with moderate hepaticimpairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factorof 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in asteeper PK/PD relationship between concentration and PT.

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

No clinical data is available in children with hepatic impairment.

In adults, there was an increase in rivaroxaban exposure correlated to decrease in renal function, asassessed via creatinine clearance measurements. In individuals with mild (creatinine clearance50-80 ml/min), moderate (creatinine clearance 30-49 ml/min) and severe (creatinine clearance15-29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5and 1.6-fold respectively. Corresponding increases in pharmacodynamic effects were morepronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition offactor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthyvolunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively.

There are no data in patients with creatinine clearance < 15 ml/min.

Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.

Use is not recommended in patients with creatinine clearance < 15 ml/min. Rivaroxaban is to be usedwith caution in patients with creatinine clearance 15-29 ml/min (see section 4.4).

No clinical data is available in children 1 year or older with moderate or severe renal impairment(glomerular filtration rate < 50 mL/min/1.73 m2).

Pharmacokinetic data in patients

In patients receiving rivaroxaban for treatment of acute DVT 20 mg once daily the geometric meanconcentration (90 % prediction interval) 2-4 h and about 24 h after dose (roughly representingmaximum and minimum concentrations during the dose interval) was 215 (22-535) and 32(6-239) mcg/l, respectively.

In paediatric patients with acute VTE receiving body weight-adjusted rivaroxaban leading to anexposure similar to that in adult DVT patients receiving a 20 mg once daily dose, the geometric meanconcentrations (90% interval) at sampling time intervals roughly representing maximum and minimumconcentrations during the dose interval are summarised in Table 13.

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

Timeintervalso.d. N 12 - N 6 -< 12 years< 18 years2.5-4h post 171 241.5 24 229.7(105-484) (91.5-777)20-24h post 151 20.6 24 15.9(5.69-66.5) (3.42-45.5)b.i.d. N 6 -< 12 years N 2 -< 6 years N 0.5 -< 2 years2.5-4h post 36 145.4 38 171.8 2 n.c.

(46.0-343) (70.7-438)10-16h post 33 26.0 37 22.2 3 10.7(7.99-94.9) (0.25-127) (n.c.-n.c.)t.i.d. N 2 -< 6 years N Birth - N 0.5 -< 2 years N Birth -< 2 years < 0.5 years0.5-3h post 5 164.7 25 111.2 13 114.3 12 108.0(108-283) (22.9-320) (22.9-346) (19.2-320)7-8h post 5 33.2 23 18.7 12 21.4 11 16.1(18.7-99.7) (10.1-36.5) (10.5-65.6) (1.03-33.6)o.d. = once daily, b.i.d. = twice daily, t.i.d. three times daily, n.c. = not calculated

Values below lower limit of quantification (LLOQ) were substituted by 1/2 LLOQ for the calculationof statistics (LLOQ = 0.5 mcg/L).

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

Safety and efficacy have not been established in the indication prevention of stroke and systemicembolism in patients with non-valvular atrial fibrillation for children and adolescents up to 18 years.

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

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

In rats, no effects on male or female fertility were seen. Animal studies have shown reproductivetoxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagiccomplications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification,hepatic multiple light coloured spots) and an increased incidence of common malformations as well asplacental changes were observed at clinically relevant plasma concentrations. In the pre-and postnatalstudy in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.

Rivaroxaban was tested in juvenile rats up to 3-month treatment duration starting at postnatal day 4showing a non dose-related increase in periinsular haemorrhage. No evidence of target organ-specifictoxicity was seen.

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 puree for up to 4 hours.

This medicinal product does not require any special storage conditions.

Clear PVC/Aluminium blisters in cartons of 10, 14, 28, 30, 42, 48, 56, 90, 98 or 100film-coated tablets or perforated unit 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 anasogastric tube or gastric feeding tube after confirming gastric placement of the tube. Afterwards, thetube should be flushed with water. Since rivaroxaban absorption is dependent on the site of activesubstance release, administration of rivaroxaban distal to the stomach should be avoided, as this canresult in reduced absorption and thereby, reduced active substance exposure. After the administrationof a crushed rivaroxaban 15 mg or 20 mg tablet, the dose should then be immediately followed byenteral feeding.

Accord Healthcare S.L.U.

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

Barcelona, 08039

Spain

EU/1/20/1488/024-038

Date of first authorisation: 16th November 2020

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

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