Each film-coated tablet contains 2.5 mg rivaroxaban. Excipient with known effect: Each film-coated tablet contains 33.92 mg lactose (as monohydrate), see section 4.4. For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Film-coated tablet (tablet). Light yellow, round biconvex tablets (6 mm diameter, 9 mm radius of curvature) marked with the BAYER-cross on one side and "2.5" and a triangle on the other side.

CLINICAL PARTICULARS

Posology and method of administration

The recommended dose is 2.5 mg twice daily. Patients should also take a daily dose of 75 - 100 mg ASA or a daily dose of 75 - 100 mg ASA in addition to either a daily dose of 75 mg clopidogrel or a standard daily dose of ticlopidine. Treatment should be regularly evaluated in the individual patient weighing the risk for ischaemic events against the bleeding risks. Extension of treatment beyond 12 months should be done on an individual patient basis as experience up to 24 months is limited (see section 5.1). Treatment with Xarelto should be started as soon as possible after stabilisation of the ACS event (including revascularisation procedures); at the earliest 24 hours after admission to hospital and at the time when parenteral anticoagulation therapy would normally be discontinued. If a dose is missed the patient should continue with the regular dose as recommended at the next scheduled time. The dose should not be doubled to make up for a missed dose.

When converting patients from VKAs to Xarelto, International Normalized Ratio (INR) values will be falsely elevated after the intake of Xarelto. The INR is not valid to measure the anticoagulant activity of Xarelto, and therefore should not be used (see section 4.5).

There is a potential for inadequate anticoagulation during the transition from Xarelto to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Xarelto can contribute to an elevated INR. In patients converting from Xarelto to VKA, VKA should be given concurrently until the INR is >= 2.0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing, as guided by INR testing. While patients are on both Xarelto and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Xarelto. Once Xarelto is discontinued INR testing may be done reliably at least 24 hours after the last dose (see sections 4.5 and 5.2).

For patients currently receiving a parenteral anticoagulant, Xarelto should be started 0 to 2 hours before the time of the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin).

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

Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Xarelto is to be used with caution in these patients. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.4 and 5.2). No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 - 80 ml/min) or moderate renal impairment (creatinine clearance 30 - 49 ml/min) (see section 5.2).

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

The safety and efficacy of Xarelto in children aged 0 to 18 years have not been established. No data are available. Therefore, Xarelto is not recommended for use in children below 18 years of age.

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active clinically significant bleeding. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin, etc. ), heparin derivatives (fondaparinux, etc. ), oral anticoagulants (warfarin, dabigatran etexilate, apixaban, etc.) except under the circumstances of switching therapy to or from rivaroxaban (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5). Concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a transient ischaemic attack (TIA) (see section 4.4). Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C (see section 5.2). Pregnancy and breast feeding (see section 4.6).

Special warnings and precautions for use

Efficacy and safety of Xarelto has been investigated in combination with the antiplatelet agents aspirin and clopidogrel/ticlopidine. Treatment in combination with other antiplatelet agents, e.g. prasugrel or ticagrelor, has not been studied and is not recommended. Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period.

As with other anticoagulants, patients taking Xarelto are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Xarelto administration should be discontinued if severe haemorrhage occurs. In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and anaemia were seen more frequently during long term rivaroxaban treatment on top of single or dual anti-platelet therapy. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate. Several sub-groups of patients, as detailed below, are at increased risk of bleeding. Therefore, the use of Xarelto in combination with dual antiplatelet therapy in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events. In addition these patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-Factor Xa assay may be useful in exceptional situations where knowledge of rivaroxaban exposure may help to inform clinical decisions, e.g., overdose and emergency surgery (see sections 5.1 and 5.2).

In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly increased (1.6 fold on average) which may lead to an increased bleeding risk. Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. Use is not recommended in patients with creatinine clearance < 15 ml/min (see sections 4.2 and 5.2). Xarelto is to be used with caution in patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations (see section 4.5).

The use of Xarelto is not recommended in patients receiving concomitant systemic treatment with azole-antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir). These active substances are strong inhibitors of both CYP3A4 and P-gp and therefore may increase rivaroxaban plasma concentrations to a clinically relevant degree (2.6 fold on average) which may lead to an increased bleeding risk (see section 4.5). Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) and platelet aggregation inhibitors. For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see section 4.5). After an acute coronary syndrome patients on treatment with Xarelto and ASA or Xarelto and ASA plus clopidogrel/ticlopidine should only receive concomitant treatment with NSAIDs if the benefit outweighs the bleeding risk.

As with other antithrombotics, rivaroxaban is not recommended in patients with an increased bleeding risk such as: congenital or acquired bleeding disorders uncontrolled severe arterial hypertension active ulcerative gastrointestinal disease vascular retinopathy bronchiectasis or history of pulmonary bleeding It should be used with caution in ACS patients: > 75 years of age if co-administered with ASA alone or with ASA plus clopidogrel or ticlopidine with low body weight (< 60 kg) if co-administered with ASA alone or with ASA plus clopidogrel or ticlopidine There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. However, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-Factor Xa tests (see sections 5.1 and 5.2).

Xarelto 2.5 mg is contraindicated for the treatment of ACS in patients with a prior stroke or TIA (see section 4.3). Few ACS patients with a prior stroke or TIA have been studied but the limited efficacy data available indicate that these patients do not benefit from treatment.

Dosing recommendations before and after invasive procedures and surgical intervention

If an invasive procedure or surgical intervention is required, Xarelto should be stopped at least 12 hours before the intervention, if possible and based on the clinical judgement of the physician. If a patient is to undergo elective surgery and anti-platelet effect is not desired, platelet aggregation inhibitors should be discontinued as directed by the manufacturer's prescribing information. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. Xarelto should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician (see section 5.2).

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

Interaction with other medicinal products and other forms of interaction

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

Active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice a day), for instance, considered as a strong CYP3A4 inhibitor and moderate P-gp inhibitor, led to a 1.5 fold increase in mean rivaroxaban AUC and a 1.4 fold increase in CRmaxR. This increase is not considered clinically relevant. (For patients with renal impairment: see section 4.4). Erythromycin (500 mg three times a day), which inhibits CYP3A4 and P-gp moderately, led to a

1.3 fold increase in mean rivaroxaban AUC and CRmaxR. This increase is not considered clinically relevant.

Fluconazole (400 mg once daily), considered as a moderate CYP3A4 inhibitor, led to a 1.4 fold increase in mean rivaroxaban AUC and a 1.3 fold increase in mean CRmaxR. This increase is not considered clinically relevant. Given the limited clinical data available with dronedarone, co-administration with rivaroxaban should be avoided.

After combined administration of enoxaparin (40 mg single dose) with rivaroxaban (10 mg single dose) an additive effect on anti-Factor Xa activity was observed without any additional effects on clotting tests (PT, aPTT). Enoxaparin did not affect the pharmacokinetics of rivaroxaban. Due to the increased bleeding risk care is to be taken if patients are treated concomitantly with any other anticoagulants (see sections 4.3 and 4.4).

No clinically relevant prolongation of bleeding time was observed after concomitant administration of rivaroxaban (15 mg) and 500 mg naproxen. Nevertheless, there may be individuals with a more pronounced pharmacodynamic response. No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with 500 mg acetylsalicylic acid. Clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) did not show a pharmacokinetic interaction with rivaroxaban (15 mg) but a relevant increase in bleeding time was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels. Care is to be taken if patients are treated concomitantly with NSAIDs (including acetylsalicylic acid) and platelet aggregation inhibitors because these medicinal products typically increase the bleeding risk (see section 4.4).

Converting patients from the vitamin K antagonist warfarin (INR 2.0 to 3.0) to rivaroxaban (20 mg) or from rivaroxaban (20 mg) to warfarin (INR 2.0 to 3.0) increased prothrombin time/INR (Neoplastin) more than additively (individual INR values up to 12 may be observed), whereas effects on aPTT, inhibition of factor Xa activity and endogenous thrombin potential were additive. If it is desired to test the pharmacodynamic effects of rivaroxaban during the conversion period, anti- factor Xa activity, PiCT, and Heptest can be used as these tests were not affected by warfarin. On the fourth day after the last dose of warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of rivaroxaban.

If it is desired to test the pharmacodynamic effects of warfarin during the conversion period, INR measurement can be used at the CRtroughR of rivaroxaban (24 hours after the previous intake of rivaroxaban) as this test is minimally affected by rivaroxaban at this time point. No pharmacokinetic interaction was observed between warfarin and rivaroxaban.

Co-administration of rivaroxaban with the strong CYP3A4 inducer rifampicin led to an approximate 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects. The concomitant use of rivaroxaban with other strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John's Wort 2T(Hypericum perforatum))2T may also lead to reduced rivaroxaban plasma concentrations. Strong CYP3A4 inducers should be co-administered with caution.

No clinically significant pharmacokinetic or pharmacodynamic interactions were observed when rivaroxaban was co-administered with midazolam (substrate of CYP3A4), digoxin (substrate of P-gp), atorvastatin (substrate of CYP3A4 and P-gp) or omeprazole (proton pump inhibitor). Rivaroxaban neither inhibits nor induces any major CYP isoforms like CYP3A4. No clinically relevant interaction with food was observed (see section 4.2).

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

Fertility, pregnancy and breast feeding

Safety and efficacy of Xarelto have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, Xarelto is contraindicated during pregnancy (see section 4.3). Women of child-bearing potential should avoid becoming pregnant during treatment with rivaroxaban.

Safety and efficacy of Xarelto have not been established in breast feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore Xarelto is contraindicated during breast feeding (see section 4.3). A decision must be made whether to discontinue breast feeding or to discontinue/abstain from therapy.

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

Effects on ability to drive and use machines

Xarelto has minor influence on the ability to drive and use machines. Adverse reactions like syncope (frequency: uncommon) and dizziness (frequency: common) have been reported (see section 4.8). Patients experiencing these adverse reactions should not drive or use machines.

Undesirable effects

Summary of the safety profile

The safety of rivaroxaban has been evaluated in eleven phase III studies including 32,625 patients exposed to rivaroxaban (see Table 1).

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

Indication	Number of patients *	Maximum daily dose	Maximum treatment duration
Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery	6,097	10 mg	39 days
Prevention of venous thromboembolism in medically ill patients	3,997	10 mg	39 days
Treatment of DVT, PE and prevention of recurrence	4,556	Day 1 - 21: 30 mg Day 22 and onwards: 20 mg	21 months
Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation	7,750	20 mg	41 months
Prevention of atherothrombotic events in patients after an ACS	10,225	5 mg or 10 mg respectively, co- administered with either ASA or ASA plus clopidogrel or ticlopidine	31 months

*Patients exposed to at least one dose of rivaroxaban In total about 67 % of patients exposed to at least one dose of rivaroxaban were reported with treatment emergent adverse events. About 22 % of patients experienced adverse events considered related to treatment as assessed by investigators. In patients treated with 10 mg Xarelto undergoing hip or knee replacement surgery and in hospitalised medically ill patients, bleeding events occurred in approximately 6.8 % and 12.6 % of patients, respectively, and anaemia occurred in approximately 5.9 % and 2.1 % of patients, respectively. In patients treated with either 15 mg twice daily Xarelto followed by 20 mg once daily for treatment of DVT or PE, or with 20 mg once daily for prevention of recurrent DVT and PE, bleeding events occurred in approximately 27.8 % of patients and anaemia occurred in approximately 2.2 % of patients. In patients treated for prevention of stroke and systemic embolism, bleeding of any type or severity was reported with an event rate of 28 per 100 patient years, and anaemia with an event rate of 2.5 per 100 patient years. In patients treated for prevention of atherothrombotic events after an acute coronary syndrome (ACS), bleeding of any type or severity was reported with an event rate of 22 per 100 patient years. Anaemia was reported with an event rate of 1.4 per 100 patient years.

Tabulated list of adverse reactions

The frequencies of adverse reactions reported with Xarelto are summarised in table 2 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)

Common	Uncommon	Rare	Not known
Blood and lymphatic system disorders
Anaemia (incl. respective laboratory parameters)	Thrombocythemia (incl. platelet count increased) A P
Immune system disorders
	Allergic reaction, dermatitis allergic
Nervous system disorders
Dizziness, headache	Cerebral and intracranial haemorrhage, syncope
Eye disorders
Eye haemorrhage (incl. conjunctival haemorrhage)
Cardiac disorders
	Tachycardia
Vascular disorders
Hypotension, haematoma
Respiratory, thoracic and mediastinal disorders
Epistaxis, Haemoptysis
Gastrointestinal disorders
Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipation A , PP diarrhoea, vomiting A P	Dry mouth
Hepatobiliary disorders
	Hepatic function abnormal	Jaundice
Skin and subcutaneous tissue disorders
Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage	Urticaria
Musculoskeletal and connective tissue disorders
A	Haemarthrosis	Muscle haemorrhage	Compartment syndrome secondary to a bleeding

Table 2: All treatment-emergent adverse reactions reported in patients in phase III studies

Pain in extremityP menorrhagiaP P) FeverP

, peripheral

Localised oedemaP phosphataseP

P,P

Common	Uncommon	Rare	Not known
Renal and urinary disorders
Urogenital tract haemorrhage (incl. haematuria and B Renal impairment (incl. blood creatinine increased, blood urea increased) A P			Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion
General disorders and administration site conditions
A oedema, decreased general strength and energy (incl. fatigue and asthenia)	Feeling unwell (incl. malaise),	A
Investigations
Increase in transaminases	Increased bilirubin, increased blood alkaline A A P increased LDH P P , increased lipase A , PP increased amylase A , PP increased GGT A P	Bilirubin conjugated increased (with or without concomitant increase of ALT)
Injury, poisoning and procedural complications
Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretion A P		Vascular pseudoaneurysm C P

A: observed in prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery B: observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55 years C: observed as uncommon in prevention of atherothrombotic events in patients after an ACS (following percutaneous coronary intervention)

Description of selected adverse reactions

Due to the pharmacological mode of action, the use of Xarelto may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic anaemia. The signs, symptoms and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see section 4.9 Management of bleeding). In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary) and anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate. The risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see Haemorrhagic risk in section 4.4). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea and unexplained shock. In some cases as a consequence of anaemia, symptoms of cardiac ischaemia like chest pain or angina pectoris have been observed. Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for Xarelto. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

Overdose

Rare cases of overdose up to 600 mg have been reported without bleeding complications or other adverse reactions. Due to limited absorption a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 50 mg rivaroxaban or above. A specific antidote antagonising the pharmacodynamic effect of rivaroxaban is not available. The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.

Should a bleeding complication arise in a patient receiving rivaroxaban, the next rivaroxaban administration should be delayed or treatment should be discontinued as appropriate. Rivaroxaban has a half-life of approximately 5 to 13 hours (see section 5.2). Management should be individualised according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets. If bleeding cannot be controlled by the above measures, administration of a specific procoagulant reversal agent should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is currently very limited clinical experience with the use of these products in individuals receiving rivaroxaban. The recommendation is also based on limited non-clinical data. Re-dosing of recombinant factor VIIa shall be considered and titrated depending on improvement of bleeding. Depending on local availability, a consultation with a coagulation expert should be considered in case of major bleedings. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use of systemic haemostatics (desmopressin, aprotinin) in individuals receiving rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Direct factor Xa inhibitors, ATC code: B01AF01 Mechanism of action Rivaroxaban is a highly selective direct Factor Xa inhibitor with oral bioavailability. Inhibition of Factor Xa interrupts the intrinsic and extrinsic pathway of the blood coagulation cascade, inhibiting both thrombin formation and development of thrombi. Rivaroxaban does not inhibit thrombin (activated Factor II) and no effects on platelets have been demonstrated.

Dose-dependent inhibition of Factor Xa activity was observed in humans. Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent way with a close correlation to plasma concentrations (r value equals 0.98) if Neoplastin is used for the assay. Other reagents would provide different results. The readout for PT is to be done in seconds, because the INR (International Normalised Ratio) is only calibrated and validated for coumarins and cannot be used for any other anticoagulant. The activated partial thomboplastin time (aPTT) and HepTest are also prolonged dose-dependently; however, they are not recommended to assess the pharmacodynamic effect of rivaroxaban. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. However, if clinically indicated, rivaroxaban levels can be measured by calibrated quantitative anti- Factor Xa tests (see section 5.2).

The rivaroxaban clinical program was designed to demonstrate the efficacy of Xarelto for the prevention of cardiovascular (CV) death, MI or stroke in subjects with a recent ACS (ST-elevation myocardial infarction [STEMI], non- ST-elevation myocardial infarction [NSTEMI] or unstable angina [UA]). In the pivotal double-blind ATLAS ACS 2 TIMI 51 trial, 15,526 patients were randomly assigned in a 1:1:1 fashion to one of three treatment groups: Xarelto 2.5 mg orally twice daily, 5 mg orally twice daily or to placebo twice daily co-administered with ASA alone or with ASA plus a thienopyridine (clopidogrel or ticlopidine). Patients with an ACS under the age of 55 had to have either diabetes mellitus or a previous MI. The median time on treatment was 13 months and overall treatment duration was up to almost 3 years. 93.2 % of patients received ASA concomitantly plus thienopyridine treatment and 6.8 % ASA only. Among patients receiving dual anti-platelets therapy 98.8% received clopidogrel, 0.9 % received ticlopidine and 0.3 % received prasugrel. Patients received the first dose of Xarelto at a minimum of 24 hours and up to 7 days (mean 4.7 days) after admission to the hospital, but as soon as possible after stabilisation of the ACS event, including revascularisation procedures and when parenteral anticoagulation therapy would normally be discontinued. Both the 2.5 mg twice daily and the 5 mg twice daily regimens of rivaroxaban were effective in further reducing the incidence of CV events on a background of standard antiplatelet care. The 2.5 mg twice daily regimen reduced mortality, and there is evidence that the lower dose had lower bleeding risks, therefore rivaroxaban 2.5 mg twice daily co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine is recommended for the prevention of atherothrombotic events in adult patients after an ACS with elevated cardiac biomarkers. Relative to placebo, Xarelto significantly reduced the primary composite endpoint of CV death, MI or stroke. The benefit was driven by a reduction in CV death and MI and appeared early with a constant treatment effect over the entire treatment period (see Table 3 and Figure 1). Also the first secondary endpoint (all cause death, MI or stroke) was reduced significantly. An additional retrospective analysis showed a nominally significant reduction in the incidence rates of stent thrombosis compared with placebo (see Table 3). The incidence rates for the principal safety outcome (non-CABG TIMI major bleeding events) were higher in patients treated with Xarelto than in patients who received placebo (see Table 5). However the incidence rates were balanced between Xarelto and placebo for the components of fatal bleeding events, hypotension requiring treatment with intravenous inotropic agents and surgical intervention for ongoing bleeding. In Table 4 the efficacy results of patients undergoing percutaneous coronary intervention (PCI) are presented. The safety results in this subgroup of patients undergoing PCI were comparable to the overall safety results. Patients with elevated biomarkers (troponin or CK-MB) and without a prior stroke/TIA constituted 80 % of the study population. The results of this patient population were also consistent with the overall efficacy and safety results.

Table 3: Efficacy results from phase III ATLAS ACS 2 TIMI 51

Hazard Ratio (95 % CI) p-value P modified intent to treat analysis set (intent to treat total analysis set for stent thrombosis) vs. placebo; Log-Rank p-value statistically superior * * nominally significant

Table 4: Efficacy results from phase III ATLAS ACS 2 TIMI 51 in patients undergoing PCI

Table 5: Safety results from phase III ATLAS ACS 2 TIMI 51

statistically significant Figure 1: Time to First Occurrence of Primary Efficacy Endpoint (CV death, MI or stroke)

The European Medicines Agency has deferred the obligation to submit the results of studies with Xarelto in one or more subsets of the paediatric population in the treatment of thromboembolic events. The European Medicines Agency has waived the obligation to submit the results of studies with Xarelto in all subsets of the paediatric population in the prevention of thromboembolic events (see section 4.2 for information on paediatric use).

Pharmacokinetic properties

Rivaroxaban is rapidly absorbed with maximum concentrations (CRmaxR) appearing 2 - 4 hours after tablet intake. Oral absorption of rivaroxaban is almost complete and oral bioavailability is high (80 - 100 %) for the

2.5 mg and 10 mg tablet dose, irrespective of fasting/fed conditions. Intake with food does not affect rivaroxaban AUC or CRmaxR at the 2.5 mg and 10 mg dose. Rivaroxaban 2.5 mg and 10 mg tablets can be taken with or without food. Rivaroxaban pharmacokinetics are approximately linear up to about 15 mg once daily. At higher doses rivaroxaban displays dissolution limited absorption with decreased bioavailability and decreased absorption rate with increased dose. This is more marked in fasting state than in fed state. Variability in rivaroxaban pharmacokinetics is moderate with inter-individual variability (CV %) ranging from 30 % to 40 %.

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

Of the administered rivaroxaban dose, approximately 2/3 undergoes metabolic degradation, with half then being eliminated renally and the other half eliminated by the faecal route. The final 1/3 of the administered dose undergoes direct renal excretion as unchanged active substance in the urine, mainly via active renal secretion. Rivaroxaban is metabolised via CYP3A4, CYP2J2 and CYP-independent mechanisms. Oxidative degradation of the morpholinone moiety and hydrolysis of the amide bonds are the major sites of biotransformation. Based on in vitro investigations rivaroxaban is a substrate of the transporter proteins P-gp (P-glycoprotein) and Bcrp (breast cancer resistance protein). Unchanged rivaroxaban is the most important compound in human plasma, with no major or active circulating metabolites being present. With a systemic clearance of about 10 l/h, rivaroxaban can be classified as a low-clearance substance. After intravenous administration of a 1 mg dose the elimination half-life is about 4.5 hours. After oral administration the elimination becomes absorption rate limited. Elimination of rivaroxaban from plasma occurs with terminal half-lives of 5 to 9 hours in young individuals, and with terminal half-lives of 11 to 13 hours in the elderly.

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

Elderly patients exhibited higher plasma concentrations than younger patients, with mean AUC values being approximately 1.5 fold higher, mainly due to reduced (apparent) total and renal clearance. No dose adjustment is necessary.

Extremes in body weight (< 50 kg or > 120 kg) had only a small influence on rivaroxaban plasma concentrations (less than 25 %). No dose adjustment is necessary.

No clinically relevant inter-ethnic differences among Caucasian, African-American, Hispanic, Japanese or Chinese patients were observed regarding rivaroxaban pharmacokinetics and pharmacodynamics.

Cirrhotic patients with mild hepatic impairment (classified as Child Pugh A) exhibited only minor changes in rivaroxaban pharmacokinetics (1.2 fold increase in rivaroxaban AUC on average), nearly comparable to their matched healthy control group. In cirrhotic patients with moderate hepatic impairment (classified as Child Pugh B), rivaroxaban mean AUC was significantly increased by 2.3 fold compared to healthy volunteers. Unbound AUC was increased 2.6 fold. These patients also had reduced renal elimination of rivaroxaban, similar to patients with moderate renal impairment. There are no data in patients with severe hepatic impairment. The inhibition of Factor Xa activity was increased by a factor of 2.6 in patients with moderate hepatic impairment as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 2.1. Patients with moderate hepatic impairment were more sensitive to rivaroxaban resulting in a steeper PK/PD relationship between concentration and PT. Xarelto is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C (see section 4.3).

There was an increase in rivaroxaban exposure correlated to decrease in renal function, as assessed via creatinine clearance measurements. In individuals with mild (creatinine clearance 50 - 80 ml/min), moderate (creatinine clearance 30 - 49 ml/min) and severe (creatinine clearance 15 - 29 ml/min) renal impairment, rivaroxaban plasma concentrations (AUC) were increased 1.4, 1.5 and 1.6 fold respectively. Corresponding increases in pharmacodynamic effects were more pronounced. In individuals with mild, moderate and severe renal impairment the overall inhibition of Factor Xa activity was increased by a factor of 1.5, 1.9 and 2.0 respectively as compared to healthy volunteers; prolongation of PT was similarly increased by a factor of 1.3, 2.2 and 2.4 respectively. There are no data in patients with creatinine clearance < 15 ml/min. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable. Use is not recommended in patients with creatinine clearance < 15 ml/min. Xarelto is to be used with caution in patients with creatinine clearance 15 - 29 ml/min (see section 4.4).

In patients receiving rivaroxaban 2.5 mg twice daily for the prevention of atherothrombotic events in patients with ACS the geometric mean concentration (90 % prediction interval) 2 - 4 h and about 12 h after dose (roughly representing maximum and minimum concentrations during the dose interval) was 47 (13 - 123) and 9.2 (4.4 - 18) ug/l, respectively.

The pharmacokinetic/pharmacodynamic (PK/PD) relationship between rivaroxaban plasma concentration and several PD endpoints (Factor Xa inhibition, PT, aPTT, Heptest) has been evaluated after administration of a wide range of doses (5 - 30 mg twice a day). The relationship between rivaroxaban concentration and Factor Xa activity was best described by an ERmaxR model. For PT, the linear intercept model generally described the data better. Depending on the different PT reagents used, the slope differed considerably. When Neoplastin PT was used, baseline PT was about 13 s and the slope was around 3 to 4 s/(100 ug/l). The results of the PK/PD analyses in Phase II and III were consistent with the data established in healthy subjects.

Safety and efficacy have not been established for children and adolescents up to 18 years.

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single dose toxicity, phototoxicity, genotoxicity, carcinogenic potential and juvenile toxicity. Effects observed in repeat-dose toxicity studies were mainly due to the exaggerated pharmacodynamic activity of rivaroxaban. In rats, increased IgG and IgA plasma levels were seen at clinically relevant exposure levels. In rats, no effects on male or female fertility were seen. Animal studies have shown reproductive toxicity related to the pharmacological mode of action of rivaroxaban (e.g. haemorrhagic complications). Embryo-foetal toxicity (post-implantation loss, retarded/progressed ossification, hepatic multiple light coloured spots) and an increased incidence of common malformations as well as placental changes were observed at clinically relevant plasma concentrations. In the pre- and post- natal study in rats, reduced viability of the offspring was observed at doses that were toxic to the dams.

PHARMACEUTICAL PARTICULARS

List of excipients

Microcrystalline cellulose Croscarmellose sodium Lactose monohydrate Hypromellose

Incompatibilities

Shelf life

Special precautions for storage

Nature and contents of container

PP/Aluminium foil blisters in cartons of 14, 28, 56, 60, 98, 168 or 196 film-coated tablets or perforated unit dose blisters in cartons of 10 x 1 or 100 x 1 film-coated tablets. Not all pack sizes may be marketed.

Special precautions for disposal

MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 30 September 2008 Date of latest renewal: 22 May 2013

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Study Population	a) Patients with a recent acute coronary syndrome P
Treatment Dosage	Xarelto 2.5 mg, twice daily, N=5,114 n (%) b)	Placebo N=5,113 n (%)
Cardiovascular death, MI or stroke	313 (6.1 %) 0.84 (0.72, 0.97) p = 0.020 *	376 (7.4 %)
All-cause death, MI or stroke	320 (6.3 %) 0.83 (0.72, 0.97) p = 0.016 *	386 (7.5 %)
Cardiovascular death	94 (1.8 %) 0.66 (0.51, 0.86) p = 0.002 * *	143 (2.8 %)
All-cause death	103 (2.0 %) 0.68 (0.53, 0.87) p = 0.002 * *	153 (3.0 %)
MI	205 (4.0 %) 0.90 (0.75, 1.09) p = 0.270	229 (4.5 %)
Stroke	46 (0.9 %) 1.13 (0.74, 1.73) p = 0.562	41 (0.8 %)
Stent thrombosis	61 (1.2 %) 0.70 (0.51, 0.97) p = 0.033 * *	87 (1.7 %)

Study Population	Patients with recent acute coronary syndrome undergoing PCI a) P
Treatment Dosage	Xarelto 2.5 mg, twice daily, N=3114 n (%) b)	Placebo N=3096 n (%)
Cardiovascular death, MI or stroke	153 (4.9 %) 0.94 (0.75, 1.17) p = 0.572	165 (5.3 %)
Cardiovascular death	24 (0.8 %) 0.54 (0.33, 0.89) p = 0.013 * *	45 (1.5 %)
All-cause death	31 (1.0 %) 0.64 (0.41, 1.01) p = 0.053	49 (1.6 %)
MI	115 (3.7 %) 1.03 (0.79, 1.33) p = 0.829	113 (3.6 %)
Stroke	27 (0.9 %) 1.30 (0.74, 2.31) p = 0.360	21 (0.7 %)
Stent thrombosis	47 (1.5 %) 0.66 (0.46, 0.95) p = 0.026 * *	71 (2.3 %)

Study Population	a) Patients with recent acute coronary syndrome P
Treatment Dosage	Xarelto 2.5 mg, twice daily, N=5,115 n (%) b)	Placebo N=5,125 n(%)
Non-CABG TIMI major bleeding event	65 (1.3 %) 3.46 (2.08, 5.77) p = < 0.001 *	19 (0.4 %)
Fatal bleeding event	6 (0.1 %) 0.67 (0.24, 1.89) p = 0.450	9 (0.2 %)
Symptomatic intracranial haemorrhage	14 (0.3 %) 2.83 (1.02, 7.86) p = 0.037	5 (0.1 %)
Hypotension requiring treatment with intravenous inotropic agents	3 (0.1 %)	3 (0.1 %)
Surgical intervention for ongoing bleeding	7 (0.1 %)	9 (0.2 %)
Transfusion of 4 or more units of blood over a 48 hour period	19 (0.4 %)	6 (0.1 %)

XARELTO	5114	4431	3943	3199	2609	2005	1425	878	415	89
Placebo	5113	4437	3974	3253	2664	2059	1460	878	421	87

ANNEX I

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION