4.1. Therapeutic indications

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

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

4.2. Posology and method of administration

Posology

The recommended dose is 2.5 mg twice daily.

• ACS

Patients taking Rivaroxaban SUN 2.5 mg twice daily 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 Rivaroxaban SUN 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.

• CAD/PAD

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

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

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

• ACS, CAD/PAD

Co-administration with antiplatelet therapy

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

Safety and efficacy of Rivaroxaban SUN 2.5 mg twice daily in combination with dual antiplatelet therapy have been studied in patients

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

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

Missed dose

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.

Converting from Vitamin K Antagonists (VKA) to Rivaroxaban SUN

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

Converting from Rivaroxaban SUN to Vitamin K antagonists (VKA)

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

Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Rivaroxaban SUN can contribute to an elevated INR.

In patients converting from Rivaroxaban SUN to VKA, VKA should be given concurrently until the INR is ≥ 2.0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing, as guided by INR testing. While patients are on both Rivaroxaban SUN and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Rivaroxaban SUN. Once Rivaroxaban SUN is discontinued INR testing may be done reliably at least 24 hours after the last dose (see sections 4.5 and 5.2).

Converting from parenteral anticoagulants to Rivaroxaban SUN

For patients currently receiving a parenteral anticoagulant, discontinue the parenteral anticoagulant and start Rivaroxaban SUN 0 to 2 hours before the time that the next scheduled administration of the parenteral medicinal product (e.g. low molecular weight heparins) would be due or at the time of discontinuation of a continuously administered parenteral medicinal product (e.g. intravenous unfractionated heparin).

Converting from Rivaroxaban SUN to parenteral anticoagulants

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

Special populations

Renal impairment

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 SUN 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).

Hepatic impairment

Rivaroxaban SUN 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).

Elderly population

No dose adjustment (see sections 4.4 and 5.2)

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

Body weight

No dose adjustment (see sections 4.4 and 5.2)

Gender

No dose adjustment (see section 5.2)

Paediatric population

The safety and efficacy of Rivaroxaban SUN 2.5 mg film-coated tablets in children aged 0 to 18 years have not been established. No data are available. Therefore, Rivaroxaban SUN 2.5 mg film-coated tablets are not recommended for use in children below 18 years of age.

Method of administration

Rivaroxaban SUN is for oral use. The tablets can be taken with or without food (see sections 4.5 and 5.2).

Crushing of tablets

For patients who are unable to swallow whole tablets, Rivaroxaban SUN tablet may be crushed and mixed with water or apple puree immediately prior to use and administered orally.

The crushed tablet may also be given through gastric tubes (see sections 5.2 and 6.6).

4.3. 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 specific circumstances of switching anticoagulant therapy (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).

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

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

Pregnancy and breast-feeding (see section 4.6).

4.4. Special warnings and precautions for use

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

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

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

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

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

Haemorrhagic risk

As with other anticoagulants, patients taking Rivaroxaban SUN are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. Rivaroxaban SUN administration should be discontinued if severe haemorrhage occurs (see section 4.9).

In the clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genito urinary including abnormal vaginal or increased menstrual bleeding) 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 and quantify the clinical relevance of overt bleeding, as judged to be appropriate.

Several sub-groups of patients, as detailed below, are at increased risk of bleeding. Therefore, the use of Rivaroxaban SUN 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).

Renal impairment

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. Rivaroxaban SUN 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). In patients with moderate renal impairment (creatinine clearance 30 - 49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations Rivaroxaban SUN is to be used with caution (see section 4.5).

Interaction with other medicinal products

The use of Rivaroxaban SUN 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 or selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see sections 4.5 and 5.1).

Patients treated with Rivaroxaban SUN and antiplatelet agents should only receive concomitant treatment with NSAIDs if the benefit outweighs the bleeding risk.

Other haemorrhagic risk factors

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

• congenital or acquired bleeding disorders

• uncontrolled severe arterial hypertension

• other gastrointestinal disease without active ulceration that can potentially lead to bleeding complications (e.g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease)

• vascular retinopathy

• bronchiectasis or history of pulmonary bleeding

It should be used with caution in ACS and CAD/PAD patients:

• ≥ 75 years of age if co-administered with ASA alone or with ASA plus clopidogrel or ticlopidine. The benefit-risk of the treatment should be individually assessed on a regular basis.

• with lower body weight (< 60 kg) if co-administered with ASA alone or with ASA plus clopidogrel or ticlopidine.

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

Patients with cancer

Patients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis. The individual benefit of antithrombotic treatment should be weighed against risk for bleeding in patients with active cancer dependent on tumour location, antineoplastic therapy and stage of disease. Tumours located in the gastrointestinal or genitourinary tract have been associated with an increased risk of bleeding 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 undergone transcatheter aortic valve replacement (TAVR). Safety and efficacy of Rivaroxaban SUN have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that Rivaroxaban SUN provides adequate anticoagulation in this patient population. Treatment with Rivaroxaban SUN is not recommended for these patients.

Patients with antiphospholipid syndrome

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

Patients with prior stroke and/or TIA

Patients with ACS

Rivaroxaban SUN 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.

Patients with CAD/PAD

CAD/PAD patients with previous haemorrhagic or lacunar stroke, or an ischaemic, non-lacunar stroke with in the previous month were not studied (see section 4.3).

Patients after recent revascularisation procedures of the lower limb due to symptomatic PAD with a previous stroke or TIA were not studied. Treatment with Rivaroxaban SUN 2.5 mg should be avoided in these patients receiving dual antiplatelet therapy.

Spinal/epidural anaesthesia or puncture

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of 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 or the concomitant use of medicinal products affecting haemostasis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g. numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of rivaroxaban 2.5 mg and antiplatelet agents in these situations. Platelet aggregation inhibitors should be discontinued as suggested by the manufacturer's prescribing information.

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

Dosing recommendations before and after invasive procedures and surgical intervention

If an invasive procedure or surgical intervention is required, Rivaroxaban SUN 2.5 mg 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.

Rivaroxaban SUN should be restarted as soon as possible after the invasive procedure or surgical intervention provided the clinical situation allows and adequate haemostasis has been established as determined by the treating physician (see section 5.2).

Elderly population

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

Dermatological reactions

Serious skin reactions, including Stevens-Johnson syndrome/toxic epidermal necrolysis and DRESS syndrome, have been reported during post-marketing surveillance in association with the use of rivaroxaban (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first weeks of treatment. Rivaroxaban should be discontinued at the first appearance of a severe skin rash (e.g. spreading, intense and/or blistering), or any other sign of hypersensitivity in conjunction with mucosal lesions.

Information about excipients

Rivaroxaban SUN 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 dosage unit, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

CYP3A4 and P-gp inhibitors

Co-administration of rivaroxaban with ketoconazole (400 mg once a day) or ritonavir (600 mg twice a day) led to a 2.6 fold / 2.5 fold increase in mean rivaroxaban AUC and a 1.7 fold / 1.6 fold increase in mean rivaroxaban Cmax, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of Rivaroxaban SUN 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 Cmax. The interaction with clarithromycin is likely not clinically relevant in most patients but can be potentially significant in high-risk patients. (For patients with renal impairment: see section 4.4).

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 Cmax. The interaction with erythromycin is likely not clinically 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 fold increase in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects with normal renal function. In subjects with moderate renal impairment, erythromycin led to a 2.0 fold increase in mean rivaroxaban AUC and 1.6 fold increase in Cmax when compared to subjects with normal renal function. The effect of erythromycin is additive to that of renal impairment (see section 4.4).

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

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

Anticoagulants

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).

NSAIDs/platelet aggregation inhibitors

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).

SSRIs/SNRIs

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

Warfarin

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 Ctrough 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.

CYP3A4 inducers

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 (Hypericum perforatum) may also lead to reduced rivaroxaban plasma concentrations. Therefore, concomitant administration of strong CYP3A4 inducers should be avoided unless the patient is closely observed for signs and symptoms of thrombosis.

Other concomitant therapies

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).

Laboratory parameters

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

4.6. Fertility, pregnancy and lactation

Pregnancy

Safety and efficacy of rivaroxaban 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, rivaroxaban is contraindicated during pregnancy (see section 4.3).

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

Breast-feeding

Safety and efficacy of rivaroxaban have not been established in breast-feeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore rivaroxaban 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.

Fertility

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).

4.7. Effects on ability to drive and use machines

Rivaroxaban SUN 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.

4.8. Undesirable effects

Summary of the safety profile

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

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

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

Indication

Number of patients*

Total 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 VTE in medically ill patients

3,997

10 mg

39 days

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

6,790

Day 1 - 21: 30 mg

Day 22 and onwards: 20 mg

After at least 6 months: 10 mg or 20 mg

21 months

Treatment of VTE and prevention of VTE recurrence in term neonates and children aged less than 18 years following initiation of standard anticoagulation treatment

329

Body weight-adjusted dose to achieve a similar exposure as that observed in adults treated for DVT with 20 mg rivaroxaban once daily

12 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

Prevention of atherothrombotic events in patients with CAD/PAD

18,244

5 mg co-administered with ASA or 10 mg alone

47 months

3,256**

5 mg co-administered with ASA

42 months

* 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 (see section 4.4. and 'Description of selected adverse reactions' below) (Table 2). The most commonly reported bleedings were epistaxis (4.5 %) and gastrointestinal tract haemorrhage (3.8 %).

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

Indication

Any bleeding

Anaemia

Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery

6.8% of patients

5.9% of patients

Prevention of venous thromboembolism in medically ill patients

12.6% of patients

2.1% of patients

Treatment of DVT, PE and prevention of recurrence

23% of patients

1.6% of patients

Treatment of VTE and prevention of VTE recurrence in term neonates and children aged less than 18 years following initiation of standard anticoagulation treatment

39.5% of patients

4.6% of patients

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

28 per 100 patient years

2.5 per 100 patient years

Prevention of atherothrombotic events in patients after an ACS

22 per 100 patient years

1.4 per 100 patient years

Prevention of atherothrombotic events in patients with CAD/PAD

6.7 per 100 patient years

0.15 per 100 patient years**

8.38 per 100 patient years#

0.74 per 100 patient 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 event collection was applied

*** A selective approach to adverse event collection was applied

# From the VOYAGER PAD study

Tabulated list of adverse reactions

The frequencies of adverse reactions reported with Rivaroxaban SUN in adult and paediatric patients are summarised in Table 3 below by system organ class (in MedDRA) and by frequency.

Frequencies are defined as:

very common (≥ 1/10)

common (≥ 1/100 to < 1/10)

uncommon (≥ 1/1,000 to < 1/100)

rare (≥ 1/10,000 to < 1/1,000)

very rare (< 1/10,000)

not known (cannot be estimated from the available data)

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

Common

Uncommon

Rare

Very rare

Not known

Blood and lymphatic system disorders

Anaemia (incl. respective laboratory parameters)

Thrombocytosis (incl. platelet count increased)A, thrombocytopenia

Immune system disorders

Allergic reaction, dermatitis allergic, Angioedema and allergic oedema

Anaphylactic reactions including anaphylactic shock

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

Eosinophilic pneumonia

Gastrointestinal disorders

Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipationA, diarrhoea, vomitingA

Dry mouth

Hepatobiliary disorders

Increase in transaminases

Hepatic impairment, Increased bilirubin, increased blood alkaline phosphataseA, increased GGTA

Jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl. hepatocellular injury)

Skin and subcutaneous tissue disorders

Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage

Urticaria

Stevens-Johnson syndrome/Toxic Epidermal Necrolysis, DRESS syndrome

Musculoskeletal and connective tissue disorders

Pain in extremityA

Haemarthrosis

Muscle haemorrhage

Compartment syndrome secondary to a bleeding

Renal and urinary disorders

Urogenital tract haemorrhage (incl. haematuria and menorrhagiaB), renal impairment (incl. blood creatinine increased, blood urea increased)

Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion, Anticoagulant-related nephropathy

General disorders and administration site conditions

FeverA, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia)

Feeling unwell (incl. malaise)

Localised oedemaA

Investigations

Increased LDHA, increased lipaseA, increased amylaseA

Injury, poisoning and procedural complications

Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretionA

Vascular pseudoaneurysmC

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

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

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

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

Description of selected adverse reactions

Due to the pharmacological mode of action, the use of rivaroxaban 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 including abnormal vaginal or increased menstrual bleeding) 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 and quantify the clinical relevance of overt 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 section 4.4 “Haemorrhagic risk”). 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, or anticoagulant-related nephropathy have been reported for rivaroxaban. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.co.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Rare cases of overdose up to 1,960 mg have been reported. In case of overdose, the patient should be observed carefully for bleeding complications or other adverse reactions (see section “Management of bleeding”). 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 reversal agent (andexanet alfa) antagonising the pharmacodynamic effect of rivaroxaban is available (refer to the Summary of Product Characteristics of andexanet alfa). The use of activated charcoal to reduce absorption in case of rivaroxaban overdose may be considered.

Management of bleeding

Should a bleeding complication arise in a patient receiving rivaroxaban, the next 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, either the administration of a specific factor Xa inhibitor reversal agent (andexanet alfa), which antagonises the pharmacodynamic effect of rivaroxaban, or a specific procoagulant agent, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa), should be considered. However, there is currently very limited clinical experience with the use of these medicinal 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 (see section 5.1).

Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in individuals receiving rivaroxaban. There is neither scientific rationale for benefit nor experience with the use of the systemic haemostatic desmopressin in individuals receiving rivaroxaban. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.