Rivoxa 10, 15 & 20 10, 15 & 20 mg FC Tablet

RIVOXA 10 mg is indicated for:

The prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs.

RIVOXA 15 mg and 20 mg are indicated for:

• Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (SPAF).
• Treatment of deep vein thrombosis (DVT) and for the prevention of recurrent deep vein thrombosis (DVT) and pulmonary embolism (PE).
• Treatment of pulmonary embolism (PE) and for the prevention of recurrent pulmonary embolism (PE) and deep vein thrombosis (DVT).

Posology

Recommended dose and frequency of administration for RIVOXA 10:

The recommended dose is one RIVOXA 10 tablet once daily for the prevention of venous thromboembolism (VTE) in major orthopaedic surgery. RIVOXA 10 may be taken with or without food. The initial dose should be taken within 6 to 10 hours after surgery provided that haemostasis has been established. If a dose is missed, the patient should take RIVOXA 10 immediately and continue on the following day with the once daily intake as before.

Duration of treatment:

The duration of treatment depends on the type of major orthopaedic surgery. After major hip surgery patients should be treated for 5 weeks. After major knee surgery patients should be treated for 2 weeks.

Special patient populations:

Elderly (above 65 years), gender and body weight: No dose adjustment is required for these patient populations. Patients with impaired liver function: RIVOXA 10 is contraindicated in patients with significant hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk (see section 4.3). No dose adjustment is necessary in patients with other hepatic diseases. Limited clinical data in patients with moderate hepatic impairment indicate a significant increase in the pharmacological activity. No clinical data are available for patients with severe hepatic impairment. Patients with impaired renal function: No dose adjustment is required if RIVOXA 10 is administered in patients with mild (creatinine clearance 80 to 50 mL/min) or moderate (creatinine clearance < 50 to 30 mL/min) renal impairment. Limited clinical data for patients with severe renal impairment (creatinine clearance < 30 mL/min) indicate that rivaroxaban plasma levels are significantly increased in this patient population. Therefore RIVOXA 10 has to be used with caution in these patients (see section 4.4). Ethnic differences: No dosage adjustment is required based on ethnic differences. Paediatric population: The safety and efficacy of RIVOXA 10 has not been established in children. No clinical data is available for children.

Recommended dose and frequency of administration for RIVOXA 15 and RIVOXA 20:

There is no need for monitoring of coagulation parameters during treatment with RIVOXA 15 and RIVOXA 20. SPAF u2013 Recommended usual dose and frequency of administration: The recommended dose is one RIVOXA 20 tablet once daily. For patients with moderate renal impairment (creatinine clearance < 50 to 30 mL/min) the recommended dose is one RIVOXA 15 tablet once daily. RIVOXA 15 and RIVOXA 20 tablets should be taken with food. SPAF u2013 Duration of treatment: Therapy should be continued as long as risk factors for stroke and systemic embolism persist. SPAF u2013 Missed dose: If a dose is missed the patient should take RIVOXA 15 or RIVOXA 20 immediately and continue with the once daily intake as recommended on the following day. The dose should not be doubled to make up for a missed dose within the same day. SPAF u2013 Maximum daily dose: The recommended maximum daily dose is one RIVOXA 20 tablet (20 mg rivaroxaban). SPAF u2013 Additional information on special populations: SPAF u2013 Patients with hepatic impairment: RIVOXA 15 and RIVOXA 20 are contraindicated in patients with hepatic disease with or without coagulopathy (see section 4.3). Limited data in patients with moderate hepatic impairment (Child Pugh B) indicate a significant increase in the pharmacological activity. No data are available for patients with severe hepatic impairment (Child Pugh C) (see section 4.3 and section 5.2).

SPAF u2013 Patients with renal impairment: No dose adjustment is required if RIVOXA 20 is administered in patients with mild (creatinine clearance u2264 80 to 50 mL/min) renal impairment. For patients with moderate (creatinine clearance < 50 to 30 mL/min) renal impairment the recommended dose is one RIVOXA 15 once daily. Limited data for patients with severe renal impairment (creatinine clearance < 30 to 15 mL/min) indicate that rivaroxaban plasma levels are significantly increased in this patient population. Therefore, RIVOXA 15 has to be used with caution in these patients. Use of RIVOXA 15 or RIVOXA 20 is not recommended in patients with creatinine clearance < 15 mL/min (see section 4.4 and section 5.2).

SPAF u2013 Converting from warfarin to RIVOXA 15 and RIVOXA 20: Warfarin treatment should be stopped and RIVOXA 15 or RIVOXA 20 therapy should be initiated when the International Normalised Ratio (INR) is u2264 3,0. When converting patients from warfarin to RIVOXA 15 or RIVOXA 20, INR values will be falsely elevated after the intake of RIVOXA 15 or RIVOXA 20. The INR is not valid to measure the anticoagulant activity of RIVOXA 15 or RIVOXA 20, and therefore should not be used (see section 4.5).

SPAF u2013 Converting from RIVOXA 15 or RIVOXA 20 to warfarin: There is a potential for inadequate anticoagulation during the transition from RIVOXA 15 or RIVOXA 20 to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that RIVOXA 15 and RIVOXA 20 can contribute to an elevated INR. In patients converting from RIVOXA 15 or RIVOXA 20 to warfarin, warfarin should be given concurrently until the INR is u2265 2,0. For the first two days of the conversion period, standard warfarin dosing should be used followed by warfarin dosing guided by INR testing. While patients are on both RIVOXA 15 or RIVOXA 20 and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of RIVOXA 15 or RIVOXA 20). Once RIVOXA 15 or RIVOXA 20 is discontinued, INR testing may be done reliably 24 hours after the latest dose (see section 4.5).

SPAF u2013 Converting from parenteral anticoagulants to RIVOXA 15 or RIVOXA 20: For patients currently receiving a parenteral anticoagulant, start RIVOXA 15 or RIVOXA 20, 0 to 2 hours before the time of the next scheduled administration of the parenteral medicine (e.g. LMWH) or at the time of discontinuation of a continuously administered parenteral medicine (e.g. intravenous unfractionated heparin).

SPAF u2013 Converting from RIVOXA 15 or RIVOXA 20 to parenteral anticoagulants: Discontinue RIVOXA 15 or RIVOXA 20 and give the first dose of parenteral anticoagulant at the time that the next RIVOXA 15 or RIVOXA 20 dose would have been taken.

SPAF u2013 Paediatric population (from birth to 18 years): Safety and efficacy have not been established in children and adolescents below 18 years.

SPAF u2013 Body weight: No dose adjustment is required based on body weight (see section 5.2).

DVT and PE treatment u2013 Recommended usual dose and frequency of administration: The recommended dose for the initial treatment of acute DVT and PE is one RIVOXA 15 tablet twice daily for the first three weeks followed by one RIVOXA 20 tablet once daily for the continued treatment and the prevention of recurrent DVT and PE. RIVOXA 15 and RIVOXA 20 tablets should be taken with food.

DVT and PE treatment u2013 Duration of treatment: Therapy should be continued as long as the VTE risk persists.

DVT and PE treatment u2013 Missed dose: It is essential to adhere to the dosage schedule provided. If a dose is missed during the RIVOXA 15 twice daily treatment phase the patient should take RIVOXA 15 immediately to ensure an intake of 30 mg per day. The patient should continue with the regular one RIVOXA 15 tablet twice daily intake as recommended on the following day. If a dose is missed during the RIVOXA 20 once daily treatment phase the patient should take RIVOXA 20 immediately to ensure intake of 20 mg per day. The patient should continue with the regular one RIVOXA 20 once daily intake as recommended on the following day.

DVT and PE treatment u2013 Maximum daily dose: The recommended maximum daily dose is 30 mg during the first 3 weeks of treatment. In the following treatment phase the recommended maximum daily dose is 20 mg.

DVT and PE treatment u2013 Additional information of special populations: DVT and PE treatment u2013 Patients with hepatic impairment: RIVOXA 15 and RIVOXA 20 are contraindicated in patients with hepatic disease with or without coagulopathy (see section 4.3). Limited data in patients with moderate hepatic impairment (Child Pugh B) indicate a significant increase in the pharmacological activity. No data are available for patients with severe hepatic impairment (Child Pugh C) (see section 4.3 and section 5.2).

DVT and PE treatment u2013 Patients with renal impairment: No dose adjustment is required if RIVOXA 15 and RIVOXA 20 is administered in patients with mild (creatinine clearance u2264 80 to 50 mL/min) or moderate (creatinine clearance < 50 to 30 mL/min) renal impairment (see section 5.2). Limited data for patients with severe renal impairment (creatinine clearance < 30 to 15 mL/min) indicate that rivaroxaban plasma levels are significantly increased in this patient population. Therefore RIVOXA 15 and RIVOXA 20 has to be used with caution in these patients. Use of RIVOXA 15 and RIVOXA 20 are not recommended in patients with creatinine clearance < 15 mL/min (see section 4.4 and section 5.2).

RIVOXA is contraindicated in patients with:

• Hypersensitivity to rivaroxaban or to any of the excipients of RIVOXA, 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).
• 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 breastfeeding (see section 4.6).

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk: Patients taking RIVOXA are to be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. RIVOXA administration should be discontinued if severe haemorrhage occurs. In clinical studies mucosal bleedings (i.e. epistaxis, gingival, gastrointestinal, genitourinary 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. Several sub-groups of patients, as detailed below, are at increased risk of bleeding. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). In patients receiving RIVOXA 10 for VTE prevention following elective hip or knee replacement surgery, this may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin. Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.

Although treatment with RIVOXA 15 and RIVOXA 20 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. RIVOXA is to be used with caution in patients with creatinine clearance 15 to 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 to 49 mL/min) concomitantly receiving other medicines which increase rivaroxaban plasma concentrations, RIVOXA is to be used with caution (see section 4.5).

Interaction with other medicines: The use of RIVOXA 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 medicines affecting haemostasis such as non-steroidal anti-inflammatory medicines (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 section 4.5).

Other haemorrhagic risk factors: 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.

Patients with prosthetic valves: Safety and efficacy of RIVOXA have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that RIVOXA provides adequate anticoagulation in this patient population. Treatment with RIVOXA 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 non-valvular atrial fibrillation who undergo percutaneous coronary intervention (PCI) with stent placement: Clinical data are available from an interventional study with the primary objective to assess safety in patients with non-valvular atrial fibrillation who undergo PCI with stent placement. Data on efficacy in this population are limited (see sections 4.2 and 5.1).

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: RIVOXA is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of RIVOXA have not been established in these clinical situations.

Spinal/epidural anaesthesia or puncture: When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is employed, patients treated with antithrombotic medicines 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 postoperative use of indwelling epidural catheters or the concomitant use of medicines 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 medical practitioner 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 15 mg and 20 mg rivaroxaban in these situations. 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. For the removal of an epidural catheter and based on the general PK characteristics at least 2 x half-life, i.e. at least 18 hours in young patients and 26 hours in elderly patients should elapse after the last administration of rivaroxaban (see section 5.2). Following removal of the catheter, at least 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.

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 C max, with significant increases in pharmacodynamic effects which may lead to an increased bleeding risk. Therefore, the use of RIVOXA 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 C max. 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 C max. 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 C max 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 C max 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 C max. 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 medicines typically increase the bleeding risk (see section 4.4).

SSRIs/SNRIs

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 u00ae ) 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 C trough 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.

Laboratory parameters

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

Women of childbearing potential should avoid becoming pregnant during treatment with rivaroxaban. Pregnancy: Safety and efficacy of RIVOXA have not been established in pregnant women. Studies in animals have shown reproductive toxicity. Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, RIVOXA is contraindicated during pregnancy (see section 4.3). Breastfeeding: Safety and efficacy of RIVOXA have not been established in breastfeeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore, RIVOXA is contraindicated during breastfeeding (see section 4.3). 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.

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

Tabulated list of adverse reactions

Blood and lymphatic system disorders:

Frequent: Anaemia (incl. respective laboratory parameters).

Less frequent: Thrombocytosis (incl. platelet count increased - observed in prevention of VTE in adult patients undergoing elective hip or knee replacement), thrombocytopenia (incl. platelet count increased).

Immune system disorders:

Less frequent: Allergic reaction, anaphylactic reactions including anaphylactic shock, angioedema and allergic oedema, allergic dermatitis.

Nervous system disorders:

Frequent: Dizziness, headache.

Less frequent: Cerebral and intracranial haemorrhage, syncope (incl. loss of consciousness).

Eye disorders:

Frequent: Eye haemorrhage (incl. conjunctival haemorrhage).

Cardiac disorders:

Less frequent: Tachycardia.

Vascular disorders:

Frequent: Haematoma, hypotension, postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage).

Less frequent: (See Gastrointestinal disorders), genital tract haemorrhage (incl. menorrhagia), haemorrhage (incl. haematoma and rare cases of muscle haemorrhage), haematuria (incl. blood urine present), nosebleed.

Respiratory, thoracic and mediastinal disorders:

Frequent: Epistaxis, haemoptysis.

Gastrointestinal disorders:

Frequent: Constipation (observed in prevention of VTE in adult patients undergoing elective hip or knee replacement), diarrhoea, dyspepsia (including epigastric discomfort), gastrointestinal and abdominal pains, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gingival bleeding, nausea, vomiting (observed in prevention of VTE in adult patients undergoing elective hip or knee replacement).

Less frequent: Dry mouth.

Hepatobiliary disorders:

Frequent: Increase in transaminases.

Less frequent: Abnormal hepatic function, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatic impairment, hepatitis (incl. hepatocellular injury), increased bilirubin, increased blood alkaline phosphatase (observed in prevention of VTE in adult patients undergoing elective hip or knee replacement), increased GGT (observed in prevention of VTE in adult patients undergoing elective hip or knee replacement), jaundice.

Skin and subcutaneous tissue disorders:

Frequent: Cutaneous and subcutaneous haemorrhage, ecchymosis, pruritus (incl. uncommon cases of generalised pruritus), rash.

Less frequent: Contusion, Stevens-Johnson syndrome/Toxic Epidermal Necrolysis, DRESS syndrome, urticaria (incl. rare cases of generalised urticaria).

Musculoskeletal and connective tissue disorders:

Frequent: Pain in extremity (observed in prevention of VTE in adult patients undergoing elective hip or knee replacement).

Less frequent: Compartment syndrome secondary to a bleeding, haemarthrosis, muscle haemorrhage.

Renal and urinary disorders:

Frequent: Renal impairment (incl. blood creatinine increased, blood urea increased observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery), urogenital tract haemorrhage (incl. haematuria and menorrhagia observed in treatment of DVT, PE and prevention of recurrence as very common in women < 55 years).

Less frequent: Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion.

General disorders and administration site conditions:

Frequent: Decreased general strength and energy (incl. fatigue and asthenia), fever (observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery), peripheral oedema.

Less frequent: Feeling unwell (incl. malaise), localised oedema (observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery).

Investigations:

Frequent: Increase in transaminases (incl. ALT increase, AST increase), increased GGT.

Less frequent: Bilirubin conjugated increased (with or without concomitant increase of ALT), blood bilirubin increased, increased alkaline phosphatase, increased LDH- lipase- and amylase observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery.

Injury, poisoning and procedural complications:

Frequent: Contusion, postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), wound secretion (observed in prevention of VTE in adult patients undergoing elective hip or knee replacement surgery).

Less frequent: Vascular pseudoaneurysm - observed as uncommon in prevention of atherothrombotic events in patients after an ACS (following percutaneous coronary intervention), wound secretion.

Description of selected adverse reactions: Due to the pharmacological mode of action, the use of RIVOXA 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, genitourinary 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 have been reported for RIVOXA. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

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 supra therapeutic 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.

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, administration of a specific procoagulant reversal medicine should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is 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 (see section 5.1). Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. There is no experience with antifibrinolytic medicines (tranexamic acid, aminocaproic acid) 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.