Rubarox 10/15/20 10 mg, 15 mg, 20 mg Tablets

RUBAROX 10 is indicated for the prevention of venous thromboembolism (VTE) in patients undergoing major orthopaedic surgery of the lower limbs. RUBAROX 15 & 20 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

There is no need for monitoring of coagulation parameters during treatment with RUBAROX.

VTE u2013 Recommended usual dose and frequency of administration:

The recommended dose is one RUBAROX 10 tablet once daily for the prevention of venous thromboembolism (VTE) in major orthopaedic surgery. The initial dose should be taken within 6 - 10 hours after surgery provided that haemostasis has been established. If a dose is missed the patient should take RUBAROX 10 immediately and continue on the following day with the once daily intake as before.

VTE u2013 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.

VTE u2013 Special patient populations

VTE u2013 Elderly (above 65 years), Gender and Body Weight: No dose adjustment is required for these patient populations.

VTE u2013 Children (up to 18 years of age) The safety and efficacy of RUBAROX 10 has not been established in children. No clinical data is available for children.

VTE u2013 Patients with impaired liver function RUBAROX 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.

VTE u2013 Patients with impaired renal function No dose adjustment is required if RUBAROX 10 is administered in patients with mild (creatinine clearance 80 u2013 50 mL/min) or moderate (creatinine clearance < 50 - 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 RUBAROX 10 must be used with caution in these patients (see section 4.4).

VTE u2013 Ethnic differences No dose adjustment is required based on ethnic differences.

SPAF u2013 Recommended usual dose and frequency of administration:

The recommended dose is one RUBAROX 20 tablet once daily. For patients with moderate renal impairment (creatinine clearance < 50 to 30 ml/min) the recommended dose is one RUBAROX 15 tablet once daily. RUBAROX 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 RUBAROX 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 RUBAROX 20 tablet (20 mg rivaroxaban).

SPAF u2013 Additional information on special populations:

SPAF u2013 Patients with hepatic impairment: RUBAROX are contraindicated in patients with hepatic disease with or without coagulopathy (see section 4.3). Limited clinical data in patients with moderate hepatic impairment (Child Pugh B) indicate a significant increase in the pharmacological activity. No clinical data are available for patients with severe hepatic impairment (Child Pugh C) (see section 4.3 & section 5.2).

SPAF u2013 Patients with renal impairment: No dose adjustment is required if RUBAROX 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 RUBAROX 15 once daily. Limited clinical 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, RUBAROX 15 must be used with caution in these patients. Use of RUBAROX is not recommended in patients with creatinine clearance < 15 ml/min (see section 4.4 & section 5.2).

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

SPAF u2013 Converting from RUBAROX to warfarin: There is a potential for inadequate anticoagulation during the transition from RUBAROX to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that RUBAROX can contribute to an elevated INR. In patients converting from RUBAROX 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 RUBAROX and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of RUBAROX). Once RUBAROX is discontinued INR testing may be done reliably 24 hours after the last dose (see section 4.5).

SPAF u2013 Converting from parenteral anticoagulants to RUBAROX: For patients currently receiving a parenteral anticoagulant, start RUBAROX, 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 RUBAROX to parenteral anticoagulants: Discontinue RUBAROX and give the first dose of parenteral anticoagulant at the time that the next RUBAROX dose would have been taken.

SPAF u2013 Children and adolescents (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 RUBAROX 15 tablet twice daily for the first three weeks followed by one RUBAROX 20 tablet once daily for the continued treatment and the prevention of recurrent DVT and PE. RUBAROX 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 RUBAROX 15 twice daily treatment phase the patient should take RUBAROX 15 immediately to ensure intake of 30 mg per day. In this case two RUBAROX 15 tablets may be taken at once. The patient should continue with the regular one RUBAROX 15 twice daily intake as recommended on the following day. If a dose is missed during the RUBAROX 20 once daily treatment phase the patient should take RUBAROX 20 immediately to ensure intake of 20 mg per day. The patient should continue with the regular one RUBAROX 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 on special populations:

DVT and PE treatment u2013 Patients with hepatic impairment: RUBAROX is contraindicated in patients with hepatic disease with or without coagulopathy (see section 4.3). Limited clinical data in patients with moderate hepatic impairment (Child Pugh B) indicate a significant increase in the pharmacological activity. No clinical 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 RUBAROX 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 clinical 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, RUBAROX must be used with caution in these patients. Use of RUBAROX is not recommended in patients with creatinine clearance < 15 ml/min (see section 4.4 and section 5.2).

DVT and PE treatment u2013 Converting from warfarin to RUBAROX 15: Warfarin treatment should be stopped and RUBAROX 15 therapy should be initiated once the INR is u2264 2,5. When converting patients from warfarin to RUBAROX 15, INR values will be falsely elevated after the intake of RUBAROX 15. The INR is not valid to measure the anticoagulant activity of RUBAROX 15, and therefore should not be used (see section 4.5).

DVT and PE treatment u2013 Converting from RUBAROX to warfarin: There is a potential for inadequate anticoagulation during the transition from RUBAROX to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that RUBAROX can contribute to an elevated INR. In patients converting from RUBAROX 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 RUBAROX and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of RUBAROX). Once RUBAROX is discontinued INR testing may be done reliably 24 hours after the last dose (see section 4.5).

DVT and PE treatment u2013 Converting from parenteral anticoagulants to RUBAROX 15: For patients currently receiving a parenteral anticoagulant, start RUBAROX 15, 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).

DVT and PE treatment u2013 Converting from RUBAROX to parenteral anticoagulants: Discontinue RUBAROX and give the first dose of parenteral anticoagulant at the time that the next RUBAROX dose would have been taken.

DVT and PE treatment u2013 Children and adolescents (from birth to 18 years): Safety and efficacy have not been established in children and adolescents below 18 years.

DVT and PE treatment u2013 Body weight: No dose adjustment is required based on body weight (see section 5.2).

Method of administration: Oral use. RUBAROX tablets should be taken with food.

RUBAROX are contra-indicated in patients with:

• Hypersensitivity to rivaroxaban or any excipient listed in section 6.1.
• Clinically significant active bleeding (e.g. intracranial bleeding, gastrointestinal bleeding).
• Known existing inherited bleeding disorders.
• Hepatic disease with or without coagulopathy.
• Patients with persistent triple positive antiphospholipid syndrome (APS)
• Pregnancy and breastfeeding (see section 4.6).

Patients with prosthetic valves: Safety and efficacy of RUBAROX have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that RUBAROX 20 (RUBAROX 15 in patients with moderate or severe renal impairment) provides adequate anti-coagulation in this patient population.

Patients with antiphospholipid syndrome (APS) Treatment of patients with established APS is not recommended as evidence regarding safety and efficacy, including the benefit/harm balance of rivaroxaban (and direct acting oral anticoagulants (DOACs) with the same mechanism of action) in APS patients, is inconclusive. There is some evidence that treatment of persistently triple positive APS patients with rivaroxaban is associated with an increased risk of recurrent arterial thrombotic events compared with treatment of these patients with warfarin; a vitamin K antagonist (see section 4.3).

Bleeding risk: RUBAROX should be used with caution in patients with an increased bleeding risk such as:

• Congenital or acquired bleeding disorders
• Uncontrolled severe arterial hypertension
• Active ulcerative gastrointestinal disease
• Recent gastrointestinal ulcerations
• Vascular retinopathy
• Recent intracranial or intracerebral haemorrhage
• Intraspinal or intracerebral vascular abnormalities
• Shortly after brain, spinal or ophthalmological surgery
• Bronchiectasis or history of pulmonary bleeding.

Care should be taken if patients are treated concomitantly with medicines affecting haemostasis such as non-steroidal anti-inflammatory medicines (NSAIDs), platelet aggregation inhibitors, or other antithrombotics (see section 4.5). For patients at risk of ulcerative gastrointestinal disease an appropriate prophylactic treatment may be considered (see section 4.5). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.

Surgery and interventions: If an invasive procedure or surgical intervention is required, RUBAROX should be stopped at least 24 hours before the intervention, if possible and based on clinical judgement of the medical practitioner. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. RUBAROX 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 (see section 5.2).

Neuraxial (epidural/spinal) anaesthesia: When neuraxial (epidural/spinal) anaesthesia or spinal puncture is performed patients treated with antithrombotics for prevention of thromboembolic complications are at risk for development of an epidural or spinal haematoma, which may result in long-term paralysis. The risk of these events is further increased by 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 punctures.

Patients should be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological deficits are noted, urgent diagnosis and treatment is necessary. The medical practitioner should consider the potential benefit versus the risk before neuraxial intervention in patients who are anticoagulated or considered to be anticoagulated for thromboprophylaxis. An epidural catheter should not be withdrawn earlier than 18 hours after the last administration of RUBAROX. RUBAROX should be administered not before 6 hours after the removal of the catheter. If a traumatic puncture occurs, the administration of RUBAROX should be delayed for 24 hours.

DVT and PE treatment u2013 Renal impairment: RUBAROX is to be used with caution in patients with moderate renal impairment (creatinine clearance < 50 to 30 ml/min) receiving co-medications leading to increased rivaroxaban plasma concentrations (see section 4.5).

SPAF, DVT and PE treatment u2013 Renal impairment: In patients with severe renal impairment (creatinine clearance < 30 ml/min) rivaroxaban plasma levels may be significantly elevated (1,6-fold on average) which may lead to an increased bleeding risk. Due to the underlying disease these patients are at an increased risk of both bleeding and thrombosis. Due to limited clinical data RUBAROX should be used with caution in patients with creatinine clearance < 30 to 15 ml/min. No clinical data are available for patients with severe renal impairment (creatinine clearance < 15 ml/min). Therefore, the use of RUBAROX is not recommended in these patients (see section 4.2; section 5.1 & 5.2). Patients with severe renal impairment or increased bleeding risk and patients receiving concomitant systemic treatment with azole-antimycotics or HIV protease inhibitors are to be carefully monitored for signs of bleeding complications after initiation of treatment.

Pharmacodynamic interactions

After combined administration of enoxaparin (40 mg single dose) with rivaroxaban 10 mg (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 (see section 4.4).

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 times was observed in a subset of patients which was not correlated to platelet aggregation, P-selectin or GPIIb/IIIa receptor levels (see section 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 more pronounced pharmacodynamic response (see section 4.4).

Converting patients from 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 (Neoplastinu00ae) 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 15 mg or 20 mg during the conversion period, anti-Factor Xa activity, prothrombinase-induced clotting time (PiCT), and HepTestu00ae can be used as these tests were not affected by warfarin. From day 4 after stopping warfarin, all tests (including PT, aPTT, inhibition of factor Xa activity and ETP) reflected only the effect of rivaroxaban 15 mg or 20 mg (see section 4.2). 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.

Pharmacokinetic interactions: Rivaroxaban is cleared mainly via cytochrome P450-mediated (CYP 3A4, CYP 2J2) hepatic metabolism and renal excretion of the unchanged drug, involving the P-glycoprotein (P-gp)/breast cancer resistance protein (Bcrp) transporter systems (see section 5.2).

CYP inhibition: Rivaroxaban does not inhibit CYP 3A4 or any other major CYP isoforms.

CYP induction: Rivaroxaban does not induce CYP 3A4 or any other major CYP isoforms.

Effects on RUBAROX: The concomitant use of rivaroxaban 10 mg or 20 mg with strong CYP 3A4 and P-gp inhibitors, may lead to both reduced hepatic and renal clearance and thus significantly increased systemic exposure. Co-administration of rivaroxaban with the azole-antimycotic ketoconazole (400 mg once daily) a strong CYP 3A4 and P-gp inhibitor, led to a 2,6-fold increase in mean rivaroxaban steady state AUC and a 1,7-fold increase in mean rivaroxaban C max, with significant increases in its pharmacodynamic effects (see section 4.4). Co-administration of rivaroxaban with the HIV protease inhibitor ritonavir (600 mg twice daily), a strong CYP 3A4 and P-gp inhibitor, led to a 2,5-fold increase in mean rivaroxaban AUC and a 1,6-fold increase in mean rivaroxaban C max, with significant increases in its pharmacodynamic effects. Data on the co-administration of rivaroxaban with the HIV protease inhibitor ritonavir (100 mg twice daily) is not available. Therefore, RUBAROX are not recommended in patients receiving concomitant systemic treatment with azole-antimycotics or HIV-protease inhibitors (see section 4.4). Other active substances strongly inhibiting only one of the rivaroxaban elimination pathways, either CYP 3A4 or P-gp, are expected to increase rivaroxaban plasma concentrations to a lesser extent. Clarithromycin (500 mg twice daily), considered a strong CYP 3A4 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. This increase, which is close to the magnitude of the normal variability of AUC and C max, is considered as clinically not relevant. Erythromycin (500 mg three times daily), which inhibits CYP 3A4 and P-gp moderately, led to a 1,3-fold increase in mean rivaroxaban AUC and C max. This increase is within the magnitude of the normal variability of AUC and C max and is considered as clinically not relevant. Fluconazole (400 mg once daily), considered a moderate CYP 3A4 inhibitor, led to a 1,4-fold increase in mean rivaroxaban AUC and a 1,3-fold increase in mean C max. This increase is within the magnitude of the normal variability of AUC and C max and is considered as clinically not relevant. Co-administration of rivaroxaban with the strong CYP 3A4 and P-gp inducer rifampicin led to an approximate 50 % decrease in mean rivaroxaban AUC, with parallel decreases in its pharmacodynamic effects (see section 5.2). The concomitant use of rivaroxaban 15 mg or 20 mg with other strong CYP 3A4 inducers (e.g. phenytoin, carbamazepine, phenobarbitone or St. Johnu2019s Wort) may also lead to a decreased rivaroxaban plasma concentration. Strong CYP 3A4 inducers should be co-administered with caution. Interactions shown not to exist: There were no mutual pharmacokinetic interactions between rivaroxaban and midazolam (substrate of CYP 3A4), digoxin (substrate of P-glycoprotein) or atorvastatin (substrate of CYP 3A4 and P-gp). Co-administration of the proton pump inhibitor omeprazole, the H2 receptor antagonist ranitidine, the antacid aluminium hydroxide/magnesium hydroxide, naproxen, clopidogrel or enoxaparin did not affect rivaroxaban bioavailability and pharmacokinetics.

Women of childbearing potential: RUBAROX should be used in women of childbearing potential only with effective contraception.

Pregnancy: Safety and efficacy of RUBAROX have not been established in pregnant women. Due to the intrinsic risk of bleeding and the evidence that rivaroxaban passes the placenta, RUBAROX is contra-indicated in pregnancy (see section 4.3).

Breastfeeding: Safety and efficacy of RUBAROX have not been established in nursing mothers. In rats rivaroxaban is secreted into breast milk. Therefore, RUBAROX may only be administered after breastfeeding is discontinued (see section 4.3).

Fertility: No specific studies with rivaroxaban in humans have been conducted to evaluate effects on fertility.

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

Due to the pharmacological mode of action, RUBAROX may be associated with an increased risk of occult or overt bleeding from any tissue and organ which may result in post haemorrhagic anaemia. The risk of bleedings may be increased in certain patient groups e.g. patients with uncontrolled severe arterial hypertension, impaired renal and hepatic function and/or on concomitant medication affecting haemostasis (see section 4.4). 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).

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 rivaroxaban. Therefore, the possibility of a haemorrhage should be considered in evaluating the condition in any anticoagulated patient.

Adverse reactions classified by system organ class and MedDRA are presented in the table below (Table 1).

Table 1: Tabulated list of adverse reactions (MedDRA) from reported placebo-controlled studies and from post-marketing experience

System organ class Frequent Less frequent Frequency unknown Blood and the lymphatic system disorders Anaemia (incl. respective laboratory parameters) Thrombocythaemia (incl. platelet count increased) Cardiac disorders Tachycardia Eye disorders Eye haemorrhage (incl. conjunctival haemorrhage) Gastrointestinal disorders Gingival bleeding Gastrointestinal tract haemorrhage (incl. rectal haemorrhage) Gastrointestinal and abdominal pains Dyspepsia (incl. epigastric discomfort) Nausea Constipation A Diarrhoea Vomiting A Dry mouth General disorders and administration site conditions Fever A Peripheral oedema Decreased general strength and energy (incl. fatigue and asthenia) Feeling unwell (incl. malaise) Localised oedema A Hepato-biliary disorders Abnormal hepatic function Jaundice Cholestasis, Hepatitis (incl. hepatocellular injury) Immune system disorders Allergic reaction Allergic dermatitis Angioedema and allergic oedema, Anaphylactic reactions including anaphylactic shock Injury, poisoning and post-procedural complications Post-procedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage) Contusion Wound secretion A Vascular pseudoaneurysm C Investigations Increase in transaminases Increase in bilirubin Increase in blood alkaline phosphatase A Increase in LDH A Increase in lipase A Increase in amylase A Increase in GGT A Increase in conjugated bilirubin (with or without concomitant increase of ALT) Musculoskeletal, connective tissue and bone disorders Pain in extremity A Haemarthrosis Muscle haemorrhage Compartment syndrome secondary to a bleeding and connective tissue disorders) Nervous system Dizziness Cerebral and intracranial disorders Headache haemorrhage Syncope Renal and urinary disorders Urogenital tract haemorrhage (incl. haematuria and menorrhagia B ) Renal impairment (incl. blood creatinine increased, blood urea increased) A Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion Respiratory tract thoracic and mediastinal disorders Epistaxis Haemoptysis 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 Vascular disorders Hypotension Haematoma A observed after major orthopaedic surgery of the lower limbs B observed in VTE treatment as very frequent in women < 55 years C observed as less frequent in prevention therapy in ACS (following percutaneous intervention)

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. 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 reversal medicine, 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.