Rivaroxaban 15 Mg/20 Mg Film-Coated Tablets

RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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

Coagulation parameters do not need to be monitored during treatment with RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR.

SPAF u2013 Recommended usual dose and frequency of administration:

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

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 RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR 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 RIVAROXABAN 20 mg SHANUR tablet (20 mg rivaroxaban).

SPAF u2013 Additional information on special populations:

SPAF u2013 Patients with hepatic impairment:

RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR are contraindicated in patients with hepatic disease with or without coagulopathy (see section 4.3). The limited data available in patients with moderate hepatic impairment (Child Pugh B) indicates 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 5.2).

SPAF u2013 Patients with renal impairment:

No dose adjustment is required if RIVAROXABAN 20 mg SHANUR 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 RIVAROXABAN 15 mg SHANUR once daily. The limited data available for patients with severe renal impairment (creatinine clearance < 30 to 15 mL/min) indicates that rivaroxaban plasma levels are significantly increased in this patient population. Therefore, RIVAROXABAN 15 mg SHANUR should be used with caution in these patients. Use of RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR is not recommended in patients with creatinine clearance < 15 mL/min (see section 4.4).

SPAF u2013 Converting from warfarin to RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR:

Warfarin treatment should be stopped, and RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR therapy should be initiated when the INR is u2264 3.0. When converting patients from warfarin to RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR, INR values will be falsely elevated after the intake of RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR. The INR is not valid to measure the anticoagulant activity of RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR, it should therefore not be used (see section 4.5).

SPAF u2013 Converting from RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR to warfarin:

There is a potential for inadequate anticoagulation during the transition from RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR can contribute to an elevated INR. In patients converting from RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR 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 RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR. Once RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR is discontinued INR testing may be done reliably 24 hours after the last dose.

SPAF - Converting from parenteral anticoagulants to RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR:

For patients currently receiving a parenteral anticoagulant, RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR should be started 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 RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR to parenteral anticoagulants:

Discontinue RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR and give the first dose of parenteral anticoagulant at the time that the next RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR 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 - Body weight:

No dose adjustment is required based on body weight.

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 RIVAROXABAN 15 mg SHANUR tablet twice daily for the first three weeks followed by one RIVAROXABAN 20 mg SHANUR tablet once daily for the continued treatment and the prevention of recurrent DVT and PE.

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 RIVAROXABAN 15 mg SHANUR twice daily treatment phase the patient should take RIVAROXABAN 15 mg SHANUR immediately to ensure an intake of 30 mg per day. In this case, two RIVAROXABAN 15 mg SHANUR may be taken at once. On the next day, the patient should continue with the regular one RIVAROXABAN 15 mg SHANUR twice daily intake as recommended. If a dose is missed during the RIVAROXABAN 20 mg SHANUR once daily treatment phase the patient should take RIVAROXABAN 20 mg SHANUR immediately to ensure intake of 20 mg per day. The patient should continue with the regular one RIVAROXABAN 20 mg SHANUR 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:

RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR are contraindicated in patients with hepatic disease with or without coagulopathy (see section 4.3). The limited data available in patients with moderate hepatic impairment (Child Pugh B) indicates 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).

DVT and PE treatment u2013 patients with renal impairment:

No dose adjustment is required if RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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 RIVAROXABAN 15 mg SHANUR once daily. The limited data available for patients with severe renal impairment (creatinine clearance < 30 to 15 mL/min) indicates that rivaroxaban plasma levels are significantly increased in this patient population. Therefore, RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR should be used with caution in these patients. Use of RIVAROXABAN 15 mg SHANUR or RIVAROXABAN 20 mg SHANUR is not recommended in patients with creatinine clearance < 15 mL/min (see section 4.4).

• Hypersensitivity to rivaroxaban 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).
• 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).
• Patients with persistent triple positive antiphospholipid syndrome (APS).

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

Haemorrhagic risk

Patients taking RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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 SHANUR administration should be discontinued if severe haemorrhage occurs. 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 Vitamin K antagonist (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). 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 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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 section 4.2 and 5.2).

The use of RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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 drugs (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
• recent intracranial or intracerebral haemorrhage
• shortly after brain spinal or ophthalmological surgery.

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 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that RIVAROXABAN SHANUR provides adequate anticoagulation in this patient population. Treatment with RIVAROXABAN SHANUR is not recommended for these patients.

Patients with antiphospholipid syndrome

Direct acting Oral Anticoagulants (DOACs) including RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome (APS). 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. Treatment of patients with established APS is not recommended (see section 4.3).

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

Clinical data are available from an interventional study with the primary objective to assess safety 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). No data are available for such patients with a history of stroke/TIA.

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy.

RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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 RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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 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 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 RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR in these situations.

To reduce the potential risk of bleeding associated with the concurrent use of RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR and neuraxial (epidural/spinal) anaesthesia or spinal puncture, consider the pharmacokinetic profile of RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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 at least 18 hours should elapse after the last administration of RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR (see section 5.2). Following removal of the catheter, at least 6 hours should elapse before the next RIVAROXABAN SHANUR dose is administered. If traumatic puncture occurs the administration of RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR is to be delayed for 24 hours.

Dosing recommendations before and after invasive procedures and surgical intervention.

If an invasive procedure or surgical intervention is required, RIVAROXABAN 20 mg SHANUR should be stopped at least 24 hours before the intervention, if possible. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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 medical practitioner (see section 5.2).

Elderly population

Increasing age may increase haemorrhagic risk (see section 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 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR (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 SHANUR 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.

Pregnancy

Safety and efficacy of RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR have not been established in pregnant women. Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that RIVAROXABAN SHANUR passes the placenta, RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR is contraindicated during pregnancy (see section 4.3). Women of child bearing potential should avoid becoming pregnant during treatment with RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR.

Breastfeeding

Safety and efficacy of RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR have not been established in breast-feeding women. RIVAROXABAN SHANUR is contraindicated during breastfeeding.

Fertility

No specific studies with RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR in humans have been conducted to evaluate effects on fertility.

RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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.

The frequencies of adverse reactions reported with RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR are summarised in Table 1 below by system organ class (in MedDRA) and by frequency.

Table 1: Tabulated list of adverse reactions

System Organ Class Adverse reactions Frequency

Blood and lymphatic system disorders Anaemia (incl. Respective laboratory parameters) Frequent

Thrombocytosis (incl. platelet count increase), thrombocytopenia Less frequent

Immune system disorder Allergic reaction, dermatitis allergic, angioedema, allergic oedema, anaphylactic reactions including anaphylactic shock Less frequent

Nervous system disorders Dizziness, headache Frequent

Cerebral and intracranial haemorrhage, syncope Less frequent

Eye disorders Eye haemorrhage (incl. conjunctival haemorrhage) Frequent

Cardiac disorders Tachycardia Less frequent

Vascular disorders Hypotension, haematoma Frequent

Respiratory, thoracic and mediastinal disorders Epistaxis, haemoptysis Frequent

Gastrointestinal disorders Gingival bleeding, gastrointestinal tract haemorrhage (incl. rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting Frequent

Dry mouth Less frequent

Hepatobiliary disorders Increase in transaminases Frequent

Hepatic impairment, increased bilirubin, increased blood alkaline phosphatase, jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl. hepatocellular injury) Less frequent

Skin and subcutaneous tissues disorders Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage syndrome Frequent

Urticaria, Stevens-Johnson syndrome/ Toxic Epidermal Necrolysis, DRESS Less frequent

Musculoskeletal and connective tissue disorders Pain in extremity Frequent

Haemarthrosis, muscle haemorrhage Less frequent

Compartment syndrome secondary to a bleeding Unknown

Renal and urinary disorders Urogenital tract haemorrhage (incl. haematuria and menorrhagia), renal impairment (incl. increased blood creatinine, increased blood urea) Frequent

Renal failure/acute renal failure secondary to a bleeding sufficient to cause hypoperfusion Unknown

General disorders and administration site conditions Fever, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia) Frequent

Feeling unwell (incl. malaise), localised oedema Less frequent

Investigations Increased LDH, increased lipase, increased amylase Less frequent

Injury, poisoning and procedural complications Postprocedural haemorrhage (incl. postoperative anaemia, and wound haemorrhage), contusion, wound secretion Frequent

Vascular pseudoaneurysm Less frequent

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 frequent in women < 55 years

C: observed as less frequent 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. As incidence of adverse reactions did not increase and no new adverse reaction was identified, COMPASS study data were not included for frequency calculation in this table.

c. Description of selected adverse reactions

Due to the pharmacological mode of action, the use of RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR 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 u201cManagement of bleedingu201d). 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 u201cHaemorrhagic risku201d). 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 RIVAROXABAN 15 mg SHANUR and RIVAROXABAN 20 mg SHANUR. 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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8. Suspected adverse reactions can also be reported directly to the HCR via [email protected].

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

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 agent should be considered, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate (APCC) or recombinant factor VIIa (r-FVIIa). However, there is currently very limited clinical experience with the use of these 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.