Xaviat 15mg & 20mg Tablet

XAVIAT 15 mg and XAVIAT 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

There is no need for monitoring of coagulation parameters during treatment with XAVIAT 15 mg and XAVIAT 20 mg.

SPAF - Recommended usual dose and frequency of administration:

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

SPAF - Duration of treatment:

Therapy should be continued as long as risk factors for stroke and systemic embolism persist.

SPAF - Missed dose:

If a dose is missed the patient should take XAVIAT 15 mg or RIVAROXABAN 20 mg 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 - Maximum daily dose:

The recommended maximum daily dose is one XAVIAT 20 mg tablet (20 mg rivaroxaban).

SPAF - Additional information on special populations:

SPAF - Patients with hepatic impairment:

XAVIAT 15 mg and XAVIAT 20 mg 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 sections 4.3 and 5.2).

SPAF - Patients with renal impairment:

No dose adjustment is required if XAVIAT 20 mg 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 XAVIAT 15 mg 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 XAVIAT 15 mg must be used with caution in these patients. Use of XAVIAT 15 mg or XAVIAT 20 mg is not recommended in patients with creatinine clearance < 15 mL/min (see sections 4.4 and 5.2).

SPAF - Converting from warfarin to XAVIAT 15 mg or XAVIAT 20 mg:

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

SPAF - Converting from XAVIAT 15 mg or XAVIAT 20 mg to warfarin:

There is a potential for inadequate anticoagulation during the transition from XAVIAT 15 mg or XAVIAT 20 mg to warfarin. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that XAVIAT 15 mg and XAVIAT 20 mg can contribute to an elevated INR. In patients converting from XAVIAT 15 mg or XAVIAT 20 mg 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 XAVIAT 15 mg or XAVIAT 20 mg and warfarin, the INR should not be tested earlier than 24 hours (after the previous dose but prior to the next dose of XAVIAT 15 mg or XAVIAT 20 mg). Once XAVIAT 15 mg or XAVIAT 20 mg is discontinued INR testing may be done reliably 24 hours after the last dose (see section 4.5).

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

For patients currently receiving a parenteral anticoagulant, start XAVIAT 15 mg or XAVIAT 20 mg, 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 - Converting from XAVIAT 15 mg or XAVIAT 20 mg to parenteral anticoagulants:

Discontinue XAVIAT 15 mg or XAVIAT 20 mg and give the first dose of parenteral anticoagulant at the time that the next XAVIAT 15 mg or XAVIAT 20 mg dose would have been taken.

SPAF - 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 (see section 5.2).

DVT and PE treatment - Recommended usual dose and frequency of administration:

The recommended dose for the initial treatment of acute DVT and PE is one XAVIAT 15 mg tablet twice daily for the first three weeks followed by one XAVIAT 20 mg tablet once daily for the continued treatment and the prevention of recurrent DVT and PE.

DVT and PE treatment - Duration of treatment:

Therapy should be continued as long as the VTE risk persists.

DVT and PE treatment - Missed dose:

It is essential to adhere to the dosage schedule provided. If a dose is missed during the XAVIAT 15 mg twice daily treatment phase the patient should take XAVIAT 15 mg immediately to ensure intake of 30 mg per day. In this case two XAVIAT 15 mg tablets may be taken at once. The patient should continue with the regular one XAVIAT 15 mg twice daily intake as recommended on the following day. If a dose is missed during the XAVIAT 20 mg once daily treatment phase the patient should take XAVIAT 20 mg immediately to ensure intake of 20 mg per day. The patient should continue with the regular one XAVIAT 20 mg once daily intake as recommended on the following day.

DVT and PE treatment - 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 - Additional information on special populations:

DVT and PE treatment - Patients with hepatic impairment:

XAVIAT 15 mg and XAVIAT 20 mg 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 sections 4.3 and 5.2).

DVT and PE treatment - Patients with renal impairment:

No dose adjustment is required if XAVIAT 15 mg and XAVIAT 20 mg 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 XAVIAT 15 mg and XAVIAT 20 mg must be used with caution in these patients. Use of XAVIAT 15 mg and XAVIAT 20 mg are not recommended in patients with creatinine clearance < 15 mL/min (see sections 4.4 and 5.2).

DVT and PE treatment - Converting from warfarin to XAVIAT 15 mg:

Warfarin treatment should be stopped and XAVIAT 15 mg therapy should be initiated once the INR is u2264 2.5. When converting patients from warfarin to XAVIAT 15 mg, INR values will be falsely elevated after the intake of XAVIAT 15 mg. The INR is not valid to measure the anticoagulant activity of XAVIAT 15 mg, and therefore should not be used (see section 4.5).

• Hypersensitivity to rivaroxaban or to any of the excipients of XAVIAT (see section 6.1).
• Active clinically significant bleeding (e.g. intracranial bleeding, gastrointestinal 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 lactation (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 XAVIAT must be carefully observed for signs of bleeding. It is recommended to be used with caution in conditions with increased risk of haemorrhage. XAVIAT administration should be discontinued if severe haemorrhage occurs (see section 4.9).

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 XAVIAT 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 XAVIAT 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. XAVIAT is to be used with caution in patients with creatinine clearance 15 - 29 mL/min. Use is not recommended in patients with creatinine clearance < 15 mL/min (see sections 4.2 and 5.2). XAVIAT should be used with caution in patients with renal impairment concomitantly receiving other medicines which increase rivaroxaban plasma concentrations (see section 4.5).

Interaction with other medicines

The use of XAVIAT 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 nonsteroidal anti-inflammatory medicines (NSAIDs), acetylsalicylic acid 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

XAVIAT 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
• recent intracranial or intracerebral haemorrhage
• intraspinal or intracerebral vascular abnormalities
• shortly after brain, spinal or ophthalmological surgery
• bronchiectasis or history of pulmonary bleeding.

Patients with prosthetic valves

XAVIAT should not be used for thromboprophylaxis in patients having recently undergone transcatheter aortic valve replacement (TAVR). Safety and efficacy of XAVIAT have not been studied in patients with prosthetic heart valves; therefore, there are no data to support that XAVIAT provides adequate anticoagulation in this patient population. Treatment with XAVIAT is not recommended for these patients.

Patients with antiphospholipid syndrome (APS)

Direct acting Oral Anticoagulants (DOACs) including XAVIAT 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 (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 nonvalvular 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

XAVIAT 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 XAVIAT have not been established in these clinical situations.

Spinal/epidural anaesthesia or puncture

When neuraxial anaesthesia (spinal/epidural anaesthesia) or spinal/epidural puncture is performed, 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 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 20 mg rivaroxaban in these situations.

To reduce the potential risk of bleeding associated with the concurrent use of XAVIAT 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. 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 2x half-life, i.e. at least 18 hours in young patients and 26 hours in elderly patients should elapse after the last administration of XAVIAT (see section 5.2). Following removal of the catheter, at least 6 hours should elapse before the next XAVIAT dose is administered. If traumatic puncture occurs the administration of XAVIAT 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, XAVIAT 20 mg should be stopped at least 24 hours before the intervention. If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention. XAVIAT 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 (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. XAVIAT 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.

Excipients

XAVIAT contains lactose monohydrate which may have an effect on the glycaemic control of patients with diabetes mellitus. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take XAVIAT.

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 XAVIAT 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 XAVIAT 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) 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 XAVIAT.

Pregnancy

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

Breastfeeding

Safety and efficacy of XAVIAT have not been established in breastfeeding women. Data from animals indicate that rivaroxaban is secreted into milk. Therefore XAVIAT is contraindicated during breastfeeding (see section 4.3).

Fertility

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

XAVIAT 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.

a. Summary of the safety profile

The safety of rivaroxaban has been evaluated in four phase III studies including 6097 patients exposed to rivaroxaban 10 mg undergoing major orthopaedic surgery of the lower limbs (total hip replacement or total knee replacement) in 3997 hospitalised medically ill patients treated up to 39 days, and in three phase III VTE treatment trials with 4556 patients exposed either to rivaroxaban 15 mg twice daily for 3 weeks followed by rivaroxaban 20 mg once daily or to rivaroxaban 20 mg once daily treated up to 21 months. Furthermore, safety of rivaroxaban has also been evaluated in 7750 patients with non-valvular atrial fibrillation from two phase III trials with at least one dose of rivaroxaban 15 mg or rivaroxaban 20 mg. Due to the pharmacological mode of action, rivaroxaban 15 mg and rivaroxaban 20 mg 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 15 mg and rivaroxaban 20 mg. Therefore, the possibility of a haemorrhage should be considered in evaluating the condition in any anticoagulated patient.

b. Tabulated summary of adverse reactions

The frequencies of adverse reactions reported with XAVIAT are summarised in the table below by system organ class (in MedDRA) and by frequency.

MedDRA system organ class Frequency Adverse reactions

Blood and lymphatic system disorders Frequent Anaemia (incl. respective laboratory parameters) Less frequent Thrombocytosis (incl. platelet count increased), thrombocytopenia

Immune system disorders Less frequent Anaphylactic reactions including anaphylactic shock. Allergic reaction, dermatitis allergic, angioedema and allergic oedema

Nervous system disorders Frequent Dizziness, headache Less frequent Cerebral and intracranial haemorrhage, syncope

Eye disorders Frequent Eye haemorrhage (incl. conjunctival haemorrhage)

Cardiac disorders Less frequent Tachycardia

Vascular disorders Frequent Hypotension, haematoma

Respiratory, thoracic and mediastinal disorders Frequent Haemoptysis, epistaxis

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

Hepato-biliary disorders Frequent Increase in transaminases Less frequent Jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl. hepatocellular injury), abnormal hepatic function, hepatic impairment, increased bilirubin, increased blood alkaline phosphatase, increased GGT

Skin and subcutaneous tissue disorders Frequent Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage Less frequent Stevens-Johnson syndrome/toxic epidermal necrolysis, dress syndrome, urticaria

Musculoskeletal and connective tissue disorders Frequent Pain in extremity Less frequent Muscle haemorrhage, haemarthrosis

Frequency Unknown Compartment syndrome secondary to a bleeding

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

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

General disorders and administration site conditions Frequent Fever, peripheral oedema, decreased general strength and energy (incl. fatigue and asthenia) Less frequent Localised oedema. Feeling unwell (incl. malaise)

Investigations Less frequent Increased LDHA, increased lipase, increased amylase

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

Less frequent Vascular pseudoaneurysm

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

* A pre-specified selective approach to adverse event collection was applied. 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 XAVIAT 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, 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). 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 XAVIAT. 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 supratherapeutic doses of 50 mg XAVIAT or above. A specific antidote antagonising the pharmacodynamic effect of XAVIAT not available. Due to the high plasma protein binding rivaroxaban is not expected to be dialysable.

The use of activated charcoal to reduce absorption in case of XAVIAT overdose may be considered.

Management of bleeding

Should a bleeding complication arise in a patient receiving XAVIAT, the next XAVIAT 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 medicine (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 medicines in individuals receiving rivaroxaban. Protamine sulphate and vitamin K are not expected to affect the anticoagulant activity of XAVIAT. There is limited experience with tranexamic acid and no experience with aminocaproic acid and aprotinin in individuals receiving XAVIAT. There is neither scientific rationale for benefit nor experience with the use of the systemic haemostatic desmopressin in individuals receiving XAVIAT. Due to the high plasma protein binding XAVIAT is not expected to be dialysable.