RIVAROXABAN

Posology Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE in adults The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE.

e. recent major surgery or trauma). Longer duration of therapy should be considered in patients with provoked DVT or PE not related to major transient risk factors, unprovoked DVT or PE, or a history of recurrent DVT or PE. When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily.

In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who have developed recurrent DVT or PE on extended prevention with Rivaroxaban 10 mg once daily, a dose of Rivaroxaban 20 once daily should be considered.

4). 5). For patients with moderate or severe renal impairment where the decision has been taken for 15 mg once daily from Day 22 onwards, other pack sizes only containing 15 mg film-coated tablets are available (see dosing instructions in section “Special populations” below).

If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take Rivaroxaban immediately to ensure intake of 30 mg Rivaroxaban per day. In this case two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.

If a dose is missed during the once daily treatment phase, the patient should take Rivaroxaban immediately, and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.

5. When converting patients from VKAs to Rivaroxaban, INR values will be falsely elevated after the intake of Rivaroxaban. 5). Converting from Rivaroxaban to Vitamin K antagonists (VKA) There is a potential for inadequate anticoagulation during the transition from Rivaroxaban to VKA.

Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Rivaroxaban can contribute to an elevated INR. 0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing, as guided by INR testing.

While patients are on both Rivaroxaban and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Rivaroxaban. 2). g. g. intravenous unfractionated heparin). Converting from Rivaroxaban to parenteral anticoagulants Give the first dose of parenteral anticoagulant at the time the next Rivaroxaban dose would be taken.

Special populations Renal impairment Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Rivaroxaban is to be used with caution in these patients.

2). In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 15- 29 ml/min) renal impairment the following dose recommendations apply: - For the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE: patients should be treated with 15 mg twice daily for the first 3 weeks.

Thereafter, when the recommended dose is 20 mg once daily, a reduction of the dose from 20 mg once daily to 15 mg once daily should be considered if the patient’s assessed risk for bleeding outweighs the risk for recurrent DVT and PE.

2). When the recommended dose is 10 mg once daily, no dose adjustment from the recommended dose is necessary. No dose adjustment is necessary in patients with mild renal impairment […]

Summary of the safety profile The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1). Overall, 69,608 adult patients in nineteen phase III studies and 488 paediatric patients in two phase II and two phase III studies were exposed to rivaroxaban.

Table 1:

Number of patients studied, total daily dose and maximum treatment duration in adult and paediatric phase III studies Indication Number of patients* Total daily dose Maximum treatment duration Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery 6,097 10 mg 39 days Prevention of VTE in medically ill patients 3,997 10 mg 39 days Treatment of deep vein Thrombosis (DVT), pulmonary Embolism (PE) and prevention of recurrence 6,790 Day 1 - 21: 30 mg Day 22 and onwards: 20 mg After at least 6 months: 10 mg or 20 mg 21 months Treatment of VTE and prevention of VTE recurrence in term neonates and children aged less than 18 years following initiation of standard anticoagulation treatment 329 Body weight-adjusted dose to achieve a similar exposure as that observed in adultstreated for DVT with 20 mg rivaroxaban once daily 12 months Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation 7,750 20 mg 41 months Prevention of atherothrombotic events in patients after an acute coronary syndrome (ACS) 10,225 5 mg or 10 mg respectively, co- administered with either ASA or ASA plus clopidogrel or 31 months ticlopidine 18,244 5 mg co-administered with ASA or 10 mg alone 47 monthsPrevention of atherothrombotic events in patients with CAD/PAD 3,256* * 5 mg co-administered with ASA 42 months * Patients exposed to at least one dose of rivaroxaban.

4. and ‘Description of selected adverse reactions’ below) (Table 2). 8 %). 74 per 100 patient years*** # * For all rivaroxaban studies all bleeding events are collected, reported and adjudicated. ** In the COMPASS study, there is a low anaemia incidence as a selective approach to adverse event collection was applied *** A selective approach to adverse event collection was applied # From the VOYAGER PAD study Tabulated list of adverse reactions The frequencies of adverse reactions reported with Rivaroxaban in adult and paediatric patients are summarised in Table 3 below by system organ class (in MedDRA) and by frequency.

Frequencies are defined as: very common (≥ 1/10) common (≥ 1/100 to < 1/10) uncommon (≥ 1/1,000 to < 1/100) rare (≥ 1/10,000 to < 1/1,000) very rare (< 1/10,000) not known (cannot be estimated from the available data) Table 3: All adverse reactions reported in adult patients in phase III clinical studies or through post-marketing use* and in two phase II and two phase III studies in paediatric patients Common Uncommon Rare Very rare Not known Blood and lymphatic system disorders Anaemia (incl.

respective laboratory parameters) Thrombocytosis (incl. platelet countincreased)A, thrombocytopenia Immune system disorders Allergic reaction, dermatitis allergic,angioedema and allergic oedema Anaphylactic reactions including anaphylactic shock Nervous system disorders Dizziness, headache Cerebral and intracranial haemorrhage, syncope Eye disorders Eye haemorrhage (incl.

conjunctival haemorrhage) Cardiac disorders Tachycardia Vascular disorders Hypotension, haematoma Respiratory, thoracic and mediastinal disorders Common Uncommon Rare Very rare Not known Epistaxis, haemoptysis Eosinophilic pneumonia Gastrointestinal disorders Gingival bleeding, gastrointestinal tract haemorrhage (incl.

rectal haemorrhage), gastrointestinal and abdominal pains, dyspepsia, nausea, constipationA, diarrhoea, vomitingA Dry mouth Hepatobiliary disorders Increase in transaminases Hepatic impairment, increased bilirubin,increased blood alkaline phosphataseA, increased GGTA Jaundice, bilirubin conjugated increased (with or without concomitant increase of ALT), cholestasis, hepatitis (incl.

hepatocellular injury) Skin and subcutaneous tissue disorders Pruritus (incl. uncommon cases of generalised pruritus), rash, ecchymosis, cutaneous and subcutaneous haemorrhage Urticaria Stevens-Johnson syndrome/ Toxic Epidermal Necrolysis, DRESS syndrome Musculoskeletal and connective tissue disorders Pain in extremityA Haemarthrosis Muscle haemorrhage Compartment syndrome secondary to a bleeding Renal and urinary disorders Urogenital tract haemorrhage (incl.

haematuria and menorrhagiaB), renal impairment (incl. blood creatinine increased, blood urea increased) Renal failure/acute renal failure secondary to a bleeding sufficient to cause Hypoperfusion Anticoaglant related nephropathy General disorders and administration site conditions […]

4. 4. 1. 3 PHARMACEUTICAL FORM Film-coated tablet (tablet) 15 mg film-coated tablet-Light red colour circular, biconvex film coated tablets debossed with J 9" on one side and plain on the other side. 1 Therapeutic indications Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults.

2 Posology and method of administration Posology Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE in adults The recommended dose for the initial treatment of acute DVT or PE is 15 mg twice daily for the first three weeks followed by 20 mg once daily for the continued treatment and prevention of recurrent DVT and PE.

e. recent major surgery or trauma). Longer duration of therapy should be considered in patients with provoked DVT or PE not related to major transient risk factors, unprovoked DVT or PE, or a history of recurrent DVT or PE. When extended prevention of recurrent DVT and PE is indicated (following completion of at least 6 months therapy for DVT or PE), the recommended dose is 10 mg once daily.

In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated comorbidities, or who have developed recurrent DVT or PE on extended prevention with Rivaroxaban 10 mg once daily, a dose of Rivaroxaban 20 once daily should be considered.

4). 5). For patients with moderate or severe renal impairment where the decision has been taken for 15 mg once daily from Day 22 onwards, other pack sizes only containing 15 mg film-coated tablets are available (see dosing instructions in section “Special populations” below).

If a dose is missed during the 15 mg twice daily treatment phase (day 1 - 21), the patient should take Rivaroxaban immediately to ensure intake of 30 mg Rivaroxaban per day. In this case two 15 mg tablets may be taken at once. The patient should continue with the regular 15 mg twice daily intake as recommended on the following day.

If a dose is missed during the once daily treatment phase, the patient should take Rivaroxaban immediately, and continue on the following day with the once daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.

5. When converting patients from VKAs to Rivaroxaban, INR values will be falsely elevated after the intake of Rivaroxaban. 5). Converting from Rivaroxaban to Vitamin K antagonists (VKA) There is a potential for inadequate anticoagulation during the transition from Rivaroxaban to VKA.

Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant. It should be noted that Rivaroxaban can contribute to an elevated INR. 0. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing, as guided by INR testing.

While patients are on both Rivaroxaban and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of Rivaroxaban. 2). g. g. intravenous unfractionated heparin). Converting from Rivaroxaban to parenteral anticoagulants Give the first dose of parenteral anticoagulant at the time the next Rivaroxaban dose would be taken.

Special populations Renal impairment Limited clinical data for patients with severe renal impairment (creatinine clearance 15 - 29 ml/min) indicate that rivaroxaban plasma concentrations are significantly increased. Therefore, Rivaroxaban is to be used with caution in these patients.

2). In patients with moderate (creatinine clearance 30 - 49 ml/min) or severe (creatinine clearance 15- 29 ml/min) renal impairment the following dose […]

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.

g. 5). 2). 6).