RIVAROXABAN

Posology Prevention of VTE in adult patients undergoing elective hip or knee replacement surgery The recommended dose is 10 mg Rivaroxaban taken orally once daily. The initial dose should be taken 6 to 10 hours after surgery, provided that haemostasis has been established.

The duration of treatment depends on the individual risk of the patient for venous thromboembolism which is determined by the type of orthopaedic surgery. • For patients undergoing major hip surgery, a treatment duration of 5 weeks is recommended.

• For patients undergoing major knee surgery, a treatment duration of 2 weeks is recommended. If a dose is missed the patient should take Rivaroxaban immediately and then continue the following day with once daily intake as before. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE 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 mg once daily should be considered.

4). Time period Dosing schedule Total daily dose Day 1 - 21 15 mg twice daily 30 mgTreatment and prevention of recurrent DVT and PE Day 22 onwards 20 mg once daily 20 mg Prevention of recurrent DVT and PE Following completion of at least 6 months therapy for DVT or PE 10 mg once daily or 20 mg once daily 10 mg or 20 mg To support the dose switch from 15 mg to 20 mg after Day 21 a first 4 weeks treatment initiation pack of Rivaroxaban for treatment of DVT/PE is available.

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.

Summary of the safety profile The safety of rivaroxaban has been evaluated in thirteen 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.

4. and ‘Description of selected adverse reactions’ below) (Table 2). 8 %). Table 2 Bleeding* and anaemia events rates in patients exposed to rivaroxaban across the completed adult and paediatric phase III studies. 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 count increased)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.

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk As with other anticoagulants, patients taking Rivaroxaban are to be carefully observed for signs of bleeding.

It is recommended to be used with caution in conditions with increased risk of haemorrhage. 9). 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. Several sub-groups of patients, as detailed below, are at increased risk of bleeding.

8). In patients receiving Rivaroxaban for VTE prevention following elective hip or knee replacement surgery, this may be done by regular physical examination of the patients, close observation of the surgical wound drainage and periodic measurements of haemoglobin Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site.

g. 2). 6 fold on average) which may lead to an increased bleeding risk. Rivaroxaban is to be used with caution in patients with creatinine clearance 15 - 29 ml/min. 2). 5). g. ritonavir). 5). Care is to be taken if patients are treated concomitantly with medicinal products affecting haemostasis such as non-steroidal anti-inflammatory medicinal products (NSAIDs), acetylsalicylic acid (ASA) and platelet aggregation inhibitors or selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).

5). g. inflammatory bowel disease, oesophagitis, gastritis and gastroesophageal reflux disease) • vascular retinopathy • bronchiectasis or history of pulmonary bleeding Patients with cancer Patients with malignant disease may simultaneously be at higher risk of bleeding and thrombosis.

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).