XANIRVA

Posology Prevention of VTE in adult patients undergoing elective hip or knee replacement surgery The recommended dose is 10mg 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 Xanirva 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 20mg 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 Xanirva 10mg once daily, a dose of Xanirva 20mg once daily should be considered.

4). Time period Dosing schedule Total daily dose Day 1-21 15mg twice daily 30mgTreatment and prevention of recurrent DVT and PE Day 22 onwards 20mg once daily 20mg Prevention of recurrent DVT and PE Following completion of at least 6 months therapy for DVT or PE 10mg once daily or 20mg once daily 10mg or 20mg If a dose is missed during the 15mg twice daily treatment phase (day 1 - 21), the patient should take Xanirva immediately to ensure intake of 30mg Xanirva per day.

In this case two 15mg capsules may be taken at once. The patient should continue with the regular 15mg twice daily intake as recommended on the following day. If a dose is missed during the once daily treatment phase, the patient should take Xanirva immediately, and continue on the following day with the once daily intake as recommended.

Summary of the safety profile The safety of rivaroxaban has been evaluated in thirteen pivotal phase III studies (see Table 1). Overall, 69608 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 6097 10mg 39 days Prevention of VTE in medically ill patients 3997 10mg 39 days Treatment of deep vein thrombosis (DVT), pulmonary embolism (PE) and prevention of recurrence 6790 Day 1 - 21: 30mg Day 22 and onwards: 20mg After at least 6 months: 10mg or 20mg 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 adults treated for DVT with 20 mg rivaroxaban once daily 12 months Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation 7750 20mg 41 months Prevention of atherothrombotic events in patients after an acute coronary syndrome (ACS) 10225 5mg or 10mg respectively, co-administered with either ASA or ASA plus clopidogrel or ticlopidine 31 months Prevention of 18244 5mg co-administered 47 months with ASA or 10mg alone atherothrombotic events in patients with CAD/PAD 3256** 5mg 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.

Clinical surveillance in line with anticoagulation practice is recommended throughout the treatment period. Haemorrhagic risk As with other anticoagulants, patients taking Xanirva 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. Xanirva is to be used with caution in patients with creatinine clearance 15 - 29ml/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).