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  1. Xarelto▼(rivaroxaban)Stroke Prevention in Atrial FibrillationPrevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors, such as congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. Prescribing Information can be found on the last page

  2. Agenda • AF and Stroke: Disease and Management • Local and National Guidance • Xarelto for stroke and systemic embolism in non-valvular AF • Xarelto - Practical Issues • Patient Case Study

  3. Atrial Fibrillation (AF) and Stroke AF prevalence roughly doubles with each advancing decade of life (9% at age 80-89 years)1 Stroke prevalence increases nearly 5 fold when AF is present2 In patients with AF, blood clots tend to form in the atria, particularly within the left atrial appendage, due to abnormal blood flow and pooling These clots may travel to the brain, causing an ischaemic stroke Around 20% of ischaemic strokes are caused by blood clots originating in the heart (cardioembolic); of these, AF is the most common cause3 NICE CG36 Atrial fibrillation 2006 Wolf PA et al. Stroke 1991;22:983–988; PaciaroniM et al. Stroke 2007;38:423–430

  4. Patients with AF have an approximately fivefold increased risk of ischaemic stroke1 Framingham Heart Study (N=5,070) 60 Risk ratio=4.8 p<0.001 50 40 2-year age-adjusted incidence of stroke/1,000 30 *Patients were seldom treated with antithrombotic therapy when this study was performed in line with clinical practice at the time 20 10 0 Individuals without AF Individuals with AF* 1. Adapted from Wolf PA et al. Stroke 1991;22:983–988

  5. AF-related stroke can be preventable By preventing thrombus formation in the heart (thrombo-prophylaxis) Antithrombotic therapy reduces the risk of stroke and thromboembolism but also increases the risk of bleeding Clinical decision-making requires an assessment of benefit–risk

  6. Many Factors Elevate AF Stroke Risk CHADS2 score Annual Risk of Stroke Score: 0 = low risk; 1 = intermediate risk; ≥2 = high risk Gage Bet al. Circulation 2004; 110:2287-2292

  7. CHADS2 and CHA2DS2-VASc both available in GRASP-AF http://www.improvement.nhs.uk/graspaf/- accessed 07/09/2012

  8. April 2012 QOF Revisions supports AF risk stratification and management1 Summary A total of 26 QOF points can be achieved by appropriate risk stratification of AF patients and ensuring that they are appropriately anti-coagulated for stroke prevention. 1. Quality and Outcomes Framework for 2012/2013; BMA 2012

  9. April 2012 QOF Revisions supports AF risk stratification and management 1 1. Quality and Outcomes Framework for 2012/2013; BMA 2012

  10. CHA2DS2 - VASc Risk Scoring for AF patientsand Thromboprophylaxis Guidelines (ESC)1 Cammet al,2010

  11. Agenda • AF and Stroke: Disease and Management • Local and National Guidance • Xarelto for stroke and systemic embolism in non-valvular AF • Xarelto - Practical Issues • Patient Case Study

  12. Choice of anticoagulant in AF: ESC Guidelines 2012 Atrial fibrillation Yes Best option Alternative option Valvular AF No (i.e. non-valvular AF) Yes <65 years and lone AF (including female) No Assess risk of stroke (CHA2DS2-VASc score) 0 1 >2 Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences No antithrombotic therapy NOAC VKA Adapted from: Camm et al. Eu Heart J August 2012

  13. National guidance for Xarelto

  14. Agenda • AF and Stroke: Disease and Management • Local and National Guidance • Xarelto for stroke and systemic embolism in non-valvular AF • Xarelto - Practical Issues • Patient Case Study

  15. Traditional anticoagulants: drawbacks UFH1 Parenteral administration Monitoring and dose adjustment required Risk of HIT LMWH1 Parenteral administration Weight-adjusted dosing (for obese patients Oral VKAs2 Narrow therapeutic window Interaction with food and drugs Frequent monitoring and dose adjustment required 1. Hirsh J et al. Chest 2008;133;141S–159S 2. Ansell J et al. Chest 2008;133;160S–198S • Hirsh J et al. Chest 2008;133;141S–159S; 2. Ansell J et al. Chest 2008;133;160S–198S

  16. VKAs have a narrow therapeutic window Adjusted odds ratios for ischaemic stroke and intracranial bleeding in relation to intensity of anticoagulation 20 Data on bleeding and stroke risk support recommendation for narrow INR target range of 2.0–3.0 15 Ischaemic stroke Intracranial bleeding Odds ratio for event 10 Target INR 5 1 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 International normalized ratio Adapted from Wann et al. Circulation 2011;123;e269-e367 16

  17. Xarelto: Comparing properties with Warfarin in SPAF • Perzbornet al. Drug discovery 2011 10:65-71 • Warfarin 0.5 mg SMPC 2010 • Xarelto SmPC June 2012

  18. Drug and food interactions with warfarin

  19. Coagulation pathway VII TF VIIa IX X Xa IXa Inactive Factor Prothrombin Active Factor Transformation Catalysis Thrombin Fibrinogen Fibrin VKA VKA Initiation Propagation VKA Direct Factor Xa inhibition Rivaroxaban II Direct Factor IIa inhibition Dabigatran IIa Spyropoulos AC et al. Expert Opin Investig Drugs2007;16:431–440 (adapted from)

  20. Xarelto: licenced indications Xarelto 10mg SmPCJune 2012; Xarelto 15/20mg SmPCJune 2012

  21. Xarelto as a solution to the epidemic of venous- arterial thromboembolism VAT (Venous Arterial Thromboembolic Space) • 800K AF patients in the UK2 • 5 fold increase in stroke risk when AF present3 SPAF VTEx • Pulmonary embolism (PE)& Deep venous thrombosis (DVT)25K deaths per year in the UK1 PE DVT VTEp • Elective hip and knee surgery % risk of DVT/PE if no prophylaxis: • 45% Hip1 • 60% Knee1 National Collaborating Centre for Acute Care; Venous Thromboembolism 2009 British Heart Foundation; http://www.bhf.org.uk/heart-health/conditions/atrial-fibrillation.aspx accessed 10/09/2012 NICE CG36 Atrial fibrillation 2006

  22. Agenda • AF and Stroke: Disease and Management • Local and National Guidance • Xarelto for stroke and systemic embolism in non-valvular AF • Xarelto - Practical Issues • Patient Case Study

  23. 6 5 4 3 Cumulative event rate (%) 2 1 0 0 120 240 480 600 720 840 360 ROCKET AF- Xarelto is effective in the prevention of stroke and SE, with comparable efficacy vs. warfarin Stroke or Systemic Embolism(SEE) HR 0.79 (0.66, 0.96) p<0.001 (non-inferiority) Warfarin Xarelto Days since randomization Per-protocolpopulation – as treated population Adapted from Patel MR et al. NEJM 2011; 365: 883-891

  24. Oral anti-coagulation is shown to be effective for stroke prevention in AF Study, year Relative risk reduction (95% CI) Absolute risk reduction AFASAK I, 1989; 1990 2.6% 4.7% 2.4% 1.2% 3.3% 8.4% SPAF I, 1991 BAATAF, 1991 CAFA, 1991 SPINAF, 1992 EAFT, 1993 All trials (n=6) 100% 50% 0 –50% –100% Favours VKA Favoursplacebo Reductionofriskofthromboembolism in AF1 primary prevention 2.7, secondary prevention 8.4 Hart RG et al. Ann Intern Med 2007;146:857–867

  25. Oral anti-coagulation: benefit–risk improves with increasing age Net clinical benefit: events prevented per 100 person-years1 2.34 ≥85 1.29 3.30 1.00 75–84 0.44 1.40 Age, years 0.11 65–74 –0.37 0.40 –0.25 <65 –0.65 0.08 –1 –0.5 0.5 1 1.5 2 2.5 3 3.5 0 Worse with warfarin Better with warfarin Singer DE et al. Ann Intern Med 2009;151:297–305

  26. ROCKET AF: Significantly fewer haemorrhagic strokes with Xarelto vs. warfarin Event Rates are per 100 patient-years Based on Intention-to-Treat Population Data on file: ROCKET

  27. ROCKET AF: Studied across a wide range of patients, including those of older age, with co-morbidities or with high CHADS score Rivaroxaban (n=7131) Warfarin (n=7133) 44.3 42.9 Mean CHADS2 score = 3.5 29.3 28.0 % Patients 13.0 13.1 13.1 12.4 2.2 1.7 CHADS2 score Patel MR et al. NEJM 2011; 365: 883-891

  28. 0.2 0.5 1 2 5 ROCKET AF- Safety Profile Hazard ratio and 95% CIs There was significantly higher GI Bleeding in Xarelto group Vs. Warfarin Patel MR et al. NEJM 2011; 365: 883-891

  29. Xarelto: No increase in non-bleeding adverse events Values are N based on safety population Any treatment-emergent adverse event: 81.4% for Xarelto vs. 81.5% for Warfarin Patel MR et al. NEJM 2011; (ROCKET Suppl)

  30. Agenda • AF and Stroke: Disease and Management • Local and National Guidance • Xarelto for stroke and systemic embolism in non-valvular AF • Xarelto - Practical Issues • Patient Case Study

  31. Xarelto dosage regimen in AF • No requirement for routine anticoagulation monitoring • For all licensed indications, no dose adjustment is required for: • Elderly, Body weight, Gender Xarelto20mg SmPCJune 2012

  32. Dosage according to renal function 1,2 150mg BD or 110mg BD Creatinine clearance 50 + ml/min 20mg Once daily Creatinine clearance 50 + ml/min 150mg BD with caution. Consider using 110mg BD if high bleeding risk Dose adjust based on age, weight and concomitant medications Creatinine clearance 30 – 50 ml/min Creatinine clearance 30 - 49 ml/min 15mg Once daily 15mg Once daily with caution Creatinine clearance 15-29 ml/min Not recommended Creatinine clearance <30 ml/min Not recommended Creatinine clearance <15 ml/min Rivaroxaban Dabigatran • XareltoSmPC 20mg June 2012 • PradaxaSmPC 150mg May 2012

  33. Practical use considerations • Current approved indications and dosing recommendations • Populations potentially at higher risk of bleeding • Perioperative management • Overdose • How to manage bleeding complications • Coagulation testing • Further information and materials

  34. 1. Patient with existing AF- Warfarin Discontinuer Clinical profile: 68, non-valvular AF diagnosed 3 years ago at annual check-up Diabetes mellitus, hypertension • Current management plan: amiodarone; metformin; atenelol; Discontinued warfarin due to compliance logistics and is now on aspirin • Other considerations • Farmer who lives with wife in the country. Does not drive but enjoys a drink and occasional trip to the theatre • Spends a few months a year in Spain where he has limited access to INR clinics • Discontinued warfarin due to his inability to attend the INR clinic frequently given personal and working situation • ‘Xarelto’ offers • Highly effective, predictable anticoagulation2 • No dietary restrictions (must be taken with food)2 • Fast onset of action2 • No need for routine coagulation monitoring2 • No increase in MI events versus warfarin3 • Clinical evaluation and next steps • Stroke risk factor(s):hypertension, diabetes • CHADS2= 2 • Annual stroke risk is 2.2%( 9 times greater than a patient without AF) • Oral anticoagulation is recommended1 • Cammet al,2010; • XareltoSmPCJune 2012 • Patel et al,2011

  35. 2. Patient with existing AF- Warfarin Naïve Clinical profile: 63, non-valvular AF diagnosed 3 months ago Congestive heart failure, hypertension • Current management plan: ace-inhibitor, verapamil, statin • ASA • Other considerations • Patient lives alone, travels often to visit her grand children • Clinical evaluation and next steps • Stroke risk factor(s):HTN, DM • CHADS2= 2 • Annual stroke risk is 2.2%( 9 times greater than a patient without AF) • Oral anticoagulation is recommended1 • ‘Xarelto’ offers • Highly effective, predictable anticoagulation2 • No dietary restrictions (must be taken with food)2 • Fast onset of action2 • No need for routine coagulation monitoring2 • No increase in MI events versus warfarin3 • Cammet al,2010; • XareltoSmPCJune 2012 • Patel et al,2011

  36. Resources available to support physicians and patients Xarelto-info.co.uk

  37. Contemporary management of stroke in AF: a summary • AF-related stroke is often preventable • Guidelines recommend OAC in majority of AF patients • VKAs whilst effective in stroke prevention are associated with limitations; • Studies show patients spend up to a third of time (on average) outside target INR levels1 • Xarelto provides a one tablet once daily NICE approved option for stroke prevention in non-valvular AF • Xarelto maybe appropriate for some patients with high unmet clinical need 1. Ansell J et al. J Thromb Thrombolysis 2007;23:83–91.

  38. Back-up slides

  39. RivaroxabanOnce-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation

  40. ROCKET AF – Study design Randomised, double-blind, double-dummy, event-driven • Non-valvular AF • History of stroke, TIA or non-CNS SE • OR • ≥2* of the following: • CHF • Hypertension • Age ≥75 years • Diabetes Rivaroxaban 20 mg once daily** N=14,264 R 30-day follow-up End of study Warfarin target INR 2–3 ~11–41 months*** **Patients with CrCl 30–49 ml/min: 15 mg rivaroxaban once daily ***Duration of therapy varied for each patient as study was event-driven (Average duration of treatment per patient- approx 19 months) Patel MR et al. NEJM 2011; 365: 883-891

  41. ROCKET AF – Study endpoints • Primary efficacy endpoint • Composite of stroke and systemic embolism (SE) • Secondary efficacy endpoints • Composite of stroke, SE, or cardiovascular death • Composite of stroke, SE, cardiovascular death, or MI • Individual components of the above endpoints • Principal safety endpoint • Composite of major and non-major clinically relevant bleeding Patel MR et al. NEJM 2011; 365: 883-891

  42. Primary Safety Endpoints Major Bleeding Fatal Outcome Involvement of critical anatomical site Fall in Haemoglobin concentration> 2m/dl Transfusion >2 units of whole blood or packed blood cells Permanent disability Non-major Bleeding (clinically relevant overt bleeding that did not meet criteria for major bleeding) associated with Medical intervention Unscheduled contact with physician Temporary cessation of study drug Pain Impairment of activities Patel MR et al. NEJM 2011; Suppl

  43. ROCKET AF: Studied across a wide range of patients, including those of older age, with co-morbidities or with high CHADS score Halperin et al, JAMA 2005 ACTIVE Writing Group of ACTIVE Investigators, 2006; 3. Connolly et al, 2009; 4. Patel et al, NEJM 2010 Supplementary Index, 5. Data on File

  44. Oral anti-coagulation: benefit–risk increases with an increasing number of risk factors Net clinical benefit: events prevented per 100 person-years 2.22 4–6 3.75 0.58 2.07 3 1.21 2.79 0.97 2 0.43 1.41 CHADS2 score 0.19 1 0.45 –0.27 –0.11 0 0.20 –0.44 –1 –0.5 0.5 1 1.5 2 2.5 3 3.5 0 Worse with warfarin Better with warfarin Singer DE et al. Ann Intern Med 2009;151:297–305

  45. Drug interactions with rivaroxaban • Rivaroxaban not recommended in combination with • Systemic azole-antimycotics (e.g ketoconazole, itraconazole) • HIV protease inhibitors • Dronedarone (lack of information) • Use rivaroxaban with caution in combination with • Other anticoagulants • NSAIDS • Platelet inhibitors • Strong CYP3A4 inducers such as rifampicin or St John’s Wort XareltoSmPC June 2012

  46. Invasive procedures and surgical intervention • Stop rivaroxaban at least 24 hours before intervention • If this is not possible, assess relative risk of bleeding compared to urgency of intervention • Restart as soon as possible after the intervention if situation allows and haemostasis has been established XareltoSmPC June 2012

  47. Converting from warfarin to rivaroxaban XareltoSmPC June 2012 47

  48. Xarelto®▼10mg film-coated tablets (rivaroxaban) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) Presentation: 10 mg rivaroxaban tablet. Indication(s): Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. Posology and method of administration: Dosage 10 mg rivaroxaban orally once daily with or without food; initial dose should be taken 6 to 10 hours after surgery provided haemostasis established. Recommended treatment duration: Dependent on individual risk of patient for VTE determined by type of orthopaedic surgery: for major hip surgery 5 weeks; for major knee surgery 2 weeks. Refer to SmPC for full information on duration of therapy & converting to/from Vitamin K antagonists (VKA) or parenteral anticoagulants. Renal impairment: Mild & moderate (creatinine clearance 50-80ml/min & 30-49 ml/min respectively) – no dose adjustment necessary; severe (creatinine clearance 15-29ml/min) - limited data indicates rivaroxaban concentrations are significantly increased, use with caution. Patients with creatinine clearance < 15ml/min – use not recommended. Hepatic impairment: Do not use in patients with hepatic disease associated with coagulopathy & clinically relevant bleeding risk including cirrhotic patients with Child Pugh B & C patients. Paediatrics: Not recommended. Contra-indications: Hypersensitivity to active substance or any excipient; clinically significant active bleeding; hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B & C; pregnancy & breast feeding. Warnings and precautions: Not recommended in patients: undergoing hip fracture surgery; in patients receiving concomitant systemic treatment with strong CYP3A4 and P-gp inhibitors, i.e. azole-antimycotics or HIV protease inhibitors; with severe renal impairment (creatinine clearance <15 ml/min). Increased risk of bleeding therefore careful monitoring for signs/symptoms of bleeding complications & anaemia required after treatment initiation: in patients with severe renal impairment (creatinine clearance 15 - 29 ml/min); or with moderate renal impairment (creatinine clearance 30 - 49 ml/min) concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations; in patients treated concomitantly with medicinal products affecting haemostasis; in patients with congenital or acquired bleeding disorders; uncontrolled severe arterial hypertension; active ulcerative gastrointestinal disease (consider appropriate prophylactic treatment for at risk patients); recent gastrointestinal ulcerations; vascular retinopathy; recent intracranial or intracerebral haemorrhage; intraspinal or intracerebral vascular abnormalities; recent brain, spinal or ophthalmological surgery, bronchiectasis or history of pulmonary bleeding. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine. If clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-Factor Xa tests. Take special care when neuraxial anaesthesia or spinal/epidural puncture is employed due to risk of epidural or spinal haematoma with potential neurologic complications. Xarelto contains lactose. Interactions: Concomitant use with strong inhibitors of both CYP3A4 & P-gp not recommended as increased rivaroxaban plasma concentrations to a clinically relevant degree are observed. Avoid co-administration with dronedarone. Use with caution in patients concomitantly receiving other anticoagulants, NSAIDs or platelet aggregation inhibitors due to the increased bleeding risk. Strong CYP3A4 inducers should be used concomitantly with caution as they may reduce rivaroxaban plasma concentrations.. Pregnancy and breast feeding: Contra-indicated. Effects on ability to drive and use machines: Adverse events like syncope and dizziness are common. Patients experiencing these effects should not drive or use machines. Undesirable effects: Common: anaemia, dizziness, headache, syncope, eye haemorrhage, tachycardia, hypotension, haematoma, epistaxis, GI tract haemorrhage, GI & abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, pruritus, rash, ecchymosis, pain in extremity, urogenital tract haemorrhage, fever, peripheral oedema, decreased general strength & energy, increase in transaminases, post-procedural haemorrhage, contusion, wound secretion. Serious: cf. CI/Warnings and Precautions – in addition: thrombocythemia, allergic reactions, occult bleeding/haemorrhage from any tissue (e.g. cerebral & intracranial, cutaneous & subcutaneous, haemoptysis, haemarthrosis, muscle) which may lead to complications (incl. compartment syndrome, renal failure, fatal outcome), abnormal hepatic function, renal impairment; hyperbilirubinaemia, jaundice, pseudoaneurysm formation following percutaneous intervention. Prescribers should consult SmPC in relation to full side effect information. Overdose: No specific antidote is available. Legal Category: POM. Package Quantities and Basic NHS Costs: 10 tablets: £21.00, 30 tablets: £63.00 and 100 tablets: £210.00. MA Number(s): EU/1/08/472/001-10 Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, U.K. Telephone: 01635 563000. Date of preparation: June 2012. Xarelto® is a trademark of the Bayer Group Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: phdsguk@bayer.co.uk

  49. Xarelto® ▼15 and 20 mg film-coated tablets (rivaroxaban) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) Presentation: 15mg/20mg rivaroxaban tablet Indication(s): 1. Prevention of stroke & systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors such as congestive heart failure, hypertension, age ≥ 75, diabetes mellitus, prior stroke or transient ischaemic attack (SPAF). 2. Treatment of deep vein thrombosis (DVT) & prevention of recurrent DVT & pulmonary embolism (PE) following an acute DVT in adults (DVT-t) Posology & method of administration: Dosage 1 (SPAF): 20 mg orally o.d. with food. Dosage 2 (DVT-t): 15 mg b.i.d. for 3 weeks followed by 20 mg o.d. for continued treatment & prevention of recurrent DVT & PE; take with food. Refer to SmPC for full information on duration of therapy & converting to/from Vitamin K antagonists (VKA) or parenteral anticoagulants. Renal impairment: mild (creatinine clearance 50-80 ml/min) - no dose adjustment necessary; moderate (creatinine clearance 30-49 ml/min) & severe (creatinine clearance 15-29 ml/min; limited data indicates rivaroxaban plasma concentrations are significantly increased, use with caution) – SPAF: reduce dose to 15mg o.d., DVT-T: 15 mg b.i.d. for 3 weeks, reduce maintenance dose to 15mg o.d.; Patients with creatinine clearance <15 ml/min - use not recommended. Hepatic impairment: Do not use in patients with hepatic disease associated with coagulopathy & clinically relevant bleeding risk including cirrhotic patients with Child Pugh B & C patients. Paediatrics: Not recommended. Contra-indications: Hypersensitivity to active substance or any excipient; clinically significant active bleeding; hepatic disease associated with coagulopathy & clinically relevant bleeding risk including cirrhotic patients with Child Pugh B & C; pregnancy & breast feeding. Warnings & precautions: Clinical surveillance in line with anticoagulant practice is recommended throughout the treatment period. There is no need for monitoring of coagulation parameters during treatment with rivaroxaban in clinical routine, if clinically indicated rivaroxaban levels can be measured by calibrated quantitative anti-Factor Xa tests. In studies mucosal bleedings & anaemia were seen more frequently during long term rivaroxaban treatment compared with VKA treatment – haemoglobin/haematocrit testing may be of value to detect occult bleeding. Following sub-groups of patients are at increased risk of bleeding & should be carefully monitored after treatment initiation. Use with caution - in patients with severe renal impairment or with renal impairment concomitantly receiving potent inhibitors of CYP3A4 (PK models show increased rivaroxaban concentrations); in patients treated concomitantly with medicines affecting haemostasis; in patients with an increased bleeding risk such as congenital or acquired bleeding disorders, uncontrolled severe arterial hypertension, active ulcerative gastrointestinal disease (consider appropriate prophylactic treatment for at risk patients), recent gastrointestinal ulcerations, vascular retinopathy, recent intracranial or intracerebral haemorrhage, intraspinal or intracerebralvascular abnormalities, recent brain / spinal / ophthalmological surgery, bronchiectasis or history of pulmonary bleeding. Use is not recommended in patients: with creatinine clearance <15 ml/min; receiving concomitant systemic treatment with azole-antimycotics or HIV protease inhibitors; with prosthetic heart valves; for treatment of acute pulmonary embolism. If invasive procedures or surgical intervention are required stop Xarelto use at least 24 hours beforehand. Restart use as soon as possible provided adequate haemostasis has been established. See SmPC for full details. Xarelto contains lactose. Interactions: Concomitant use with strong inhibitors of both CYP3A4 & P-gp not recommended as increased rivaroxaban plasma concentrations to a clinically relevant degree are observed. Avoid co-administration with dronedarone. Use with caution in patients concomitantly receiving other anticoagulants, NSAIDs or platelet aggregation inhibitors due to the increased bleeding risk. Strong CYP3A4 inducers should be used concomitantly with caution as they may reduce rivaroxaban plasma concentrations. Pregnancy & breast feeding: Contra-indicated. Effects on ability to drive and use machines: Adverse reactions like syncope & dizziness are common. Patients experiencing these effects should not drive or use machines. Undesirable effects: Common: anaemia, dizziness, headache, syncope, eye haemorrhage, tachycardia, hypotension, haematoma, epistaxis, GI tract haemorrhage, GI & abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, pruritus, rash, ecchymosis, pain in extremity, urogenital tract haemorrhage, fever, peripheral oedema, decreased general strength & energy, increase in transaminases, post-procedural haemorrhage, contusion, wound secretion. Serious: cf. CI/Warnings and Precautions – in addition: thrombocythemia, allergic reactions, occult bleeding/haemorrhage from any tissue (e.g. cerebral & intracranial, cutaneous & subcutaneous, haemoptysis, haemarthrosis, muscle) which may lead to complications (incl. compartment syndrome, renal failure, fatal outcome), abnormal hepatic function, renal impairment; hyperbilirubinaemia, jaundice, pseudoaneurysm formation following percutaneous intervention. Prescribers should consult SmPC in relation to full side effect information. Overdose: No specific antidote is available. Legal Category: POM. Package Quantities and Basic NHS Costs: 15mg – 28 tablets: £58.80, 42 tablets: £88.20, 100 tablets: £210.00; 20mg – 28 tablets: £58.80, 100 tablets £210.00 MA Number(s): EU/1/08/472/011-21 Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, U.K. Telephone: 01635 563000. Date of preparation: June 2012. Xarelto® is a trademark of the Bayer Group. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Bayer plc. Tel.: 01635 563500, Fax.: 01635 563703, Email: phdsguk@bayer.co.uk

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