Quick Guide Xarelto Across Indications

Transcription

1 Quick Guide Xarelto Across Indications VTE Prevention Since 28 Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery Stroke Prevention in NVAF Since 211 Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factorsa DVT Treatment Since 211 Treatment of deep vein thrombosis (DVT) and extended treatment for prevention of recurrent DVT and pulmonary embolism (PE) in adult patients PE Treatment Since 212 Treatment of PE and extended treatment for prevention of recurrent DVT and PE in adult patients ACS Secondary Prevention Since 213 Secondary prevention after acute coronary syndrome (ACS) in combination with standard antiplatelet therapy b in adult patients with elevated cardiac biomarkers c a Such as congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. b Acetylsalicylic acid (ASA) alone or ASA plus clopidogrel or ticlopidine. c Troponin-I/T; creatine kinase-muscle and brain isoenzyme (CK-MB).

2 Mode of Action is a fast-acting, oral, direct Factor Xa inhibitor that provides simple protection for your patients Characteristics Administration Oral 1 Bioavailability Half-life Time to peak plasma concentration Renal excretion as unchanged drug 8 1% 1 : 2.5 mg and 1 mg independent of food intake 1 15 mg and 2 mg when taken with food h in young adults h in elderly patients hours 1 ~33% 1 Rapid onset of action without injections 2 Indications and Dosing 1 Detailed information can be found on pages 4 15 Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation with one or more risk factors a Treatment of DVT and PE b and extended treatment for prevention of recurrent DVT and PE in adults 2 mg OD 15 mg OD 15 mg BID Patients with CrCl>49 ml/min with food OR Patients with CrCl 15 to 49 ml/min # with food FROM DAY 1 TO DAY 21 Patients with CrCl>15 ml/min # with food AT DAY 22 TRANSITION TO 2 mg OD c Patients with CrCl>15 ml/min # with food Overview Factor Xa inhibition as fast as enoxaparin ANTI FACTOR Xa ACTIVITY a TIME (HOURS) 2 n=1 n=11 24 Prevention of VTE in adults undergoing elective hip or knee replacement surgery Secondary prevention after ACS in combination with standard antiplatelet therapy d in adults with elevated cardiac biomarkers e 1 mg OD Patients with CrCl>15 ml/min # The initial dose should be taken 6 to 1 hours after surgery once haemostasis has been established 2.5 mg BID Patients with CrCl>15 ml/min # The initial dose should be taken after stabilisation of the ACS event * enoxaparin s.c. Graph adapted from Kubitza D, et al a Such as congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. b Not recommended as an alternative to unfractionated heparin in patients with PE who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy. c A reduction of the dose from 2 mg OD to 15 mg OD should be considered in patients with CrCl 15 to 49 ml/min when the patients assessed risk for bleeding outweighs the risk for recurrent DVT and PE. The recommendation for the use of 15 mg OD is based on PK modelling and has not been studied in this clinical setting. a Change from baseline (ng/ml enoxaparin). d Acetylsalicylic acid (ASA) alone or ASA in combination with clopidogrel or ticlopidine. * 1 mg. e Troponin-I/T; creatine kinase-muscle and brain isoenzyme (CK-MB). Enoxaparin 4 mg. # Not recommended in patients with CrCl<15 ml/min; use with caution in patients with CrCl 15 to 2 s.c.=subcutaneous. 29 ml/min and in patients with renal impairment when concomitantly receiving other medicinal products which increase rivaroxaban plasma concentration. 3

3 Hip or Knee Replacement Surgery RECORD 1 3 Study Results Indication 1 Prevention of VTE after elective hip or knee replacement surgery in adults delivers early and sustained significant reduction in the incidence of symptomatic VTE and death vs. enoxaparin* Treatment 1 n=9,581 ** OR.44; 95% CI.23 to.79 Surgery Day 1 Initiate Recommended treatment duration after: Hip replacemet surgery: 5 weeks 1 Knee replacement surgery: 2 weeks 1 No routine coagulation monitoring required a One 1 mg tablet, once daily with or without food CUMULATIVE INCIDENCE OF SYMPTOMATIC VTE AND ALL-CAUSE MORTALITY (%)* 1.5 Day 1 1. Day of surgery.5 RRR 56% Day %**.4% 2 p= Indications DAYS AFTER SURGERY For renally impaired patients 1 Creatinine Clearance Recommended Dosage 3 49 ml/min 1 mg once daily b ml/min 1 mg once daily, use with caution <15 ml/min Not recommended Important notes 1 No preoperative anticoagulation necessary Initiate 6 to 1 hours after surgery, provided that haemostasis has been established enoxaparin # Graph adapted from Eriksson BI, et al % RRR in the primary efficacy outcome of symptomatic VTE and all cause mortality at 2 weeks 62% RRR at the end of the planned medication period (.5% vs. 1.3%, respectively; OR.38; 95% CI.22.62; p<.1) vs. enoxaparin similar rates of the main safety outcome of major bleedings at 2 weeks (.2% for both) and at the end of the planned medication period (.3% vs..2%) vs. enoxaparin comparable rates of bleedings and haemorrhagic wound complications # Do NOT start earlier than 6 hours after surgery in order not to interfere with haemostasis a INR values should not be used as they are not a dependable measure of the anticoagulant activity of. b Use with caution when concomitantly receiving other medicinal products which increase plasma concentrations. End of the planned medication period=five weeks (up to day 42) in RECORD1 and RECORD2 including the placebo-controlled period in RECORD2, two weeks (up to day 17) in RECORD3. # Enoxaparin regimen includes placebo phase in RECORD2. INCIDENCE AT END OF PLANNED MEDICATION PERIOD (%) %.3% Major bleeding 2.5% 3.% 1.7% NON-MAJOR CLINICALLY RELE- VANT BLEEDINg enoxaparin # 1.8% HAEMORRHAGIC WOUND COMPLICATIONS * Kaplan-Meier survival curve: Cumulative incidence of symptomatic VTE and all-cause mortality over the total study duration (planned medication period plus follow-up). # Haemorrhagic wound complications=composite of excessive wound haematoma, reported surgical-site 4 CI=confidence interval; OR=odds ratio; RRR=relative risk reduction; VTE=venous thromboembolism. bleeding, and wound infections. 5

4 Non-valvular Atrial Fibrillation Indication 1 Prevention of stroke and systemic embolism in adults with non-valvular AF with one or more risk factors ROCKET AF Study Results 4 Highly effective protection against stroke and systemic embolism 4 ITT analysis Risk factors include: congestive heart failure, hypertension, age 75 years, diabetes mellitus, and prior stroke or transient ischaemic attack 6 n=14,171 HR,.88; 95% CI,.75 to 1.3 p<.1 (non-inferiority) p=.12 (superiority) Treatment 1 Day 1 Initiate One 2 mg tablet, once daily with food No routine coagulation monitoring required a STROKE OR SYSTEMIC EMBOLISM c (%/YR) Indications TIME TO FIRST EVENT (DAYS) warfarin Creatinine Clearance Recommended Dosage 3 49 ml/min 15 mg once daily b ml/min 15 mg once daily, use with caution <15 ml/min Not recommended Graph adapted from Patel MR et al Pre-specified, primary on-treatment analysis in the per-protocol population 6 n=13,962 HR,.79; 95% CI,.66 to.96 p<.1 (non-inferiority) Important notes 1 provides early protection and should be continued long term provided the benefit of prevention of stroke and systemic embolism outweighs the risk of bleeding is not recommended for patients with prosthetic heart valves STROKE OR SYSTEMIC EMBOLISM c (%/YR) NS 21% TIME TO FIRST EVENT (MONTHS) Xarelto warfarin (55% TTR) Graph adapted from Patel MR et al a INR values should not be used as they are not a dependable measure of the anticoagulant activity of. b Use with caution when concomitantly receiving other medicinal products which increase plasma concentrations. c Primary efficacy endpoint: Composite of all stroke (both ischaemic and haemorrhagic) and systemic embolism. No significant differences in major or clinically relevant non-major bleeding vs. warfarin d 1,475 pts 14.9% / yr warfarin 1,449 pts 14.5% / yr HR, 1.3; 95% CI,.96 to 1.11; p=.44 AF=atrial fibrillation; CI=confidence interval; HR=hazard ratio; ITT=intention-to-treat; 6 RRR=relative risk reduction; YR=year. d Primary safety endpoint. Major or non-major clinically relevant bleeding. 7

5 Reduces the Bleedings that are Feared Most 4 Significant reduction of ICH, critical organ and fatal bleeding vs warfarin 1 Safety on-treatment analysis Proven Protection in Patients with Moderate Renal Impairment a,4,11 Highly effective stroke prevention that you can rely on for patients you treat every day a,4,11 ITT analysis n=14,236 n=2,921 MAJOR BLEEDING b (%/YR) % p=.7 RRR 31%.8% CRITICAL ORGAN BLEEDING.7% p=.2 RRR 33%.5%.5% p=.3 RRR 5%.2% ICH FATAL BLEEDING stroke or systemic embolism c (%/YR) % Efficacy 3.% Indications warfarin 15 mg OD warfarin No significant differences in major or clinically relevant non-major bleeding vs. warfarin d Proven safety for non-valvular AF patients with moderate renal impairment a,11 showed significantly more overt bleedings with drops in haemoglobin levels of 2 g per deciliter or more, or leading to transfusion of two or more units blood, than warfarin Safety on-treatment analysis n=2,95 Patients receiving experienced significantly more gastro intestinal (GI) bleeding events, which included upper GI, lower GI and rectal bleeds than those receiving warfarin clinically relevant bleeding d (%/YR) % safety 17.8% 15 mg OD warfarin : The only novel OAC with a prospectively tested, specific renal dose in patients with non-valvular AF...15 mg OD 4,11 a Creatinine clearance: 3 49 ml/min. b Bleeding was defined as major if it was clinically overt and associated with a decrease in the hemoglobin level of 2. g per deciliter or more, if bleeding led to the transfusion of 2 or more units of red cells, or if bleeding was intracranial or retroperitoneal, occurred in another critical site, or contributed to death. c Primary efficacy endpoint: Composite of all stroke (both ischaemic and haemorrhagic) and systemic embolism. d Primary safety endpoint: Major or non-major clinically relevant bleeding. AF=atrial fibrillation; HR=hazard ratio; ICH=intracranial haemorrhage; ITT=intention-to-treat; 8 OAC=oral antigoagulant; OD=once daily; RRR=relative risk reduction; YR=year. 9

6 Deep Vein Thrombosis and Pulmonary Embolism EINSTEIN PE/DVT Study Results 9 PE DVT Indication 1 Highly effective oral single drug treatment c Treatment of DVT and PE and prevention of recurrent DVT and PE in adults Simplified dosing that demonstrated clot regression within 21 days and enduring protection 1 DOSING REGIMEN 15 mg BID for 21 days treats the initial clot and protects against early recurrence 1,9 For renally impaired patients 1 Creatinine Clearance 15 mg twice daily Initial high risk period Recommended Dosage Weeks 1 3 After 3 Weeks 3 49 ml/min 15 mg twice daily a 2 mg once daily a ml/min weeks 15 mg twice daily, use with caution 2 mg once daily for 21 days from day 22 For as long as the risk persists 2 mg once daily, use with caution <15 ml/min Not recommended Not recommended No need for heparin injections to initiate treatment 1 The primary efficacy outcome was symptomatic, recurrent VTE the composite of DVT and non-fatal or fatal PE recurrent symptomatic vte (%) b TIME TO EVENT (DAYs) n=8,281 HR,.89; 95% CI,.66 to 1.19 p<.1 (non-inferiority) enoxaparin + VKA 27 3 Comparable rate of major or non-major clinically relevant bleeding events 388 pts 9.4% PE DVT Graph adapted from Prins MH, et al enoxaparin + VKA 412 pts 1.% HR,.93; 95% CI,.81 to 1.6; p= Indications A reduction of the dose from 2 mg once daily to 15 mg once daily in renally impaired patients should be considered if the patient s assessed risk for bleeding outweighs the risk for recurrent DVT and PE 1 Important notes 1 The duration of therapy should be individualised after careful assessment of the treatment benefit against bleeding risk is not recommended as an alternative to UFH in patients with PE who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy a b c Use with caution when concomitantly receiving other medicinal products which increase plasma concentrations. Primary efficacy outcome. Pooled analysis of randomized EINSTEIN DVT and EINSTEIN PE studies. BID=twice daily; CI=confidence interval; DVT=deep vein thrombosis; HR=hazard ratio; PE=pulmonary 1 embolism; UFH=unfractionated heparin; VKA=vitamin K antagonist; VTE=venous thromboembolism. 11

7 EINSTEIN PE/DVT Study Results 9 PE DVT Consistent Efficacy and Safety Across Challenging PE and DVT Patients Halves the risk of major bleeding b,9 Proven effectiveness in your challenging patients Major BLEEDING (%) PE 3 DVT TIME TO EVENT (DAYs) n=8,246 HR,.54; 95% CI,.37 to.79 p=.2 (ARR.8%) enoxaparin + VKA Graph adapted from Prins MH, et al RRR 46% Recurrent symptomatic VTE Major bleeding b PE DVT Favours Favours enoxaparin + VKA HR (95% CI).68 Frail a ( ) n=51/1, Previous VTE (.22.91) n=36/1,61.69 Cancer c ( ) n=36/ Frail (.13.54) n=45/1, Previous VTE ( ) n=21/1,61.53 Cancer c ( ) n=23/594 Indications HR (95% CI) Graph adapted from Prins MH, et al Previous VTE patients: Significantly reduced recurrent VTE events by 55% (ARR=1.7%) Patients with cancer: Significantly reduced major bleeding by 47% (ARR=3.%) a Frail patients were defined as aged >75 years or creatinine clearance <5 ml/min or body weight 5 kg. b Major bleeding was the secondary efficacy endpoint. There were no significant differences in the primary safety endpoint (major and clinically relevant non-major bleeding). c The presence of cancer was categorized as known active cancer at study entry or cancer diagnosed during treatment. ARR=absolute risk reduction; CI=confidence interval; DVT=deep vein thrombosis; HR=hazard ratio; 12 PE=pulmonary embolism; RRR=relative risk reduction; VKA=vitamin K antagonist; VTE=venous thromboembolism. 13

8 The Only Novel OAC with a Separate Clinical Trial in PE EINSTEIN PE Study Results 6 PE is highly effective in protecting against the life-threatening risk of PE significantly lowers the risk of major bleeding * compared with enoxaparin followed by VKA The primary efficacy outcome was symptomatic, recurrent venous thromboembolism the composite of DVT and non-fatal or fatal pulmonary embolism 3. PE n=4,817 HR,.49; 95% CI,.31 to.79 p=.3 RECURRENT SYMPTOMATIC VTE (%) a PE TIME TO EVENT (DAYs) n=4,832 HR, 1.12; 95% CI,.75 to 1.68 p=.3 (non-inferiority) major bleeding (%) b TIME TO EVENT (DAYs) enoxaparin + VKA Graph adapted from Büller H.R., et al (ARR 1.1%) 27 3 RRR 51% Indications enoxaparin + VKA Graph adapted from Büller H.R., et al Comparable rates of clinically relevant bleeding vs. enoxaparin followed by VKA b 249 pts 1.3% enoxaparin + VKA 274 pts 11.4% HR,.9; 95% CI,.76 to 1.7; p=.23 a b Primary efficacy endpoint. Primary safety endpoint. ARR=absolute risk reduction; CI=confidence interval; DVT=deep vein thrombosis; HR=hazard ratio; * Bleeding was defined as major if it was clinically overt and associated with a decrease in the hemoglobin OAC=oral anticoagulant; PE=pulmonary embolism; RRR=relative risk reduction; VKA=vitamin K level of 2. g per deciliter or more, if bleeding led to the transfusion of 2 or more units of red cells, or if 14 antagonist; VTE=venous thromboembolism. bleeding was intracranial or retroperitoneal, occurred in another critical site, or contributed to death. 15

9 Acute Coronary Syndrome Patient Selection Matters Indication mg BID, co-administered with ASA alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an ACS with elevated cardiac biomarkers a Ensure responsible use: 2.5 mg BID for 12 months Appropriate patients for 2.5 mg BID in combination with standard antiplatelet therapy 1,b Adult patients after an acute coronary syndrome with elevated cardiac biomarkers a without prior stroke/ TIA Exclude patients with Active clinically significant bleeding 2.5 mg twice daily in combination with standard antiplatelet therapy b With or without food 1 Current or recent condition at significant risk of major bleeding (such as GI bleeding, ICH) Concomitant anticoagulation History of stroke or transient ischaemic attack (TIA) Indications Treatment beyond 12 months (up to 24 months) should be done on an individual patient basis d For renally impaired patients 1 Creatinine Clearance Recommended Dosage 3 49 ml/min 2.5 mg twice daily c ml/min 2.5 mg twice daily, use with caution <15 ml/min Not recommended Important notes 1 Initiate 2.5 mg BID as soon as possible after stabilisation of the ACS event At the earliest 24 hours after admission to hospital When parenteral anticoagulation therapy would normally be discontinued Therapy with 2.5 mg BID is recommended for 12 months. Extension of treatment beyond 12 months should be done on an individual patient basis d Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C Use not recommended in patients with Creatinine clearance <15 ml/min Concomitant systemic treatment with strong concurrent CYP3A4- and P-gp-inhibitors Efficacy and safety of 2.5 mg BID has been investigated in combination with the antiplatelet agents aspirin and clopidogrel / ticlopidine. Treatment in combination with other antiplatelet agents, e.g. prasugrel or ticagrelor, has not been studied and is not recommended For full list of contraindications please see page 32 of this document and the full SmPC Use with caution in patients with Expected increased bleeding risk, e.g. Creatinine clearance ml/min Other risk factors 75 years of age or with low body weight (<6 kg) Refer to full SmPC before prescribing a b c d Troponin-I/T; creatine kinase muscle and brain isoenzyme (CK-MB). Acetylsalicylic acid (ASA) alone or ASA plus clopidogrel or ticlopidine. Use with caution when concomitantly receiving other medicinal products which increase plasma concentrations. Experience up to 24 months is limited. The use of 2.5 mg BID in combination with standard antiplatelet therapy b in patients at known increased risk for bleeding should be balanced against the benefit in terms of prevention of atherothrombotic events 1 ACS=acute coronary syndrome; ASA=acetylsalicylic acid; BID=twice daily; GI=gastro intestinal; 16 ICH=intracranial haemorrhage. 17

10 ATLAS ACS 2-TIMI 51 Study Results 7,12 In ACS patients with elevated cardiac biomarkers a and without prior stroke or TIA, 2.5 mg BID in combination with standard antiplatelet therapy b reduces mortality and CV events further # : Significant reduction of CV mortality, MI or stroke (primary endpoint) 12 In ACS patients with elevated cardiac biomarkers a and without prior stroke or TIA, 2.5 mg BID in combination with standard antiplatelet therapy b reduces mortality and CV events further # : Significant reduction of CV mortality 12 CV Death, MI or stroke C (%) n=12,353 HR,.8; 95% CI,.68 to.94 p=.7 (superiority) 54 RRR 2% 72 CV Death (%) n=12,353 HR,.55; 95% CI,.41 to.74 p<.1 (superiority) 54 RRR 45% 72 Indications TIME TO EVENT (days) TIME TO EVENT (days) 2.5 mg BID* placebo* 2.5 mg BID* placebo* Graph adapted from Mega JL, et al Significant reduction of all-cause mortality 12 All-cause mortality (%) TIME TO EVENT (DAYs) n=12,353 HR,.58; 95% CI,.44 to.77 p<.1 (superiority) 54 RRR 42% 72 Graph adapted from Mega JL, et al In ACS patients with elevated cardiac biomarkers a and without prior stroke or TIA, 2.5 mg BID in combination with standard antiplatelet therapy b Increased, as expected, the rate of non-cabg TIMI major bleeding c (p<.1) 7,12 Showed comparable rates of fatal bleeding and fatal ICH throughout the two year study 7,12 Placebo in combination with standard antiplatelet therapy b n=4, mg BID in combination with standard antiplatelet therapy b n=4,96 Non-CABG TIMI major bleeding c 16 events (.7%) p<.1 54 events (1.9%) 2.5 mg BID placebo ICH 4 events (.2%) p=ns 1 events (.4%) Graph adapted from Mega JL, et al Fatal bleeding 8 events (.3%) p=ns 3 events (.1%) Fatal ICH 3 events (.2%) p=ns 2 events (.1%) a Troponin-I/T; creatine kinase muscle and brain isoenzyme (CK-MB). b ASA alone or ASA plus clopidogrel or ticlopidine. c Primary efficacy endpoint: Composite of CV death, MI or stroke. * In combination with ASA alone or ASA plus clopidogrel or ticlopidine. # Beyond ASA alone or ASA plus clopidogrel or ticlopidine. a Troponin-I/T; creatine kinase muscle and brain isoenzyme (CK-MB). b ASA alone or ASA plus clopidogrel or ticlopidine. ACS=acute coronary syndrome; ASA=acetylsalicylic acid; BID=twice daily; CABG=coronary artery bypass c is TIMI major bleeding event is defined as any intracranial bleeding of clinically overt bleeding event that graft; CI=confidence interval; CV=cardiovascular; HR=hazard ratio; MI=myocardial infarction; NS=not associated with a decrease in haemoglobin of >5g/dl or an absolute drop in haematorcrit of >15%. 18 statistically relevant; RRR=relative risk reduction; TIA=transient ischemic attack; TIMI=thrombolysis in * In combination with ASA alone or ASA plus clopidogrel or ticlopidine. myocardial infarction. # Beyond ASA alone or ASA plus clopidogrel or ticlopidine. 19

11 Think Responsible Use INR testing was developed for measuring VKA effects If the pharmacodynamic effects of VKA during a conversion period wish to be known, INR measurement can be used at the C through of (24 hours after the previous intake of ) as this test is minimally affected by at this time point all dosages INR values are minimally affected 24h after last intake of Neuraxial anaesthesia Catheters At least 18 hours should elapse after the last administration of before removal of an epidural catheter Following removal of the catheter, at least 6 hours should elapse before the next dose is administered If traumatic puncture occurs, the administration of should be delayed for 24 hours 24h Last dose Catheter removed Next dose Perioperative management for patients on Stop 24 hrs before surgery Surgery Restart Once haemostasis is achieved should be stopped at least 24 hours before the intervention 2.5 mg should be stopped at least 12 hours before the intervention If the procedure cannot be delayed the increased risk of bleeding should be assessed against the urgency of the intervention should be RESTARTED after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows, and adequate haemostasis has been established Wait 18 hours Wait 6 hours Switching patients following elective hip or knee replacement surgery 1 In case a patient has been given a LMWH post surgery, e.g. because of vomiting, start to 2 hours before the time of the next scheduled administration of LMWH Surgery Stop LMWH LMWH (sc) Switch to to 2 hours before the next scheduled administration of LMWH 2 h Continue One 1 mg tablet, once daily No routine coagulation monitoring required a Responsible Use 2 LMWH=low-molecular-weight heparin; sc=subcutaneous; VKA=vitamin K antagonist. 21 a INR values should not be used as they are not dependable measure of the anticoagulant activity of

12 Switching Patients from VKA to VKA Stop VKA INR testing (duration according to individual decrease of VKA plasma levels) Switching patients with non-valvular AF treated for prevention of stroke and systemic embolism 1 Treatment with VKAs should be stopped PREVENTION OF STROKE AND SYSTEMIC EMBOLISM: Initiate once INR 3. TREATMENT OF DVT AND PE AND PREVENTION OF RECURRENT DVT AND PE: Initiate once INR 2.5 See dosing recommendations for required daily dose. To assess the residual effect of VKAs, closely monitor the INR therapy should be initiated when the INR is 3. Switching Patients from to VKA Switching patients with non-valvular AF treated for prevention of stroke and systemic embolism 1 It is important to ensure adequate anticoagulation while minimising the risk of bleeding during conversion of therapy When converting to VKA, administration of and VKA should overlap until the INR is 2.. For the first two days of the conversion period, standard initial dosing of VKA should be used followed by VKA dosing guided by INR testing INR measurement is not appropriate to measure the anticoagulant activity of. While patients are on both and VKA the INR should not be tested earlier than 24 hours after the previous dose but prior to the next dose of. Once is discontinued, INR values obtained at least 24 hours after the last dose reliably reflect the VKA dosing After intake of INR values will be falsely elevated and should not be used Switching patients treated for DVT or PE or treated to prevent the recurrence of DVT and PE 1 Treatment with VKAs should be stopped To assess the residual effect of VKAs, closely monitor the INR Responsible Use therapy should be initiated when the INR is 2.5 After intake of INR values will be falsely elevated and should not be used 22 AF=atrial fibrillation; DVT=deep vein thrombosis; PE=pulmonary embolism; VKA=vitamin K antagonist. 23

13 Switching Patients from LMWH to Switching Patients from to LMWH Start to 2 hours before the time of the next scheduled administration of parenteral anticoagulant. If a continuously-administered intravenous anticoagulant, e.g. unfractionated heparin, is used, start when this treatment is discontinued Give the first dose of parenteral anticoagulant when the next dose would have been taken days all dosages LMWH days LMWH all dosages Switching patients treated for DVT or PE or prevention of recurrent DVT and PE 1 Dosing for patients on anticoagulation therapy for the first 3 weeks Start to 2 hours before the time of the next scheduled administration of LMWH Continue the twice-daily regimen of until patients have received a total of 3 weeks of anticoagulant therapy, then switch to the once-daily regimen of according to the label LMWH (sc) Responsible Use STOP LMWH Switch to to 2 hours before the next scheduled administration of LMWH CONTINUE XARELTO After 21 Days -2 h One 15 mg tablet twice daily b No routine coagulation monitoring required a One 2 mg tablet once daily b Dosing for patients on anticoagulation therapy after 3 weeks Start to 2 hours before the time of the next scheduled administration of LMWH LMWH (sc) STOP LMWH Switch to to 2 hours before the next scheduled administration of LMWH CONTINUE XARELTO One 2 mg tablet, once daily b a INR values should not be used as they are not a dependable measure of the anticoagulant activity of b For dosing for renally impaired patients, see page h No routine coagulation monitoring required a LMWH=low-molecular-weight heparin; DVT=deep vein thrombosis; PE=pulmonary embolism; 24 sc=subcutaneous. 25

14 Missed Dose Overdose Once-daily treatment of 1 / 15 / 2 mg 1 Due to limited absorption a ceiling effect with no further increase in average plasma exposure is expected at supratherapeutic doses of 5 mg and above A specific reversal agent antagonising the pharmacodynamic effect of is not available If a dose is missed, the patient should take immediately Continue on the following day with the once daily intake as recommended The use of activated charcoal to reduce absorption in case of overdose may be considered The dose should not be doubled within the same day to make up for a missed dose Twice daily treatment phase of 15 mg 1 If a dose is missed, the patient should take immediately to ensure intake of 3 mg per day, in this case two 15 mg tablets may be taken at once Continue with the regular 15 mg twice daily intake on the following day Responsible Use Twice daily treatment of 2.5 mg 1 If a dose is missed the patient should continue with the regular dose as recommended at the next scheduled time The dose should not be doubled to make up for a missed dose 26 27

15 Bleeding Management Severity of bleeding Minor 1. Delay next dose or discontinue * Major 2. Symptomatic & Local Measures: 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, as appropriate) Life-Threatening 3. Special Haemostatic Management Consider coagulation factor products PCC, apcc/feiba, Factor VIIa Responsible Use * half-life: 5 13 hours. Temporary or permanent discontinuation should always balance the risk of 28 bleeding against the increased risk of ischaemia occasioned by the discontinuation. 29

16 Think Responsible Use Like all anticoagulants, may increase the risk of bleeding Patients potentially at higher risk of bleeding 1 is not recommended for use 1 In patients below 18 years of age In patients with creatinine clearance <15 ml/min Patients with decreased renal function Elderly patients Patients concomitantly receiving certain other drugs affecting haemostasis (such as NSAIDs, ASA, platelet aggregation inhibitors) or increasing plasma concentrations (concomitant inhibitors of CYP3A4 and P-gp) Patients with other risk factors for bleeding Several sub-groups of patients are at increased risk and should be carefully monitored for signs and symptoms of bleeding complications. Treatment decision in these patients should be done after assessment of treatment benefit against the risk for bleeding Patients with decreased renal function: See dosing recommendations for patients with moderate (creatinine clearance 3 49 ml/min) or severe (15 29 ml/min) renal impairment. is to be used with caution in patients with creatinine clearance ml/min and in patients with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations. Use of is not recommended in patients with creatinine clearance <15 ml/min Patients concomitantly receiving other medicinal products Systemic azole antimycotics (such as ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g. ritonavir): use of is not recommended Care is to be taken in patients concomitantly receiving drugs affecting hemostasis such as NSAIDs, acetylsalicylic acid, platelet aggregation inhibitors After an acute coronary syndrome patients on treatment with and ASA or and ASA plus clopidogrel/ ticlopidine should only receive concomitant treatment with NSAIDs if the benefit outweighs the bleeding risk Other anticoagulants are contraindicated in patients treated with In patients receiving concomitant systemic treatment with strong inhibitors of both CYP3A4 and P-gp such as azoleantimycotics (ketoconazole, itraconazole, voriconazole and posaconazole) or HIV protease inhibitors (e.g., ritonavir) In patients with prosthetic heart valves As an alternative to UFH in patients with PE who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy In patients receiving concomitant treatment with strong CYP3A4 inducers unless they are closely observed for signs and symptoms of thrombosis Given the limited clinical data available with dronedarone, co-administration with should be avoided Efficacy and safety of 2.5 mg BID has been investigated in combination with the antiplatelet agents aspirin and clopidogrel / ticlopidine. Treatment in combination with other antiplatelet agents, e.g. prasugrel or ticagrelor, has not been studied and is not recommended Other haemorrhagic risk factors 1 As with other antithrombotics, 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 Bronchiectasis or history of pulmonary bleeding Responsible Use ASA=acetylsalicylic acid; BID=twice daily; NSAIDs=nonsteroidal anti-inflammatory drugs; PE=pulmonary 3 embolism; UFH=unfractionated heparin. 31

17 Contraindications References is contraindicated in case of 1 Hypersensitivity to the active substance or to any of the excipients Active clinically significant bleeding Lesion or condition if considered to be a significant risk for major bleeding such as current or recent GI 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 the circumstances of switching anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter Hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C 1. (rivaroxaban) Summary of Product Characteristics as approved by the European Commission. 2. Kubitza D et al. Clin Pharmacol Drug Dev. 213;2(3): Clexane (summary of product characteristics): Guildford, Surrey, United Kingdom: Sanofi-Aventis; December Patel MR et al. N Engl J Med. 211;365(1): EINSTEIN Investigators et al. N Engl J Med. 1;363(26): EINSTEIN-PE Investigators et al. N Engl J Med. 212;366(14): Mega JL et al. N Engl J Med. 212;366(1): Eriksson BI et al. J Bone Joint Surg Br. 29;91(5): Prins MH et al. Thromb J. 213;11(1): Prins MH et al. The Lancet Haematol. 214;1(1):e37 e Fox KA et al. Eur Heart J. 211;32(19): Mega JL et al. Poster presented at European Society of Cardiology (ESC), 3 August 3 September 214; Barcelona, Spain. Pregnancy and breast feeding 2.5 mg BID is also contraindicated in case of 1 Prior stroke or TIA References 32 GI=gastrointestinal; TIA=transient ischaemic attack; UFH=unfractionated heparin. 33

18 2.5 mg film-coated tablets (Refer to full SmPC before prescribing.) This medicinal product is subject to additional monitoring. Composition: Active ingredient: 2.5 mg rivaroxaban. Excipients: Microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, hypromellose, sodium laurilsulfate, magnesium stearate, macrogol 335, titanium dioxide (E171), iron oxide yellow (E172). Indication: Prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine. Contraindications: Hypersensitivity to the active substance or any of the excipients; active clinically significant bleeding; lesion or condition considered a significant risk for major bleeding; concomitant treatment with any other anticoagulants except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter; concomitant treatment of ACS with antiplatelet therapy in patients with a prior stroke or a transient ischaemic attack (TIA); hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C; pregnancy and breast feeding. Warnings and Precautions: Clinical surveillance in line with anticoagulation practice is recommended throughout treatment. should be discontinued if severe haemorrhage occurs. Increasing age may increase haemorrhagic risk. Not recommended: in patients with severe renal impairment (creatinine clearance <15 ml/min); in patients receiving concomitant systemic treatment with strong concurrent CYP3A4- and P-gp-inhibitors, i.e. azole-antimycotics or HIV protease inhibitors; in patients with increased bleeding risk; in patients receiving concomitant treatment with strong CYP3A4 inducers unless the patient is closely observed for signs and symptoms of thrombosis; not recommended due to lack of data: treatment in combination with antiplatelet agents other than ASA and clopidogrel/ticlopidine; in patients below 18 years of age; in patients concomitantly treated with dronedarone. Use with caution: in conditions with increased risk of haemorrhage; in patients with severe renal impairment (creatinine clearance ml/min) or with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations; in patients treated concomitantly with medicinal products affecting haemostasis; in patients >75 years of age or with low body weight; when neuraxial anaesthesia or spinal/epidural puncture is employed. Patients on treatment with and ASA or and ASA plus clopidogrel/ticlopidine should only receive concomitant treatment with NSAIDs if the benefit outweighs the bleeding risk. In patients at risk of ulcerative gastrointestinal disease prophylactic treatment may be considered. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations. contains lactose. Undesirable effects: Common: anaemia, dizziness, headache, eye haemorrhage, hypotension, haematoma, epistaxis, haemoptysis, gingival bleeding, gastrointestinal tract haemorrhage, gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, pruritus, rash, ecchymosis, cutaneous and subcutaneous haemorrhage, pain in extremity, urogenital tract haemorrhage, renal impairment, fever, peripheral oedema, decreased general strength and energy, increase in transaminases, post-procedural haemorrhage, contusion, wound secretion. Uncommon: thrombocythemia, allergic reaction, dermatitis allergic, cerebral and intracranial haemorrhage, syncope, tachycardia, dry mouth, hepatic function abnormal, urticaria, haemarthrosis, feeling unwell, increases in: bilirubin, blood alkaline phosphatase, LDH, lipase, amylase, GGT. Rare: jaundice, muscle haemorrhage, localised oedema, bilirubin conjugated increased, vascular pseudoaneurysm (uncommon in prevention therapy in ACS following percutaneous intervention). Frequency not known: compartment syndrome or (acute) renal failure secondary to a bleeding, angioedema and allergic oedema (uncommon in pooled phase III trials). Classification for supply: Medicinal product subject to medical prescription. Marketing Authorisation Holder: Bayer Pharma AG, D Berlin, Germany Further information available from: xarelto.medinfo@bayer.com Version: EU/3 1 mg / 15 mg / 2 mg film-coated tablets (Refer to full SmPC before prescribing.) This medicinal product is subject to additional monitoring. Composition: Active ingredient: 1 mg / 15 mg / 2 mg rivaroxaban. Excipients: Microcrystalline cellulose, croscarmellose sodium, lactose monohydrate, hypromellose, sodium laurilsulfate, magnesium stearate, macrogol 335, titanium dioxide (E171), iron oxide red (E172). Indications: 1 mg: Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. 15 mg/2 mg: Prevention 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. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. Special populations: Patients undergoing cardioversion: can be initiated or continued in patients who may require cardioversion. Contraindications: Hypersensitivity to the active substance or any of the excipients; active clinically significant bleeding; lesion or condition if considered a significant risk for major bleeding; concomitant treatment with any other anticoagulants except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin is given at doses necessary to maintain an open central venous or arterial catheter; hepatic disease associated with coagulopathy and clinically relevant bleeding risk including cirrhotic patients with Child Pugh B and C; pregnancy and breast feeding. Warnings and Precautions: Clinical surveillance in line with anticoagulation practice is recommended throughout treatment. should be discontinued if severe haemorrhage occurs. Increasing age may increase haemorrhagic risk. Not recommended: in patients with severe renal impairment (creatinine clearance <15 ml/min); in patients receiving concomitant systemic treatment with strong concurrent CYP3A4- and P-gp-inhibitors, i.e. azole-antimycotics or HIV protease inhibitors; in patients with increased bleeding risk; in patients receiving concomitant treatment with strong CYP3A4 inducers unless the patient is closely observed for signs and symptoms of thrombosis; not recommended due to lack of data: in patients below 18 years of age, in patients concomitantly treated with dronedarone. 15 mg / 2 mg add*: in patients with prosthetic heart valves, in patients with PE who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy. Use with caution: in conditions with increased risk of haemorrhage; in patients with severe renal impairment (creatinine clearance ml/min) or with renal impairment concomitantly receiving other medicinal products which increase rivaroxaban plasma concentrations; in patients treated concomitantly with medicinal products affecting haemostasis; when neuraxial anaesthesia or spinal/epidural puncture is employed; 15 mg / 2 mg add*: specific dose recommendations apply for patients with moderate to severe renal impairment and in case of DVT/PE-patients only if the patient s assessed risk for bleeding outweighs the risk for recurrent DVT/PE. In patients at risk of ulcerative gastrointestinal disease prophylactic treatment may be considered. Although treatment with rivaroxaban does not require routine monitoring of exposure, rivaroxaban levels measured with a calibrated quantitative anti-factor Xa assay may be useful in exceptional situations. contains lactose. Undesirable effects: Common: anaemia, dizziness, headache, eye haemorrhage, hypotension, haematoma, epistaxis, haemoptysis, gingival bleeding, gastrointestinal tract haemorrhage, gastrointestinal and abdominal pains, dyspepsia, nausea, constipation, diarrhoea, vomiting, pruritus, rash, ecchymosis, cutaneous and subcutaneous haemorrhage, pain in extremity, urogenital tract haemorrhage (menorrhagia very common in women <55 years treated for DVT, PE or prevention of recurrence), renal impairment, fever, peripheral oedema, decreased general strength and energy, increase in transaminases, post-procedural haemorrhage, contusion, wound secretion. Uncommon: thrombocythemia, allergic reaction, dermatitis allergic, cerebral and intracranial haemorrhage, syncope, tachycardia, dry mouth, hepatic function abnormal, urticaria, haemarthrosis, feeling unwell, increases in: bilirubin, blood alkaline phosphatase, LDH, lipase, amylase, GGT. Rare: jaundice, muscle haemorrhage, localised oedema, bilirubin conjugated increased, vascular pseudoaneurysm. Frequency not known: compartment syndrome or (acute) renal failure secondary to a bleeding, angioedema and allergic oedema (uncommon in pooled phase III trials). Classification for supply: Medicinal product subject to medical prescription. Marketing Authorisation Holder: Bayer Pharma AG, D Berlin, Germany Further information available from: xarelto.medinfo@bayer.com Version: EU/4 * add = additional precautions to be followed for individual dosages Short SmPC 34

19 Think Highly effective clot treatment and prevention with more licensed indications than any other novel OAC a,1 Only approved once-daily novel OAC for stroke prevention in adult patients with non-valvular AF with over 2 years of real world experience #,1 Only oral single drug approach for treatment of DVT and PE and prevention of recurrent VTE with over 2 years of real world experience 1,+ Only approved novel OAC for secondary prevention after ACS in combination with standard antiplatelet therapy in adults 1,** First licensed in 28 in VTE prevention in adults following elective hip or knee replacement surgery 1 Broad real life experience millions of patients treated because Matters Please visit ThrombosisAdviser.com and Xarelto.com a OAC=oral anticoagulant. # With 1 additional risk factor such as congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischaemic attack. + Not recommended as an alternative to unfractionated heparin in patients with PE who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy. Acetylsalicylic acid (ASA) alone or ASA plus clopidogrel or ticlopidine. ** With elevated biomarkers Troponin-I/T; creatine kinase-muscle and brain isoenzyme (CK-MB). Based on an estimated calculation of IMS sales data (Source: IMS Health MIDAS, Database: Monthly Sales July 214). Please note that details of the marketing authorization for rivaroxaban as noted in this document, including the approved indications, may differ from those in your country. Therefore you should always be guided by your local Prescribing Information. BHP/1668/315 L.DE.GM Bayer HealthCare Pharmaceuticals March 215