1 Effective practical management of patients with thromboembolic disorders using rivaroxaban Symposium at the 58 th Annual Meeting of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis June 28, 2012 in Liverpool, UK Distributed in association with Item Code: L.GB Date of Preparation: November 2012 This supplement and the symposium on which it is based were sponsored by Bayer HealthCare Pharmaceuticals. Prescribing Information can be found on page 9.
2 3 Effective practical management of patients with thromboembolic disorders using rivaroxaban Introduction Management of thromboembolic disorders has been transformed with the introduction of novel oral anticoagulants such as the direct Factor Xa inhibitors rivaroxaban and apixaban, and the direct thrombin inhibitor dabigatran. Rivaroxaban is the only oral, non-vitamin K antagonist (VKA) anticoagulant that has been approved for three indications in Europe, commencing with approval in 2008 for the prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. This was followed in 2011 by successive approvals for the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (AF), and the treatment of deep vein thrombosis (DVT) and prevention of recurrent DVT and pulmonary embolism (PE) after an acute DVT in adults. Rivaroxaban is currently the only novel oral anticoagulant that has been approved in this latter indication. In the US, rivaroxaban also gained approval in 2011 for prophylaxis of DVT, which may lead to PE, in adults undergoing hip or knee replacement surgery, and for stroke prevention in patients with non-valvular AF. It is anticipated that rivaroxaban use in clinical practice will increase in the future; therefore, physicians need to gain experience and confidence using the drug across both venous and arterial thromboembolic (VAT) disorders. This review highlights important topics relating to practical patient management with rivaroxaban that were discussed by Dr Alexander Cohen (King s College Hospital, London, UK) and an Expert Panel (see Appendix) at the 58 th Annual Meeting of the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis, held in Liverpool, UK, on 28 June The Expert Panel comprised leaders in the fields of haematology, vascular medicine, orthopaedic surgery and palliative care. What are the appropriate doses of rivaroxaban for the venous and arterial indications? Rivaroxaban is approved in three VAT indications. In each case, dose selection was based on data from phase II clinical trials, population pharmacokinetic modelling or a combination of the two. Across all approved indications, rivaroxaban does not need dose adjustment for age, weight or sex, and does not require routine coagulation monitoring (1). Prevention of venous thromboembolism after elective hip or knee replacement surgery The selection of a 10 mg once daily (od) rivaroxaban dose for VTE prevention was derived from four phase II dose-finding studies (2 5). Total daily doses of 5 60 mg of rivaroxaban (od and twicedaily [bid] regimens) were shown to have efficacy similar to enoxaparin, with a dose-dependent effect on major bleeding in patients undergoing total hip or knee replacement surgery. The rivaroxaban 10 mg od dose was chosen for investigation in the phase III RECORD programme because it provided the most favourable balance between efficacy and safety, relative to enoxaparin (4). Support for od dosing was provided by a study in healthy volunteers, which showed that rivaroxaban inhibits peak thrombin generation for up to 24 hours (6). The half-life of rivaroxaban has been shown to range from 5 to 9 hours in young individuals and from 11 to 13 hours in the elderly (1). The dose selection was confirmed by phase III data in patients undergoing total hip or total knee replacement surgery, which showed that rivaroxaban 10 mg od was superior to enoxaparin for reductions in total VTE (the composite of DVT, non-fatal PE and all-cause mortality), without significantly increasing the risk of major bleeding (7 10). Treatment of deep vein thrombosis Previous studies of VTE treatment with ximelagatran and idraparinux showed high rates of recurrence during the first 2 4 weeks of treatment, suggesting that a more intense anticoagulation regimen may be beneficial in the acute treatment phase (11, 12). In the ODIXa-DVT phase II study, rivaroxaban bid regimens were shown to optimise clot regression over 3 weeks (13); on this basis, rivaroxaban 15 mg bid was selected for the first 3 weeks of Approved indications for rivaroxaban* Prevention of VTE in adult patients undergoing elective hip or knee replacement surgery Prevention of stroke and systemic embolism in adult patients with non-valvular AF 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 DVT and prevention of recurrent DVT and PE following an acute DVT in adults *The approval status of rivaroxaban may differ between countries. Please refer to the approval status of rivaroxaban in your country.
3 4 treatment. The benefits of anticoagulation must always be balanced against the risks of bleeding, and this is a key factor when considering continued and long-term treatment. Phase II studies demonstrated that rivaroxaban was effective, with a good safety profile across a range of doses tested. However, the relative safety of rivaroxaban, in terms of bleeding versus standard therapy, was better for od versus bid regimens (13, 14). To provide adequate protection but minimise the risk of bleeding, the lowest effective dose of 20 mg od was selected for continuous and long-term treatment (14). The phase III EINSTEIN DVT, EINSTEIN PE and EINSTEIN EXT studies confirmed the efficacy and safety profile of rivaroxaban at the selected doses (15, 16). Pharmacokinetic studies indicated that as expected rivaroxaban clearance was reduced in patients with decreased renal function but that this did not lead to an increase in major bleeding (17). Stroke prevention in patients with atrial fibrillation Achieving the optimal balance between benefit and risk is crucial in patients with AF who require long-term anticoagulation therapy. Because of the structural similarities between venous clots and clots associated with AF (18), data from the phase II DVT treatment studies were used to develop a pharmacokinetic model for predicting exposure in patients with AF (19). Based on these data, a rivaroxaban 20 mg od dose was selected for stroke prevention in patients with AF, with a reduced 15 mg od dose being recommended for patients with moderate or severe renal impairment (creatinine clearance [CrCl] ml/min) (19). Results of a phase III study, ROCKET AF, confirmed the dose selections and demonstrated that, in patients with moderate renal impairment, the lower rivaroxaban dose yielded results that were consistent with the overall trial results (20, 21). For each indication, the dosing regimen has been tailored to the patient population to provide the optimum benefit risk balance with rivaroxaban. What is the recommended duration of rivaroxaban therapy? Physicians will always need to consider the duration of therapy and this varies according to the thromboembolic disorder. In all cases, there is a need to balance prevention or treatment of the thromboembolic disorder with the risk of bleeding associated with the use of any anticoagulant. The decision on how long to treat should be based on clinical judgement and discussion with the patient. Prevention of venous thromboembolism after elective hip or knee replacement surgery The recommended duration of rivaroxaban thromboprophylaxis is dependent on the type of surgery. Rivaroxaban 10 mg od is recommended for 5 weeks in patients undergoing major hip replacement surgery and for 2 weeks in patients undergoing major knee replacement surgery (1). Treatment of deep vein thrombosis As with other anticoagulants, the treatment duration of rivaroxaban should be based on clinical judgement of the treatment benefit against the risk of bleeding. Guidelines recommend at least 3 months treatment, irrespective of risk factors, and extended therapy is recommended in patients with unprovoked VTE if the risk of bleeding is low or moderate (22). In line with guidelines, rivaroxaban should be given for 3 months in patients with transient risk factors and for longer durations in patients with permanent risk factors or unprovoked DVT. The EINSTEIN EXT study showed that, in patients where there was uncertainty about whether to continue treatment, long-term rivaroxaban 20 mg od for an additional 6 or 12 months after initial treatment significantly reduced the risk of recurrent VTE versus placebo. This was achieved without a significant increase in the risk of major bleeding (15). The maximum total duration of rivaroxaban treatment in this study was 21 months, but real-world experience with rivaroxaban for more than 12 months is limited (1). Stroke prevention in patients with atrial fibrillation For patients with AF who have one or more risk factors for stroke or systemic embolism, such as congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischaemic attack, rivaroxaban 20 mg od (or 15 mg od in patients with moderate or severe renal impairment; CrCl ml/min) should be continued long-term, provided that the benefits of prevention of stroke and systemic embolism outweigh the risk of bleeding (1). Table 1 provides a summary of rivaroxaban dosing regimens and the recommended duration of therapy for each indication. How should patients taking rivaroxaban be managed in the perioperative setting? If a patient is undergoing planned surgery, rivaroxaban should be stopped at least 24 hours before the operation, if possible. In some
4 5 Table 1 Summary of dosing regimens and the recommended duration of therapy for approved rivaroxaban indications (1). Indication Dose Recommended duration VTE prevention after elective hip or knee replacement surgery Treatment of DVT and recurrent DVT and PE Stroke prevention in patients with AF 10 mg od 2 weeks after knee replacement surgery 15 mg bid From day 21 onwards: 20 mg od 5 weeks after hip replacement surgery 3 weeks 3 months in patients with transient risk factors Longer durations in patients with permanent risk factors or unprovoked DVT 20 mg od For as long as the risk of stroke outweighs the risk of bleeding Dose adjustment No. Not recommended in patients with CrCl <15 ml/min No. Not recommended in patients with CrCl <15 ml/min No 15 mg od in patients with moderate (CrCl ml/min) or severe* (15 29 ml/min) renal impairment Not recommended in patients with CrCl <15 ml/min 15 mg od in patients with moderate (CrCl ml/min) or severe* (15 29 ml/min) renal impairment Not recommended in patients with CrCl <15 ml/min * Use caution in these patients. AF, atrial fibrillation; bid, twice daily; CrCl, creatinine clearance; DVT, deep vein thrombosis; od, once daily; PE, pulmonary embolism; VTE, venous thromboembolism. cases for example, for minor interventions such as dental surgery the procedure may be undertaken earlier based on the clinical judgement of the physician (1). After planned surgery, rivaroxaban should be restarted as soon as possible after the intervention, provided the clinical situation allows and adequate haemostasis has been established (1). After uncomplicated surgery, adequate haemostasis usually occurs within 6 8 hours. Even with the introduction of novel oral anticoagulants, such as rivaroxaban, many patients will still be taking VKAs. For patients who require temporary interruption of VKA therapy before surgery, it is recommended that VKA therapy is stopped approximately 5 days before the intervention; for patients with AF or VTE who are at high risk of thromboembolism, guidelines suggest that bridging therapy may be beneficial (23). If anticoagulant therapy is resumed after an intervention, rivaroxaban has a practical advantage over VKAs because it provides immediate effective anticoagulation. If a VKA is used, low-molecular-weight heparin (LMWH) bridging is necessary until the international normalised ratio (INR) is within range. Can rivaroxaban be measured or monitored? In normal circumstances, rivaroxaban does not require routine coagulation measuring, monitoring, or individual dose adjustment (1). However, plasma concentrations of rivaroxaban can be measured if needed, which may be particularly important in certain clinical situations for example, prior to emergency surgery or intervention in patients who experience a thrombotic or haemorrhagic event, or if there is suspicion of overdose. Anti-Factor Xa chromogenic assays with rivaroxaban calibrators and controls are suitable for quantitative measurement of rivaroxaban in plasma (ng/ml) and are now available commercially (24). Haemostatic status can also be assessed qualitatively by prolongation of prothrombin time expressed in seconds using a sensitive reagent such as Néoplastine CI Plus (Diagnostica Stago) (25). However, this method is not sensitive at low plasma concentrations and, as a global clotting test, is not specific for rivaroxaban and thus subject to non-rivaroxaban-related variations. The INR should not be used for measuring the anticoagulant effect of rivaroxaban because it was developed specifically for measuring VKA activity (26). Although rivaroxaban also affects other coagulation assays, such as the activated partial thromboplastin time, prothrombinase-induced clotting time and the heparin clotting time, these tests are not suitable for measuring rivaroxaban and should not be used (26). How do you switch a patient between rivaroxaban and another anticoagulant? Switching from a vitamin K antagonist to rivaroxaban When switching a patient from a VKA to rivaroxaban, VKA therapy should be stopped, but INR monitoring should continue, to assess the remaining VKA activity. In patients with AF receiving anticoagulant therapy for stroke prevention, rivaroxaban should only be initiated when the INR is 3.0; in patients requiring treatment of DVT, the INR should be 2.5 (1) ( Figure 1).
5 6 Figure 1 Switching from a VKA to rivaroxaban in patients with AF or in those who require treatment for DVT (1). AF, atrial fibrillation; DVT, deep vein thrombosis; INR, international normalised ratio; VKA, vitamin K antagonist. Figure 4 Algorithm for how to manage bleeding if it occurs in a patient taking rivaroxaban (1). Figure 2 Switching from rivaroxaban to a VKA (1). INR, international normalised ratio; VKA, vitamin K antagonist. Owing to the slow onset of VKA activity, the VKA and rivaroxaban should initially be given concomitantly until an INR 2.0 is reached, at which point rivaroxaban can be stopped. During concomitant treatment with the VKA and rivaroxaban, INR testing should be performed to measure VKA activity. However, because rivaroxaban treatment can result in an elevated INR, a reliable measurement of the INR can only be obtained 24 hours after the last dose of rivaroxaban and prior to the next dose of rivaroxaban (1) ( Figure 2). Switching from a parenteral anticoagulant to rivaroxaban or rivaroxaban to a parenteral anticoagulant When switching a patient from a parenteral anticoagulant to rivaroxaban, rivaroxaban should be started 0 2 hours before the time of the next scheduled administration of LMWH or at the time of discontinuation of continuously administered intravenous unfractionated heparin ( Figure 3). In patients receiving rivaroxaban who need to be switched to a parenteral anticoagulant, the first dose of parenteral anticoagulant should replace the next scheduled rivaroxaban dose (1). Figure 3 Switching from parenteral LMWH to rivaroxaban (1). LMWH, low-molecular-weight heparin. Switching from rivaroxaban to a vitamin K antagonist In some situations, such as when a patient receiving rivaroxaban requires dual antiplatelet therapy for acute coronary syndrome, switching the patient from rivaroxaban to a VKA may be necessary. If bleeding occurs in a patient taking rivaroxaban, how should it be managed? Across the phase III clinical trials that supported the approved indications, overall rates of major bleeding with rivaroxaban were low and similar to standard of care (15, 20, 27). In ROCKET AF, rivaroxaban significantly reduced the incidence of intracranial haemorrhage one of the most feared complications of anticoagu-
6 7 Real-world clinical scenarios: Unlike clinical trials, patients often present with associated co-morbidities, and their management is not always straightforward. So, what should you do in the following situations? Patient Action Continued management Case 1 Patient had a DVT 2 weeks previously, after surgery Currently receiving rivaroxaban 15 mg bid but develops AF Do not change the rivaroxaban dose Case 2 Patient has AF and is receiving rivaroxaban 20 mg od Develops an unprovoked DVT after 1 month of treatment Case 3 Patient has AF and is receiving rivaroxaban 20 mg od but requires emergency surgery Case 4 Patient had a lower limb DVT 2 weeks ago after a period of prolonged immobilisation The patient is currently receiving rivaroxaban 15 mg bid but has a recurrent DVT Case 5 Patient had a proximal DVT 2 months ago after a period of prolonged immobilisation Currently receiving rivaroxaban 20 mg od but has a recurrent DVT Continue treatment with rivaroxaban 15 mg bid for a total of 3 weeks followed by 20 mg od (15 mg od in case of moderate or severe renal impairment) Increase the rivaroxaban dose to 15 mg bid for 3 weeks After 3 weeks, reduce the dose back down to rivaroxaban 20 mg od (15 mg od in case of moderate or severe renal impairment) Immediately stop rivaroxaban therapy Check patient compliance Consider alternative treatment with LMWH / VKA Check patient compliance Increase rivaroxaban dose to 15 mg bid for 3 weeks followed by 20 mg od Treat for at least 3 months and as long as the risk of stroke outweighs the risk of bleeding (CHA 2 DS 2 -VASc and HAS-BLED scores can be used) Continue treatment for at least 3 months, depending on risk factors for recurrence and as long as the risk of stroke outweighs the risk of bleeding Delay surgery for at least 24 hours if possible and based on clinical judgement, bearing in mind the relatively short half-life of rivaroxaban Measurement of rivaroxaban activity using an anti-factor Xa chromogenic assay could be considered If surgery can no longer be delayed and major bleeding occurs, use blood products and consider the use of a procoagulant agent, such as PCC Restart rivaroxaban therapy only once adequate haemostasis has been achieved Treat for 3 months and then re-evaluate the risk of recurrence Treat for 3 months and then re-evaluate the risk of recurrence AF, atrial fibrillation; bid, twice daily; DVT, deep vein thrombosis; LMWH, low-molecular-weight heparin; od, once daily; PCC, prothrombin complex concentrate; VKA, vitamin K antagonist. lation compared with warfarin, although major bleeding from a gastrointestinal site was more common with rivaroxaban (20). If a bleeding event does occur while a patient is receiving rivaroxaban, the management strategies are not new and are similar to those used with the traditional anticoagulants. These strategies include general measures, such as delaying the next dose or interrupting treatment. Because of the relatively short half-life of rivaroxaban, these measures will often be adequate to manage minor bleeding events (1). To manage more serious bleeding events, supportive measures such as mechanical compression, fluid replacement, haemodynamic support or blood products may be used in combination with general measures (1). If bleeding cannot be stopped by these strategies, the haemostatic procoagulant agents prothrombin complex concentrate (PCC), activated PCC and Factor VIIa can be considered, although clinical experience with these measures is limited (1). Figure 4 provides an algorithm for how to manage bleeding if it occurs in a patient taking rivaroxaban. A small study in healthy subjects has shown that PCC can immediately and completely reverse the anticoagulant effects of rivaroxaban (28).
7 8 Conclusions In clinical trials, rivaroxaban has demonstrated superiority for total VTE prevention and non-inferiority for the treatment of DVT and the prevention of stroke in patients with AF compared with the standard of care in these indications. Coupled with the reassuring safety profile of rivaroxaban, these data have led to its approval across the broadest range of VAT indications of the novel oral anticoagulants. Rivaroxaban has several practical advantages over traditional anticoagulants: unlike the heparins it is administered orally, and unlike the VKAs it does not require routine monitoring of coagulation, monitoring or dose adjustment, and has few drug drug interactions. The simple, single-drug approach with rivaroxaban for the treatment of DVT provides a further advantage over the traditional dual-drug approach of LMWH and VKA. In order to fully appreciate the efficacy, safety profile and practical benefits of rivaroxaban, it is vital that physicians manage patients responsibly. This includes knowing the correct dose and regimen of rivaroxaban to use in each patient and when to consider dose adjustment for renal impairment, what the appropriate duration of therapy is, how to safely switch patients between anticoagulants, and how to manage adverse events. Responsible use of rivaroxaban will allow physicians to improve the management of patients with thromboembolic disorders by ensuring that patients receive the optimal benefits of rivaroxaban without a compromise in safety. Appendix Expert Panel: Dr Alexander T Cohen, King s College Hospital, London, UK (Chair); Dr Gerard Dolan, University Hospital, Nottingham, UK; Dr Jan Beyer-Westendorf, Dresden University Clinic Vascular Medicine, Dresden, Germany; Dr Patrick Mouret, Orthopädische Klinik, Frankfurt, Germany; Dr Simon Noble, Royal Gwent Hospital, Newport, UK; Dr Raj Patel, King s College Hospital, London, UK References 1. Bayer Pharma AG. Xarelto Summary of Product Characteristics EU. May 2012 [document in the internet]. Berlin: Bayer HealthCare; 2012 [Accessed 2012 October 18]. Available from: Prescribing_Information-May-2012.pdf 2. Turpie AGG, Fisher WD, Bauer KA, et al. BAY : an oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study. J Thromb Haemost 2005; 3: Eriksson BI, Borris L, Dahl OE, et al. Oral, direct Factor Xa inhibition with BAY for the prevention of venous thromboembolism after total hip replacement. J Thromb Haemost 2006; 4: Eriksson BI, Borris LC, Dahl OE, et al. A once-daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY ), for thromboprophylaxis after total hip replacement. Circulation 2006; 114: Eriksson BI, Borris LC, Dahl OE, et al. Dose-escalation study of rivaroxaban (BAY ) an oral, direct Factor Xa inhibitor for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Res 2007; 120: Harder S, Graff J, Hentig NV, et al. Effects of BAY , an oral, direct Factor Xa inhibitor, on thrombin generation in healthy volunteers. Blood (ASH Annual Meeting Abstracts) 2003; 102: Abstract Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet 2008; 372: Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: Turpie AGG, Lassen MR, Davidson BL, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: Fiessinger JN, Huisman MV, Davidson BL, et al. Ximelagatran vs low-molecularweight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. JAMA 2005; 293: van Gogh Investigators, Büller HR, Cohen AT, et al. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007; 357: Agnelli G, Gallus A, Goldhaber SZ, et al. Treatment of proximal deep-vein thrombosis with the oral direct Factor Xa inhibitor rivaroxaban (BAY ): the ODIXa-DVT (oral direct Factor Xa inhibitor BAY in patients with acute symptomatic deep-vein thrombosis) study. Circulation 2007; 116: Büller HR, Lensing AW, Prins MH, et al. A dose-ranging study evaluating oncedaily oral administration of the Factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis. The EINSTEIN-DVT Dose-Ranging Study. Blood 2008; 112: The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: The EINSTEIN PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2010; 70: Goon PK, Lip GYH. Arterial disease and venous thromboembolism: a modern paradigm? Thromb Haemost 2006; 96: Mueck W, Lensing AW, Agnelli G, et al. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50: Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: Fox KAA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 2011; 32: Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th Ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141: e419s e494s. 23. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis: American College of Chest Physicians evidence-based clinical practice guidelines (9th Edition). Chest 2012; 141: e326s e350s. 24. Samama MM, Contant G, Spiro TE, et al. Evaluation of the anti-factor Xa chromogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 2012; 107: Samama MM, Contant G, Spiro TE, et al. Evaluation of the prothrombin time for measuring rivaroxaban plasma concentrations using calibrators and controls: results of a multicenter field trial. Clin Appl Thromb Hemost 2012; 18: Samama MM, Martinoli JL, Le Flem L, et al. Assessment of laboratory assays to measure rivaroxaban an oral, direct Factor Xa inhibitor. Thromb Haemost 2010; 103: Turpie AGG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 105: Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebocontrolled, crossover study in healthy subjects. Circulation 2011; 124:
8 9 Xarelto 10, 15 and 20 mg film-coated tablets (rivaroxaban) Prescribing Information (Refer to full Summary of Product Characteristics (SmPC) before prescribing) Presentation: 10mg/15mg/20mg rivaroxaban tablet Indication(s): 1. Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. 2. 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). 3. 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 (Hip/knee surgery): 10mg orally o.d. 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. Dosage 2 (SPAF): 20 mg orally o.d. with food. Dosage 3 (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 ml/min) no dose adjustment necessary; moderate (creatinine clearance ml/min) Hip/knee surgery: no dose adjustment necessary, SPAF: reduce dose to 15mg o.d., DVT-t: 15mg b.i.d. for 3 weeks, reduce maintenance dose to 15mg o.d.; severe (creatinine clearance ml/min) limited data indicates rivaroxaban concentrations are significantly increased, use with caution SPAF: reduce dose to 15mg o.d., DVT-t: 15mg 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: 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 other medicinal products which increase rivaroxaban concentrations; in patients treated concomitantly with medicines 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 / 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 strong CYP3A4 and P-gp inhibitors, e.g. azole-antimycotics or HIV protease inhibitors; Hip/knee surgery patients undergoing hip fracture surgery; SPAF & DVT-t only with prosthetic heart valves; for treatment of acute pulmonary embolism. Hip/knee surgery: Take special care when neuraxial anaesthesia or spinal/epidural puncture is employed due to risk of epidural or spinal haematoma with potential neurologic complications. SPAF & DVT-t only: 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. Clinical surveillance in line with anticoagulant practice is recommended throughout the treatment period. 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: 10mg 10 tablets: 21.00, 30 tablets: and 100 tablets: mg 28 tablets: 58.80, 42 tablets: 88.20, 100 tablets: ; 20mg 28 tablets: 58.80, 100 tablets MA Number(s): EU/1/08/472/ Further information available from: Bayer plc, Bayer House, Strawberry Hill, Newbury, Berkshire RG14 1JA, U.K. Telephone: Date of preparation: July Xarelto is a trademark of the Bayer Group. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Bayer plc. Tel.: +44 (0) , Fax.: +44 (0) ,
9 Imprint Text: Source: Chameleon Communications International Ltd., London, UK Symposium Xarelto: The First Factor Xa Oral Single Drug Approach for DVT Treatment and Thromboprophylaxis A Practical Overview on 28 June 2012 at the 58 th Annual Meeting of the Scientific and Standardisation Committee (SSC) in Liverpool, UK. This insert and the symposium on which it is based were sponsored by Bayer HealthCare Pharmaceuticals. Schattauer GmbH, Publishers for Medicine and Natural Sciences, Hölderlinstr. 3, Stuttgart, Germany Loose insert, distributed in association with the December 2012 issue of Thrombosis and Haemostasis Editorial Manager: Dr. Andrea Schürg, Stuttgart, Germany Editorial Staff: Dr. Elinor Switzer, Stuttgart, Germany Printed by: Mayr Miesbach GmbH, Prepress Printing Binding, Am Windfeld 15, Miesbach, Germany Neither the Publisher nor the Editors-in-Chief accept responsibility for the content of information published herein.
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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use POMALYST safely and effectively. See full prescribing information for POMALYST. POMALYST (pomalidomide)
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