Bedfordshire and Luton Joint Prescribing Committee

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1 Bedfordshire and Luton Joint Prescribing Committee December 2015 Updated: February 2016 Review: February 2019 Bulletin 224: Choice of Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) February 16 Update: Further to clarification from NICE, the nomenclature used throughout this bulletin has been change to refer to this class of drugs as Non-vitamin K antagonist Oral Anticoagulants (NOACs) instead of the previous nomenclature of DOACs (Direct Acting Anticoagulants). JPC Recommendation (Updated Feb 2016) Where more than one Non-Vitamin K antagonist Oral Anticoagulant (NOAC) is clinically suitable for a patient, the drug with the least acquisition cost in primary care should be initiated. Currently, the drug with the lowest acquisition cost in primary care is Edoxaban followed by Dabigatran, Rivaroxaban and Apixaban. A decision aid has been produced by East of England Priorities Advisory Committee (EoE PAC) (Updated March 2016) and this may be used to assist in the choice of NOAC. (N.B. This has been developed to support the use of NOACs principally for the AF indication). This decision aid is available for downloading via the GP Ref website listed under Advice and Guidance section: Anticoagulants in Atrial Fibrillation (AF) (EoE PAC resource - Clinical Decision Aid Updated March 2016 For information and JPC recommendations regarding the use of Anticoagulants in Atrial Fibrillation, please refer to Bulletin 216, available at 1

2 Choice of Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) 1. Introduction There are four licensed Non-Vitamin K antagonist Oral Anticoagulants (NOACs) for use on the UK market Apixaban, Dabigatran, Edoxaban and Rivaroxaban. All have been subject to NICE technology appraisal guidance relating to their licensed indications and approved as treatment options. (See table 1 for more detailed information). This means that NICE has judged the products to be clinically and cost-effective for these indications. When NICE recommends a treatment 'as an option', the NHS must make sure it is available within 3 months (unless otherwise specified) of its date of publication. This means that, if a patient has a disease or condition and the doctor responsible for their care thinks that the technology is the right treatment, it should be available for use, in line with NICE's recommendations. As a result of this, all NOACs are available for use (included in primary and secondary care formularies) within the local Health Economy. While all of the NOACs are considered (by NICE) to be cost-effective treatments, they have different acquisition costs. In a market where the use of these drugs is increasing year on year (see Diagram 1), the choice of NOAC can make a large financial impact on drug budgets, particularly in primary care. The JPC is therefore asked to consider whether it is appropriate to recommend the use of a particular NOAC to the Health Economy (initiation of new patients and/or switching of existing patients) in situations where more than one NOAC is clinically suitable for a patient. Where NICE has issued a multiple technology appraisal guidance, many of the guidance include a statement that if all treatments are suitable for a patient, treatment should normally be initiated with the least expensive drug. 2

3 Table 1 NOAC Approved Indications and NICE Technology Appraisal Guidance Approved Name Apixaban Brand Name and (presenta tion) Eliquis (filmcoated tablets) Strength Dosing frequency Approved Therapeutic Indication* 2.5 mg 5.0 mg Twice daily Prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery. Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class II). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. Applicable NICE Technology Appraisal Guidance. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults (January 2012) Apixaban is an option for the prevention of venous thromboembolism in adults after elective hip or knee replacement surgery. Apixaban for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation (February 2013) Apixaban is an option for the prevention of stroke and systemic embolism in non-valvular atrial fibrillation in accordance with its licensed indication. The risks and benefits of apixaban compared to warfarin, dabigatran etexilate, and rivaroxaban should be discussed with the patient. Subject to additional monitoring by the EMA 1 Yes 1 EMA European Medicines Agency 3

4 Approved Name Brand Name and (presenta tion) Strength Dosing frequency Approved Therapeutic Indication* Applicable NICE Technology Appraisal Guidance. Apixaban for the treatment and secondary prevention of deep vein thrombosis and/or pulmonary embolism (June 2015) Apixaban is an option for the treatment and prevention of recurrent deep vein thrombosis and pulmonary embolism in adults. Subject to additional monitoring by the EMA 1 Dabigatran Pradaxa (hard capsules) 110 mg Once or 150 mg Twice daily 75mg (indication dependent) Primary prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery. Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF), with one or more risk factors, such as prior stroke or transient ischemic attack (TIA); age 75 years; heart failure (NYHA Class II); diabetes mellitus; hypertension. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults (September 2008) Dabigatran etexilate is an option for the prophylaxis of venous thromboembolism in adults after total hip replacement or total knee replacement surgery. Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation (March 2012) Dabigatran etexilate is an option for the prevention of stroke and systemic embolism in patients with non-valvular No 4

5 Approved Name Brand Name and (presenta tion) Strength Dosing frequency Approved Therapeutic Indication* and prevention of recurrent DVT and PE in adults. Applicable NICE Technology Appraisal Guidance. atrial fibrillation and with one or more of the following risk factors: previous stroke, transient ischaemic attack, or systemic embolism left ventricular ejection fraction < 40% symptomatic heart failure age 75 years age 65 years in patients with diabetes mellitus, coronary artery disease, or hypertension The risks and benefits of dabigatran compared to warfarin should be discussed with the patient. Dabigatran etexilate for the treatment and secondary prevention of deep vein thrombosis and /or pulmonary embolism (December 2014) Dabigatran etexilate is recommended, within its marketing authorisation, as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults. Subject to additional monitoring by the EMA 1 5

6 Approved Name Edoxaban Brand Name and (presenta tion) Lixiana (filmcoated tablets) Strength Dosing frequency Approved Therapeutic Indication* 15 mg 30 mg 60 mg Once daily Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. Applicable NICE Technology Appraisal Guidance. Edoxaban for preventing stroke and systemic embolism in people with non-valvular atrial fibrillation Edoxaban is recommended, within its marketing authorisation, as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation with one or more risk factors, including: congestive heart failure hypertension diabetes prior stroke or transient ischaemic attack age 75 years or older. The decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the person about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran etexilate and rivaroxaban. For people considering switching from warfarin, edoxaban's potential benefits should be considered against its potential risks, taking into account the person's level of international normalised ratio (INR) control. Subject to additional monitoring by the EMA 1 Yes 6

7 Approved Name Brand Name and (presenta tion) Strength Dosing frequency Approved Therapeutic Indication* Applicable NICE Technology Appraisal Guidance. Subject to additional monitoring by the EMA 1 Edoxaban for treating and for preventing deep vein thrombosis and pulmonary embolism (August 2015) Edoxaban is recommended, within its marketing authorisation, as an option for treating and for preventing recurrent deep vein thrombosis and pulmonary embolism in adults. Rivaroxaban Xarelto (filmcoated tablets) 10 mg Once or 20 mg twice daily 30 mg (indication 15 mg dependent) 2.5 mg Prevention of venous thromboembolism (VTE) in adult patients undergoing elective hip or knee replacement surgery. 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. Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults (April 2009) Rivaroxaban is an option for the prophylaxis of venous thromboembolism in adults after total hip replacement or total knee replacement surgery. Rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation (May 2012) Rivaroxaban is an option for the prevention of stroke and systemic Yes 7

8 Approved Name Brand Name and (presenta tion) Strength Dosing frequency Approved Therapeutic Indication* Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. Rivaroxaban, coadministered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers. Applicable NICE Technology Appraisal Guidance. embolism in accordance with its licensed indication (see notes above). The risks and benefits of rivaroxaban compared with warfarin should be discussed with the patient. NICE guidance Rivaroxaban for the treatment of deep-vein thrombosis and prevention of recurrent deep-vein thrombosis and pulmonary embolism (July 2012) Rivaroxaban is an option for the treatment of deep-vein thrombosis and prevention of recurrent deep-vein thombosis and pulmonary embolism in adults after diagnosis of acute deep-vein thrombosis. Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism (June 2013) Rivaroxaban is an option for treating pulmonary embolism and preventing recurrent deep-vein thrombosis and pulmonary embolism in adults. Subject to additional monitoring by the EMA 1 8

9 Approved Name Brand Name and (presenta tion) Strength Dosing frequency Approved Therapeutic Indication* Applicable NICE Technology Appraisal Guidance. Rivaroxaban for preventing adverse outcomes after acute management of acute coronary syndrome (March 2015) Rivaroxaban is an option within its marketing authorisation, in combination with aspirin plus clopidogrel or aspirin alone, for preventing atherothrombotic events in patients who have had an acute coronary syndrome with elevated cardiac biomarkers. The patient's risk of bleeding should be carefully assessed before treatment is initiated and the risks and benefits of rivaroxaban in combination with aspirin plus clopidogrel or with aspirin alone, compared with aspirin plus clopidogrel or aspirin alone should be discussed with the patient. A decision on continuation of treatment should be taken no later than 12 months after starting treatment. Subject to additional monitoring by the EMA 1 *Consult Summary of Product Characteristics (SPC) at for full prescribing details as not all strengths are approved for all indications. 9

10 Apr-13 May-13 Jun-13 Jul-13 Aug-13 Sep-13 Oct-13 Nov-13 Dec-13 Jan-14 Feb-14 Mar-14 Apr-14 May-14 Jun-14 Jul-14 Aug-14 Sep-14 Oct-14 Nov-14 Dec-14 Jan-15 Feb-15 Mar-15 Apr-15 May-15 Jun-15 Jul-15 Aug-15 BCCG monthly cost Diagram 1 70,000 Trend in the Monthly Cost of Dabigatran Etexilate, Apixaban and Rivaroxaban for Bedfordshire CCG 60,000 50,000 40,000 30,000 20,000 10,000 0 Dabigatran Etexilate Apixaban Rivaroxaban Warfarin Sodium 10

11 2. Acquisition Costs (Updated February 16) The table below indicates the NHS list price for each of the drugs as listed in the Chemist & Druggist (April 2016) (This is included for information only). List Price 1st April 2016 (Chemist and Druggist April 2016) Daily cost Annual cost Apixaban Edoxaban Rivaroxaban Dabigatran The actual acquisition cost for each of the drugs to Bedfordshire CCG is different to the NHS list prices because 1 out of 4 of the NOACs is subject to a primary care rebate scheme. Due to the confidential nature of this rebate scheme, the actual acquisition costs of individual NOACs to the Health Economy cannot be included in the paper. The following therefore is a list of the drugs in increasing acquisition cost order: o o o o Edoxaban (Lixiana ) lowest acquisition cost to primary care due to rebate Dabigatran (Pradaxa ) Rivaroxaban (Xarelto ) Apixaban (Eliquis ) highest acquisition cost to primary care Based upon BCCG Primary Care Prescribing volume (March 2015 February 2016), if 50% of patients were switched from Apixaban, Rivaroxaban or Dabigatran to Edoxaban this would result in a potential saving to BCCG of around 70,000 per annum. 3. Other Considerations Additional selected information relating to the use of the NOACs is outlined in Appendix 1. 11

12 References:- 1. The Electronic BNF, accessed 12/10/ Summary of Product Characteristics for Pradaxa, accessed 12/10/ Summary of Product Characteristics for Eliquis, accessed 12/10/ Summary of Product Characteristics for Lixiana, accessed 12/10/ Summary of Product Characteristics for Xarelto. Accessed 12/10/ UKMi, New product evaluations, Number 153, September Prescribing Committee Report, BCCG, Rebate Proposal (confidential), Edoxaban, September The National Institute for Health and Care Excellence Website accessed 20/10/15 Appendix 1 - Selected information relating to the use of the NOACs Please note, that this is not an exhaustive list, please consult the Summary of Product Characteristics ( or BNF ( for full prescribing information. Drug Contra-indications Cautions Hepatic Impairment Apixaban active bleeding; risk of bleeding; avoid in significant risk of concomitant use severe major bleeding (e.g. of drugs that impairment recent gastrointestinal increase risk of and in hepatic ulcer, bleeding; disease oesophageal varices, prosthetic heart associated recent brain, spine, valve (efficacy not with or ophthalmic established); coagulopathy Renal Impairment for prophylaxis of venous thromboembolism following knee or hip replacement surgery, prophylaxis of recurrent deep-vein thrombosis or pulmonary embolism, and treatment of deep-vein thrombosis or Side-effects nausea, haemorrhage, bruising, anaemia; less commonly hypotension, thrombocytopenia, rash 12

13 Drug Contra-indications Cautions Hepatic Impairment surgery, recent anaesthesia with intracranial postoperative haemorrhage, indwelling epidural malignant catheter (risk of neoplasms, vascular paralysis monitor aneurysm) neurological signs and wait hours after apixaban dose before removing catheter and do not give next dose until at least 5 hours after catheter removal); Elevated liver enzymes > 2 x Dabigatran active bleeding; significant risk of major bleeding (e.g. recent gastrointestinal ulcer, oesophageal varices, recent brain, spine, or ophthalmic surgery, recent intracranial haemorrhage, malignant neoplasms, vascular aneurysm); do not use as anticoagulant for prosthetic heart valve. Not recommended in patients with ULN. elderly; bodyweight less than 50 kg; anaesthesia with postoperative indwelling epidural catheter (risk of paralysis give initial dose at least 2 hours after catheter removal and monitor neurological signs); bacterial endocarditis; bleeding disorders; thrombocytopenia; recent biopsy or avoid in severe liver disease, especially if prothrombin time already prolonged 13 Renal Impairment pulmonary embolism, use with caution if creatinine clearance ml/minute; for prophylaxis of stroke and systemic embolism in atrial fibrillation, reduce dose to 2.5 mg twice daily if creatinine clearance ml/minute, or if serum-creatinine 133 micromol/litre and age 80 years or body-weight 60kg; manufacturer advises avoid if creatinine clearance less than 15 ml/minute no information available avoid if creatinine clearance less than 30 ml/minute; for prophylaxis of venous thromboembolism following knee or hip replacement surgery, reduce initial dose to 75 mg and subsequent doses to 150 mg once daily if creatinine clearance ml/minute; reduce dose to 75 mg once daily if creatinine clearance ml/minute and patient receiving concomitant treatment with verapamil; for treatment of deep-vein thrombosis and pulmonary embolism, prophylaxis of recurrent deepvein thrombosis and Side-effects nausea, dyspepsia, diarrhoea, abdominal pain, anaemia, haemorrhage less commonly hepatobiliary disorders, vomiting, dysphagia, gastro-intestinal ulcer, gastro-oesophageal reflux, oesophagitis, thrombocytopenia

14 Drug Contra-indications Cautions Hepatic Impairment elevated liver major trauma; enzymes > 2 upper oesophagitis, limit of normal (ULN) gastritis, gastrooesophageal reflux; assess renal function (manufacturer recommends Cockcroft and Gault formula to calculate creatinine clearance) before treatment in all patients and at least annually in elderly and patients with renal impairment; concomitant use of drugs that increase risk of Edoxaban Clinically significant active bleeding. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal bleeding Patients at increased risk of bleeding; low body weight (dose reduction required); assess renal function (manufacturer recommends Cockcroft and Gault formula to calculate creatinine clearance) before Not recommended in patients with severe hepatic impairment. and in patients with hepatic disease associated with coagulopathy; Use with caution in patients with 14 Renal Impairment pulmonary embolism, prophylaxis of stroke and systemic embolism in nonvalvular atrial fibrillation, consider reduced dose of 110 mg twice daily if creatinine clearance ml/minute, based on individual assessment of thromboembolic risk and risk of bleeding; monitor renal function at least annually (manufacturer recommends Cockcroft and Gault formula to calculate creatinine clearance) In patients with mild renal impairment (CrCL > ml/min), the recommended dose is 60 mg edoxaban once daily. In patients with moderate or severe renal impairment (CrCL ml/min), the recommended dose is 30 mg edoxaban once daily. In patients with end stage renal disease (ESRD) (CrCL < 15 ml/min) or on dialysis, the Side-effects In clinical studies, the most common adverse reactions related to bleeding with edoxaban 60 mg based on adjudicated terms included cutaneous soft tissue haemorrhage (up to 5.9%) and epistaxis (up to 4.7%), while vaginal haemorrhage (9.0%) was the most common bleeding-related adverse reaction in Hokusai- VTE study only.

15 Drug Contra-indications Cautions Hepatic Impairment ulceration, presence treatment in all mild or of malignant patients; elderly; moderate neoplasms at high concomitant use hepatic risk of bleeding, of drugs that impairment. recent brain or spinal increase risk of injury, recent brain, bleeding; patients spinal or ophthalmic with active cancer; surgery, recent surgery; prosthetic intracranial heart valve haemorrhage, known (efficacy not or suspected established); oesophageal varices, Elevated liver arteriovenous enzymes > 2 x malformations, ULN. vascular aneurysms or major intraspinal or intracerebral vascular abnormalities. Uncontrolled severe hypertension. Concomitant treatment with any other anticoagulants except under specific circumstances of switching oral anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter. Pregnancy and breast-feeding. Renal Impairment use of edoxaban is not recommended. Side-effects Bleeding can occur at any site and may be severe and even fatal. Other common adverse reactions for edoxaban were anaemia, rash and abnormal liver function tests. 15

16 Drug Contra-indications Cautions Hepatic Impairment Rivaroxaban active bleeding; risk of bleeding; avoid in liver significant risk of concomitant use disease with major bleeding (e.g. of drugs that coagulopathy recent gastrointestinal increase risk of ulcer, bleeding; severe oesophageal varices, hypertension; recent brain, spine, prosthetic heart or ophthalmic valve (efficacy not surgery, recent established); intracranial vascular haemorrhage, retinopathy; malignant anaesthesia with neoplasms, vascular postoperative aneurysm); in acute indwelling epidural coronary syndrome catheter (risk of previous stroke or paralysis monitor transient ischaemic neurological signs attack and wait at least 18 hours after rivaroxaban dose before removing catheter and do not give next dose until at least 6 hours after catheter removal); bronchiectasis; 16 Renal Impairment for prophylaxis of venous thromboembolism following knee or hip replacement surgery and prophylaxis of atherothrombotic events in acute coronary syndrome, use with caution if creatinine clearance ml/minute; for treatment of deep-vein thrombosis or pulmonary embolism and prophylaxis of recurrent deep-vein thrombosis and pulmonary embolism, initially 15 mg twice daily for 21 days, then 20 mg once daily (but consider reducing to 15 mg once daily if risk of bleeding outweighs risk of recurrent deep-vein thrombosis or pulmonary embolism) if creatinine clearance ml/minute; for prophylaxis of stroke and systemic embolism in atrial fibrillation, reduce dose to 15 mg once daily if creatinine clearance ml/minute; use with caution if concomitant use of drugs that increase plasma-rivaroxaban concentration (consult product literature); avoid if creatinine clearance less than 15 ml/minute; manufacturer recommends Cockcroft and Gault formula to calculate creatinine clearance Side-effects nausea, vomiting, diarrhoea, constipation, dyspepsia, abdominal pain, hypotension, dizziness, headache, renal impairment, haemorrhage, pain in extremities, pruritus, rash; less commonly dry mouth, thrombocythaemia, tachycardia, syncope, angioedema, malaise; rarely jaundice, oedema

17 Drug Apixaban Dabigatran Edoxaban Interactions increased risk of haemorrhage when apixaban given with other anticoagulants (avoid concomitant use except when switching with other anticoagulants or using heparin to maintain catheter patency); plasma concentration of apixaban possibly reduced by carbamazepine manufacturer of apixaban advises avoid concomitant use when given for treatment of deep-vein thrombosis or pulmonary embolism; plasma concentration of apixaban possibly reduced by fosphenytoin; plasma concentration of apixaban increased by ketoconazole manufacturer of apixaban advises avoid concomitant use; plasma concentration of apixaban possibly reduced by phenobarbital; plasma concentration of apixaban possibly reduced by phenytoin; plasma concentration of apixaban possibly reduced by primidone; plasma concentration of apixaban possibly reduced by rifampicin manufacturer of apixaban advises avoid concomitant use when given for treatment of deep-vein thrombosis or pulmonary embolism plasma concentration of apixaban possibly reduced by St John's wort manufacturer of apixaban advises avoid concomitant use when given for treatment of deep-vein thrombosis or pulmonary embolism increased risk of haemorrhage when anticoagulants given with ketorolac (avoid concomitant use, including low-dose heparins) increased risk of haemorrhage when anticoagulants given with intravenous diclofenac (avoid concomitant use, including low-dose heparins) plasma concentration of dabigatran increased by amiodarone; increased risk of haemorrhage when dabigatran given with other anticoagulants (avoid concomitant use except when switching with other anticoagulants or using heparin to maintain catheter patency); possible increased risk of bleeding when dabigatran given with SSRIs; possible increased risk of bleeding when dabigatran given with SSRI-related antidepressants; plasma concentration of dabigatran possibly increased by ciclosporin manufacturer of dabigatran advises avoid concomitant use; plasma concentration of dabigatran increased by dronedarone avoid concomitant use; plasma concentration of dabigatran increased by ketoconazole avoid concomitant use; possible increased risk of bleeding when dabigatran given with NSAIDs; plasma concentration of dabigatran reduced by rifampicin manufacturer of dabigatran advises avoid concomitant use; possible increased risk of bleeding when dabigatran given with sulfinpyrazone; plasma concentration of dabigatran possibly increased by tacrolimus manufacturer of dabigatran advises avoid concomitant use; plasma concentration of dabigatran increased by ticagrelor; plasma concentration of dabigatran possibly increased by verapamil; increased risk of haemorrhage when anticoagulants given with intravenous diclofenac (avoid concomitant use, including low-dose heparins); increased risk of haemorrhage when anticoagulants given with ketorolac (avoid concomitant use, including low-dose heparins) In patients concomitantly taking edoxaban and the following P- glycoprotein (P-gp) inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole, the recommended dose is 30 mg edoxaban once daily. No dose reduction is required for concomitant use of amiodarone, quinidine or verapamil. 17

18 Drug Interactions The use of Lixiana with other P-gp inhibitors including HIV protease inhibitors has not been studied. Rivaroxaban Use with caution with P-gp inducers e.g. rifampicin, phenytoin, carbamazepine, phenobarbital or St John s Wort Chronic use of NSAIDs with edoxaban, not recommended. Edoxaban can be administered with low dose ( 100mg/day) aspirin. Use of concomitant high dose aspirin (325mg) is not recommended and concomitant administration of higher doses than 100mg of aspirin should only be performed under medical supervision. Co-administration of edoxaban with other anticoagulants is contraindicated due to increased risk of bleeding. increased risk of haemorrhage when rivaroxaban given with other anticoagulants (avoid concomitant use except when switching with other anticoagulants or using heparin to maintain catheter patency); plasma concentration of rivaroxaban possibly reduced by carbamazepine manufacturer of rivaroxaban advises monitor for signs of thrombosis; anticoagulant effect of rivaroxaban possibly enhanced by cobicistat avoid concomitant use; plasma concentration of rivaroxaban possibly reduced by fosphenytoin manufacturer of rivaroxaban advises monitor for signs of thrombosis; plasma concentration of rivaroxaban increased by ketoconazole avoid concomitant use; plasma concentration of rivaroxaban possibly reduced by phenobarbital manufacturer of rivaroxaban advises monitor for signs of thrombosis; plasma concentration of rivaroxaban possibly reduced by phenytoin manufacturer of rivaroxaban advises monitor for signs of thrombosis; plasma concentration of rivaroxaban possibly reduced by primidone manufacturer of rivaroxaban advises monitor for signs of thrombosis; plasma concentration of rivaroxaban reduced by rifampicin manufacturer of rivaroxaban advises monitor for signs of thrombosis; plasma concentration of rivaroxaban increased by ritonavir avoid concomitant use; plasma concentration of rivaroxaban possibly reduced by St John's wort manufacturer of rivaroxaban advises monitor for signs of thrombosis; increased risk of haemorrhage when anticoagulants given with ketorolac (avoid concomitant use, including low-dose heparins); increased risk of haemorrhage when anticoagulants given with intravenous diclofenac (avoid concomitant use, including low-dose heparins) 18

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