Roteas

Posology Prevention of stroke and systemic embolism The recommended dose is 60 mg edoxaban once daily. Therapy with edoxaban in NVAF patients should be continued long term. 1). Edoxaban and initial parenteral anticoagulant should not be administered simultaneously.

4). g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE. For NVAF and VTE the recommended dose is 30 mg edoxaban once daily in patients with one or more of the following clinical factors: • Moderate or severe renal impairment (creatinine clearance (CrCl) 15 - 50 mL/min) • Low body weight ≤ 60 kg • Concomitant use of the following P-glycoprotein (P-gp) inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole.

Table 1:

Summary of posology in NVAF and VTE (DVT and PE) Summary guide for dosing Recommended dose 60 mg edoxaban once daily Dose recommendation for patients with one or more of the following clinical factors: Renal impairment Moderate or severe (CrCl 15 – 50 mL/min) 30 mg edoxaban once dailyLow body weight ≤ 60 kg P-gp inhibitors Ciclosporin, dronedarone, erythromycin, ketoconazole Missed dose If a dose of edoxaban is missed, the dose should be taken immediately and then be continued the following day with the once-daily intake as recommended.

The patient should not take double the prescribed dose on the same day to make up for a missed dose. Switching to and from edoxaban Continued anticoagulant therapy is important in patients with NVAF and VTE. There may be situations that warrant a change in anticoagulation therapy (Table 2).

5. 1). Parenteral anticoagulants Edoxaban These medicinal products should not be administered simultaneously. e. low molecular weight heparin (LMWH), fondaparinux): Discontinue subcutaneous anticoagulant and start edoxaban at the time of the next scheduled subcutaneous anticoagulant dose.

Intravenous unfractionated heparin (UFH):

Discontinue the infusion and start edoxaban 4 hours later. 5 Switching from edoxaban From To Recommendation Edoxaban VKA There is a potential for inadequate anticoagulation during the transition from edoxaban to VKA. Continuous adequate anticoagulation should be ensured during any transition to an alternate anticoagulant.

Summary of the safety profile The safety profile of edoxaban is based on two Phase 3 studies (21,105 patients with NVAF and 8,292 patients with VTE (DVT and PE)), and from post-authorisation experience. 3%). 4). Tabulated list of adverse reactions Table 3 provides the list of adverse reactions from the two pivotal Phase 3 studies in patients with VTE and NVAF combined for both indications and adverse drug reactions identified in the post- marketing setting.

The adverse reactions are classified according to the MedDRA system organ class (SOC) and frequency, using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Table 3:

List of adverse reactions for NVAF and VTE System organ class Frequency Blood and lymphatic system disorders Anaemia Common Thrombocytopenia Uncommon Immune system disorders Hypersensitivity Uncommon Anaphylactic reaction Rare Allergic oedema Rare Nervous system disorders Dizziness Common Headache Common Intracranial haemorrhage (ICH) Uncommon Subarachnoid haemorrhage Rare Eye disorders Conjunctival/scleral haemorrhage Uncommon Intraocular haemorrhage Uncommon Cardiac disorders Pericardial haemorrhage Rare Vascular disorders Other haemorrhage Uncommon Respiratory, thoracic and mediastinal disorders Epistaxis Common Haemoptysis Uncommon Gastrointestinal disorders Abdominal pain Common Lower GI haemorrhage Common Upper GI haemorrhage Common Oral/pharyngeal haemorrhage Common Nausea Common Retroperitoneal haemorrhage Rare Hepatobiliary disorders Blood bilirubin increased Common Gammaglutamyltransferase increased Common Blood alkaline phosphatase increased Uncommon 14 System organ class Frequency Transaminases increased Uncommon Skin and subcutaneous tissue disorders Cutaneous soft tissue haemorrhage Common Rash Common Pruritus Common Urticaria Uncommon Musculoskeletal and connective tissue disorders Intramuscular haemorrhage (no compartment syndrome) Rare Intra-articular haemorrhage Rare Renal and urinary disorders Macroscopic haematuria/urethral haemorrhage Common Anticoagulant-related nephropathy Not known Reproductive system and breast disorders Vaginal haemorrhage1 Common General disorders and administration site conditions Puncture site haemorrhage Common Investigations Liver function test abnormal Common Injury, poisoning and procedural complications Surgical site haemorrhage Uncommon Subdural haemorrhage Rare Procedural haemorrhage Rare 1 Reporting rates are based on the female population in clinical studies.

Edoxaban 15 mg is not indicated as monotherapy, as it may result in decreased efficacy. 2). Haemorrhagic risk Edoxaban increases the risk of bleeding and can cause serious, potentially fatal bleeding. Edoxaban, like other anticoagulants, is recommended to be used with caution in patients with increased risk of bleeding.

9). g. epistaxis, gastrointestinal, genitourinary) and anaemia were seen more frequently during long term edoxaban treatment compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value to detect occult bleeding, as judged to be appropriate.

Several sub-groups of patients, as detailed below, are at increased risk of bleeding. 8). Any unexplained fall in haemoglobin or blood pressure should lead to a search for a bleeding site. The anticoagulant effect of edoxaban cannot be reliably monitored with standard laboratory testing.

9). 2). 5). 2 for dose reduction). 2). 1 for ENGAGE AF-TIMI 48 and additional data from E314 and ETNA-AF). Edoxaban should be used in patients with NVAF and high CrCl only after a careful evaluation of the individual thromboembolic and bleeding risk.

2). 2). 2). 5 x ULN were excluded in clinical studies. 2). Prior to initiating edoxaban, liver function testing should be performed. Periodic hepatic monitoring is recommended for patients on edoxaban treatment beyond 1 year. Discontinuation for surgery and other interventions If anticoagulation must be discontinued to reduce the risk of bleeding with surgical or other procedures, edoxaban should be stopped as soon as possible and preferably at least 24 hours before the procedure.

In deciding whether a procedure should be delayed until 24 hours after the last dose of edoxaban, the increased risk of bleeding should be weighed against the urgency of the intervention. Edoxaban should be restarted after the surgical or other procedures as soon as adequate haemostasis has been established, noting that the time to onset of the edoxaban anticoagulant therapeutic effect is 1 – 2 hours.

1. 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 ulceration, presence of malignant neoplasms at high risk of bleeding, recent 8 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.

Uncontrolled severe hypertension. g. 5). 6).