Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Edoxaban 15 mg is not indicated as monotherapy, as it may result in decreased efficacy. It is only indicated in the process of switching from edoxaban 30 mg (patients with one or more clinical factors for increased exposure; see table 1) to VKA, together with an appropriate VKA dose (see table 2, section 4.2).

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. Edoxaban administration should be discontinued if severe haemorrhage occurs (see sections 4.8 and 4.9).

In the clinical studies mucosal bleedings (e.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. These patients are to be carefully monitored for signs and symptoms of bleeding complications and anaemia after initiation of treatment (see section 4.8). 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.
A specific anticoagulant reversal agent for edoxaban is not available (see section 4.9).

Haemodialysis does not significantly contribute to edoxaban clearance (see section 5.2).
Elderly

The co-administration of edoxaban with acetylsalicylic acid (ASA) in elderly patients should be used cautiously because of a potentially higher bleeding risk (see section 4.5).

Renal impairment

The plasma area under the curve (AUC) for subjects with mild (CrCl > 50 - 80 mL/min), moderate (CrCl 30 - 50 mL/min) and severe (CrCl < 30 mL/min but not undergoing dialysis) renal impairment was increased by 32%, 74%, and 72%, respectively, relative to subjects with normal renal function (see section 4.2 for dose reduction).

In patients with end stage renal disease or on dialysis, Lixiana is not recommended (see sections 4.2 and 5.2).

Renal function in NVAF
A trend towards decreasing efficacy with increasing CrCl was observed for edoxaban compared to well-managed warfarin (see section 5.1 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.

Assessment of renal function: CrCl should be monitored at the beginning of the treatment in all patients and afterwards when clinically indicated (see section 4.2).

Hepatic impairment

Edoxaban is not recommended in patients with severe hepatic impairment (see sections 4.2 and 5.2).
Edoxaban should be used with caution in patients with mild or moderate hepatic impairment (see section 4.2).

Patients with elevated liver enzymes (ALT/AST > 2 x ULN) or total bilirubin ≥ 1.5 x ULN were excluded in clinical studies. Therefore edoxaban should be used with caution in this population (see sections 4.2 and 5.2). 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. If oral medicinal products cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant and then switch to oral once daily edoxaban (see section 4.2).

Interaction with other medicinal products affecting haemostasis

Concomitant use of medicinal products affecting haemostasis may increase the risk of bleeding.
These include ASA, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), and chronic nonsteroidal anti-inflammatory drugs (NSAIDs) (see section 4.5).

Prosthetic heart valves and moderate to severe mitral stenosis

Edoxaban has not been studied in patients with mechanical heart valves, in patients during the first 3 months after implantation of a bioprosthetic heart valve, with or without atrial fibrillation, or in patients with moderate to severe mitral stenosis. Therefore, use of edoxaban is not recommended in these patients.

Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy

Edoxaban is not recommended as an alternative to UFH in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of edoxaban have not been established in these clinical situations.

Patients with active cancer

Efficacy and safety of edoxaban in the treatment and/or prevention of VTE in patients with active cancer have not been established.Patients with antiphospholipid syndrome Direct acting oral anticoagulants (DOACs) including edoxaban are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome. In particular for patients that are triple positive (for lupus anticoagulant, anticardiolipin antibodies, and anti-beta 2-glycoprotein I antibodies), treatment with DOACs could be associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Laboratory coagulation parameters

Although treatment with edoxaban does not require routine monitoring, the effect on anticoagulation can be estimated by a calibrated quantitative anti-Factor Xa (anti-FXa) assay which may help to inform clinical decisions in particular situations as, e.g. overdose and emergency surgery (see also section 5.2).

Edoxaban prolongs standard clotting tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT) as a result of Factor Xa (FXa) inhibition. Changes observed in these clotting tests at the expected therapeutic dose are, however, small, subject to a high degree of variability, and not useful in monitoring the anticoagulation effect of edoxaban.

Effects on Driving

4.7 Effects on ability to drive and use machines

Lixiana has no or negligible influence on the ability to drive and use machines.