ROTEAS Film-coated tablet Ref.[49825] Active ingredients: Edoxaban

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, Roteas 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 medicines 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.

Edoxaban is predominantly absorbed in the upper gastrointestinal (GI) tract. Thus, medicines or disease conditions that increase gastric emptying and gut motility have the possibility of reducing edoxaban dissolution and absorption.

P-gp inhibitors

Edoxaban is a substrate for the efflux transporter P-gp. In pharmacokinetic (PK) studies, concomitant administration of edoxaban with the P-gp inhibitors ciclosporin, dronedarone, erythromycin, ketoconazole, quinidine, or verapamil resulted in increased plasma concentrations of edoxaban. Concomitant use of edoxaban with ciclosporin, dronedarone, erythromycin, or ketoconazole requires dose reduction to 30 mg once daily. Concomitant use of edoxaban with quinidine, verapamil, or amiodarone does not require dose reduction based on clinical data (see section 4.2).

The use of edoxaban with other P-gp inhibitors including human immunodeficiency virus (HIV) protease inhibitors has not been studied.

Edoxaban 30 mg once daily must be administered during concomitant use with the following P-gp inhibitors:

• Ciclosporin: Concurrent administration of a single dose of ciclosporin 500 mg with a single dose of edoxaban 60 mg increased edoxaban AUC and maximum serum concentration (Cmax) by 73% and 74%, respectively.
• Dronedarone: Dronedarone 400 mg twice daily for 7 days with a single concomitant dose of edoxaban 60 mg on day 5 increased edoxaban AUC and C_max by 85% and 46%, respectively.
• Erythromycin: Erythromycin 500 mg four times daily for 8 days with a single concomitant dose of edoxaban 60 mg on day 7 increased the edoxaban AUC and C_max by 85% and 68%, respectively.
• Ketoconazole: Ketoconazole 400 mg once daily for 7 days with a single concomitant dose of edoxaban 60 mg on day 4, increased edoxaban AUC and C_max by 87% and 89%, respectively.

Edoxaban 60 mg once daily is recommended during concomitant use with the following P-gp inhibitors:

• Quinidine: Quinidine 300 mg once daily on days 1 and 4 and three times daily on days 2 and 3, with a single concomitant dose of edoxaban 60 mg on day 3, increased edoxaban AUC over 24 hours by 77% and C_max by 85%, respectively.
• Verapamil: Verapamil 240 mg once daily for 11 days with a single concomitant dose of edoxaban 60 mg on day 10 increased the edoxaban AUC and C_max by approximately 53%.
• Amiodarone: Co-administration of amiodarone 400 mg once daily with edoxaban 60 mg once daily increased AUC by 40% and C_max by 66%. This was not considered clinically significant. In ENGAGE AF-TIMI 48 study in NVAF, efficacy and safety results were similar for subjects with and without concomitant amiodarone use.

P-gp inducers

Co-administration of edoxaban with the P-gp inducer rifampicin led to a decrease in mean edoxaban AUC and a shortened half-life, with possible decreases in its pharmacodynamic effects. The concomitant use of edoxaban with other P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbital or St. John’s Wort) may lead to reduced edoxaban plasma concentrations. Edoxaban should be used with caution when co-administered with P-gp inducers.

P-gp substrates

Digoxin

Edoxaban 60 mg once daily on days 1 to 14 with coadministration of multiple daily doses of digoxin 0.25 mg twice daily (days 8 and 9) and 0.25 mg once daily (days 10 to 14) increased the C_max of edoxaban by 17%, with no significant effect on AUC or renal clearance at steady state. When the effects of edoxaban on digoxin PK were also examined, the C_max of digoxin increased by approximately 28% and AUC by 7%. This was not considered clinically relevant. No dose modification is necessary when edoxaban is administered with digoxin.

Anticoagulants, antiplatelets, NSAIDs and SSRIs/SNRIs

Anticoagulants: Co-administration of edoxaban with other anticoagulants is contraindicated due to increased risk of bleeding (see section 4.3).

ASA

Co-administration of ASA (100 mg or 325 mg) and edoxaban increased bleeding time relative to either medicine alone. Co-administration of high dose ASA (325 mg) increased the steady state C_max and AUC of edoxaban by 35% and 32%, respectively. The concomitant chronic use of high dose ASA (325 mg) with edoxaban is not recommended. Concomitant administration of higher doses than 100 mg ASA should only be performed under medical supervision.

In clinical studies concomitant use of ASA (low dose ≤100 mg/day), other antiplatelet agents, and thienopyridines was permitted and resulted in approximately a 2-fold increase in major bleeding in comparison with no concomitant use, although to a similar extent in the edoxaban and warfarin groups (see section 4.4). Co-administration of low dose ASA (≤100 mg) did not affect the peak or total exposure of edoxaban either after single dose or at steady-state. Edoxaban can be co-administered with low dose ASA (≤100 mg/day).

Platelet inhibitors

In ENGAGE AF-TIMI 48 concomitant use of thienopyridines (e.g. clopidogrel) monotherapy was permitted and resulted in increased clinically relevant bleeding although with a lower risk of bleeding on edoxaban compared to warfarin (see section 4.4).

There is very limited experience on the use of edoxaban with dual antiplatelet therapy or fibrinolytic agents.

NSAIDs

Co-administration of naproxen and edoxaban increased bleeding time relative to either medicine alone. Naproxen had no effect on the C_max and AUC of edoxaban. In clinical studies, co-administration of NSAIDs resulted in increased clinically relevant bleeding. Chronic use of NSAIDs with edoxaban is not recommended.

SSRIs/SNRIs

As with other anticoagulants the possibility may exist that patients are at increased risk of bleeding in case of concomitant use with SSRIs or SNRIs due to their reported effect on platelets (see section 4.4).

Effect of edoxaban on other medicinal products

Edoxaban increased the C_max of concomitantly administered digoxin by 28%; however, the AUC was not affected. Edoxaban had no effect on the C_max and AUC of quinidine.

Edoxaban decreased the C_max and AUC of concomitantly administered verapamil by 14% and 16%, respectively.

Women of childbearing potential

Women of childbearing potential should avoid becoming pregnant during treatment with edoxaban.

Pregnancy

Safety and efficacy of edoxaban have not been established in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that edoxaban passes the placenta, Roteas is contraindicated during pregnancy (see section 4.3).

Breast-feeding

Safety and efficacy of edoxaban have not been established in breast-feeding women. Data from animals indicate that edoxaban is secreted into breast milk. Therefore Roteas is contraindicated during breast-feeding (see section 4.3). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy.

Fertility

No specific studies with edoxaban in human beings have been conducted to evaluate effects on fertility. In a study on male and female fertility in rats no effects were seen (see section 5.3).

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

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. The most commonly reported adverse reactions associated with edoxaban treatment are epistaxis (7.7%), haematuria (6.9%) and anaemia (5.3%).

Bleeding can occur at any site and may be severe and even fatal (see section 4.4).

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 postmarketing 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).

Table 3. List of adverse reactions for NVAF and VTE:

¹ Reporting rates are based on the female population in clinical studies. Vaginal bleeds were reported commonly in women under the age of 50 years, while it was uncommon in women over the age of 50 years.

Description of selected adverse reactions

Haemorrhagic anaemia

Due to the pharmacological mode of action, the use of edoxaban may be associated with an increased risk of occult or overt bleeding from any tissue or organ which may result in post haemorrhagic anaemia. The signs, symptoms, and severity (including fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see section 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. The risk of bleedings may be increased in certain patient groups e.g. those patients with uncontrolled severe arterial hypertension and/or on concomitant treatment affecting haemostasis (see section 4.4). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, paleness, dizziness, headache or unexplained swelling, dyspnoea, and unexplained shock.

Known complications secondary to severe bleeding such as compartment syndrome and renal failure due to hypoperfusion have been reported for edoxaban. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.