4.1. Therapeutic indications

Lixiana is indicated in 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).

Lixiana is indicated in treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and for the prevention of recurrent DVT and PE in adults (see section 4.4 for haemodynamically unstable PE patients).

4.2. Posology and method of administration

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.

Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTE)

The recommended dose is 60 mg edoxaban once daily following initial use of parenteral anticoagulant for at least 5 days (see section 5.1). Edoxaban and initial parenteral anticoagulant should not be administered simultaneously.

The duration of therapy for treatment of DVT and PE (venous thromboembolism (VTE)), and prevention of recurrent VTE should be individualised after careful assessment of the treatment benefit against the risk for bleeding (see section 4.4). Short duration of therapy (at least 3 months) should be based on transient risk factors (e.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 daily

Low 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).

Table 2: Switching of anticoagulant treatment in NVAF and VTE (DVT and PE)

Switching to edoxaban

From

To

Recommendation

Vitamin K antagonist (VKA)

Edoxaban

Discontinue the VKA and start edoxaban when the international normalised ratio (INR) is ≤ 2.5.

Oral anticoagulants other than VKA

• dabigatran

• rivaroxaban

• apixaban

Edoxaban

Discontinue dabigatran, rivaroxaban or apixaban and start edoxaban at the time of the next dose of the oral anticoagulant (see section 5.1).

Parenteral anticoagulants

Edoxaban

These medicinal products should not be administered simultaneously.

Subcutaneous anticoagulant (i.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.

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.

Oral option: For patients currently on a 60 mg dose, administer an edoxaban dose of 30 mg once daily together with an appropriate VKA dose.

For patients currently on a 30 mg dose (for one or more of the following clinical factors: moderate to severe renal impairment (CrCl 15 – 50 mL/min), low body weight, or use with certain P-gp inhibitors), administer an edoxaban dose of 15 mg once daily together with an appropriate VKA dose.

Patients should not take a loading dose of VKA in order to promptly achieve a stable INR between 2 and 3. It is recommended to take into account the maintenance dose of VKA and if the patient was previously taking a VKA or to use valid INR driven VKA treatment algorithm, in accordance with local practice.

Once an INR ≥ 2.0 is achieved, edoxaban should be discontinued. Most patients (85%) should be able to achieve an INR ≥ 2.0 within 14 days of concomitant administration of edoxaban and VKA. After 14 days it is recommended that edoxaban is discontinued and the VKA continued to be titrated to achieve an INR between 2 and 3.

It is recommended that during the first 14 days of concomitant therapy the INR is measured at least 3 times just prior to taking the daily dose of edoxaban to minimise the influence of edoxaban on INR measurements. Concomitant edoxaban and VKA can increase the INR post edoxaban dose by up to 46%.

Parenteral option: Discontinue edoxaban and administer a parenteral anticoagulant and VKA at the time of the next scheduled edoxaban dose. Once a stable INR of ≥ 2.0 is achieved, the parenteral anticoagulant should be discontinued and the VKA continued.

Edoxaban

Oral anticoagulants other than VKA

Discontinue edoxaban and start the non-VKA anticoagulant at the time of the next scheduled dose of edoxaban.

Edoxaban

Parenteral anticoagulants

These medicinal products should not be administered simultaneously. Discontinue edoxaban and start the parenteral anticoagulant at the time of the next scheduled dose of edoxaban.

Special populations

Elderly population

No dose reduction is required (see section 5.2).

Renal impairment

Renal function should be assessed in all patients by calculating the CrCl prior to initiation of treatment with edoxaban to exclude patients with end stage renal disease (i.e. CrCl < 15 mL/min), to use the correct edoxaban dose in patients with CrCl 15 – 50 mL/min (30 mg once daily), in patients with CrCl > 50 mL/min (60 mg once daily) and when deciding on the use of edoxaban in patients with increased CrCl (see section 4.4).

Renal function should also be assessed when a change in renal function is suspected during treatment (e.g. hypovolaemia, dehydration, and in case of concomitant use of certain medicinal products).

The method used to estimate renal function (CrCl in mL/min) during the clinical development of edoxaban was the Cockcroft-Gault method. The formula is as follows:

• For creatinine in µmol/L:

• For creatinine in mg/dL:

This method is recommended when assessing patients' CrCl prior to and during edoxaban treatment.

In patients with mild renal impairment (CrCl > 50 – 80 mL/min), the recommended dose is 60 mg edoxaban once daily.

In patients with moderate or severe renal impairment (CrCl 15 – 50 mL/min), the recommended dose is 30 mg edoxaban once daily (see section 5.2).

In patients with end stage renal disease (ESRD) (CrCl < 15 mL/min) or on dialysis, the use of edoxaban is not recommended (see sections 4.4 and 5.2).

Hepatic impairment

Edoxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk (see section 4.3).

In patients with severe hepatic impairment edoxaban is not recommended (see sections 4.4 and 5.2).

In patients with mild to moderate hepatic impairment the recommended dose is 60 mg edoxaban once daily (see section 5.2). Edoxaban should be used with caution in patients with mild to moderate hepatic impairment (see section 4.4).

Patients with elevated liver enzymes (alanine aminotransferase (ALT) or aspartate transaminase (AST) > 2 x upper limit of normal (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 4.4 and 5.2). Prior to initiating edoxaban, liver function testing should be performed.

Body weight

For patients with body weight ≤ 60 kg, the recommended dose is 30 mg edoxaban once daily (see section 5.2).

Gender

No dose reduction is required (see section 5.2).

Concomitant use of Lixiana with P-glycoprotein (P-gp) inhibitors

In patients concomitantly taking Lixiana and the following P-gp inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole, the recommended dose is 30 mg Lixiana once daily (see section 4.5).

No dose reduction is required for concomitant use of amiodarone, quinidine or verapamil (see section 4.5).

The use of Lixiana with other P-gp inhibitors including HIV protease inhibitors has not been studied.

Patients undergoing cardioversion

Lixiana can be initiated or continued in patients who may require cardioversion. For transoesophageal echocardiogram (TEE) guided cardioversion in patients not previously treated with anticoagulants, Lixiana treatment should be started at least 2 hours before cardioversion to ensure adequate anticoagulation (see sections 5.1 and 5.2). Cardioversion should be performed no later than 12 hours after the dose of Lixiana on the day of the procedure.

For all patients undergoing cardioversion: Confirmation should be sought prior to cardioversion that the patient has taken Lixiana as prescribed. Decisions on initiation and duration of treatment should follow established guidelines for anticoagulant treatment in patients undergoing cardioversion.

Paediatric population

Edoxaban is not recommended for use in children and adolescents from birth to 18 years of age with confirmed VTE (PE and/or DVT) event as the efficacy has not been established. Available data in VTE patients are described in sections 4.8, 5.1 and 5.2.

Method of administration

For oral use.

Edoxaban can be taken with or without food (see section 5.2).

For patients who are unable to swallow whole tablets, Lixiana tablets may be crushed and mixed with water or apple puree and immediately administered orally (see section 5.2).

Alternatively, Lixiana tablets may be crushed and suspended in a small amount of water and immediately delivered through a nasogastric tube or gastric feeding tube after which it should be flushed with water (see section 5.2). Crushed Lixiana tablets are stable in water and apple puree for up to 4 hours.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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 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.

Concomitant treatment with any other anticoagulants e.g. UFH, LMWH (enoxaparin, dalteparin, etc.), heparin derivatives (fondaparinux, etc.), oral anticoagulants (warfarin, dabigatran etexilate, rivaroxaban, apixaban etc.) except under specific circumstances of switching oral anticoagulant therapy (see section 4.2) or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section 4.5).

Pregnancy and breast-feeding (see section 4.6).

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.

4.5. Interaction with other medicinal products and other forms of interaction

Edoxaban is predominantly absorbed in the upper gastrointestinal (GI) tract. Thus, medicinal products 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 Cmax 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 Cmax 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 Cmax 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 Cmax 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 Cmax by approximately 53%.

• Amiodarone: Co-administration of amiodarone 400 mg once daily with edoxaban 60 mg once daily increased AUC by 40% and Cmax 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.

• Clarithromycin: Clarithromycin (500 mg twice daily) for 10 days with a single concomitant dose of edoxaban 60 mg on day 9 increased the edoxaban AUC and Cmax by approximately 53% and 27%, respectively.

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 Cmax 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 Cmax 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 medicinal product alone. Co-administration of high dose ASA (325 mg) increased the steady state Cmax 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 medicinal product alone. Naproxen had no effect on the Cmax 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 Cmax of concomitantly administered digoxin by 28%; however, the AUC was not affected. Edoxaban had no effect on the Cmax and AUC of quinidine.

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

4.6. Fertility, pregnancy and lactation

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, Lixiana 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 Lixiana 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).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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 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

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. 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, or anticoagulant-related nephropathy have been reported for edoxaban. Therefore, the possibility of haemorrhage is to be considered in evaluating the condition in any anticoagulated patient.

Paediatric population

The safety of edoxaban was evaluated in two Phase 3 studies (Hokusai VTE PEDIATRICS and ENNOBLE-ATE) in paediatric patients from birth to less than 18 years of age with VTE (286 patients, 145 patients treated with edoxaban) and cardiac diseases at risk of thrombotic events (167 patients, 109 patients treated with edoxaban). Overall, the safety profile in children was similar as in the adult patient population (see Table 3). In total, 16.6% of paediatric patients treated with edoxaban for VTE experienced adverse reactions.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Overdose with edoxaban may lead to haemorrhage. Experience with overdose cases is very limited.

A specific antidote antagonising the pharmacodynamic effect of edoxaban is not available.

Early administration of activated charcoal may be considered in case of edoxaban overdose to reduce absorption. This recommendation is based on standard treatment of medicinal product overdose and data available with similar compounds, as the use of activated charcoal to reduce absorption of edoxaban has not been specifically studied in the edoxaban clinical programme.

Management of bleeding

Should a bleeding complication arise in a patient receiving edoxaban, the next edoxaban administration should be delayed or treatment should be discontinued as appropriate. Edoxaban has a half-life of approximately 10 to 14 hours (see section 5.2). Management should be individualised according to the severity and location of the haemorrhage. Appropriate symptomatic treatment could be used as needed, such as mechanical compression (e.g. for severe epistaxis), surgical haemostasis with bleeding control procedures, fluid replacement and haemodynamic support, blood products (packed red cells or fresh frozen plasma, depending on associated anaemia or coagulopathy) or platelets.

For life-threatening bleeding that cannot be controlled with the measures such as transfusion or haemostasis, the administration of a 4-factor prothrombin complex concentrate (PCC) at 50 IU/kg has been shown to reverse the effects of edoxaban 30 minutes after completing the infusion.

Recombinant factor VIIa (r-FVIIa) can also be considered. However, there is limited clinical experience with the use of this product in individuals receiving edoxaban.

Depending on local availability, a consultation with a coagulation expert should be considered in case of major bleedings.

Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of edoxaban.

There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving edoxaban. There is neither scientific rationale for benefit nor experience with the use of systemic haemostatics (desmopressin, aprotinin) in individuals receiving edoxaban. Due to the high plasma protein binding edoxaban is not expected to be dialysable.