Edoksakord

INSTRUCTIONS

for medical use of the medicinal product

EDOXACORD

(EDOKSAKORD)

Composition:

active substance: edoxaban;

1 tablet contains edoxaban (as tosilate monohydrate) 15 mg or 30 mg, or 60 mg;

excipients: mannitol (E 421); pregelatinised starch; crospovidone; hydroxypropylcellulose; magnesium stearate;

film coating:

15 mg tablets: Opadry II Orange 32F230000: hypromellose (hydroxypropyl methylcellulose); lactose monohydrate; polyethylene glycol (macrogol); titanium dioxide (E 171); iron oxide yellow (E 172), iron oxide red (E 172);

30 mg tablets: Opadry II Pink 32F240010: hypromellose (hydroxypropyl methylcellulose); lactose monohydrate; polyethylene glycol (macrogol); titanium dioxide (E 171); iron oxide red (E 172);

60 mg tablets: Opadry II Yellow 32F220004: hypromellose (hydroxypropyl methylcellulose); lactose monohydrate; polyethylene glycol (macrogol); titanium dioxide (E 171); iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physical and chemical properties:

15 mg tablets: round, biconvex film-coated tablets, light brown to brown in colour;

30 mg tablets: round, biconvex film-coated tablets, light pink to pink in colour;

60 mg tablets: round, biconvex film-coated tablets, light yellow to brownish-yellow in colour.

Pharmacotherapeutic group. Antithrombotic agents. Direct factor Xa inhibitors. Edoxaban. ATC code B01A F03.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Edoxaban is a highly selective, direct, reversible inhibitor of factor Xa, the serine protease located in the final common pathway of the coagulation cascade. Edoxaban inhibits free factor Xa and prothrombinase activity. Inhibition of factor Xa in the coagulation cascade reduces thrombin generation, prolongs clotting time and reduces the risk of thrombus formation.

Pharmacodynamic effects

Edoxaban produces a rapid onset of pharmacodynamic effect within 1–2 hours, corresponding to peak edoxaban plasma concentration (Cmax). The pharmacodynamic effects measured by the anti-factor Xa assay are predictable and correlate with the dose and concentration of edoxaban. As a result of factor Xa inhibition, edoxaban also prolongs clotting time in tests such as prothrombin time (PT) and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests at the therapeutic dose are small, subject to a high degree of variability, and are not recommended for monitoring the anticoagulant effect of edoxaban.

Effect on coagulation markers when switching from rivaroxaban, dabigatran or apixaban to edoxaban

In clinical pharmacology studies, healthy subjects received rivaroxaban 20 mg once daily, dabigatran 150 mg twice daily or apixaban 5 mg twice daily, followed by a single dose of edoxaban 60 mg on Day 4. The effect on PT and other coagulation biomarkers (e.g. anti-FXa activity, aPTT) was measured. After switching to edoxaban on Day 4, PT was equivalent to that observed on Day 3 of rivaroxaban and apixaban. aPTT values were higher after edoxaban with prior dabigatran treatment compared with edoxaban alone. This is considered to be due to the residual effect of dabigatran treatment; however, it did not result in prolongation of bleeding time.

Based on these data, when switching from these anticoagulants to edoxaban, the first dose of edoxaban can be given at the time of the next scheduled dose of the previous anticoagulant (see section "Posology and method of administration").

Clinical efficacy and safety

Prevention of stroke and systemic embolism

The edoxaban clinical programme in atrial fibrillation was designed to demonstrate the efficacy and safety of two dose groups of edoxaban compared with warfarin for the prevention of stroke and systemic embolic events in patients with non-valvular atrial fibrillation (NVAF) and moderate to high risk of stroke and systemic embolic events. The primary efficacy endpoint was the composite of stroke and systemic embolic events. Secondary efficacy endpoints included: the composite of stroke, systemic embolic events and cardiovascular death; major adverse cardiovascular events (MACE), which is a composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-fatal systemic embolic event and death due to cardiovascular causes or bleeding; and the composite of stroke, systemic embolic event and all-cause mortality.

The aim of the primary efficacy analysis was to demonstrate that edoxaban was non-inferior to warfarin for first stroke or systemic embolic events occurring during treatment or within three days after the last dose in the modified intention-to-treat population. Edoxaban 60 mg was non-inferior to warfarin for the primary efficacy endpoint of stroke or systemic embolic event.

The primary safety endpoint was major bleeding.

There was a significant reduction in the risk of major bleeding, intracranial haemorrhage and other types of bleeding in the edoxaban 60 mg group compared with the warfarin group.

The edoxaban 60 mg group also showed a significant reduction in fatal bleeding compared with the warfarin group, mainly due to a reduction in fatal intracranial haemorrhage.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE [VTE (venous thromboembolism)]

The edoxaban clinical programme in VTE was designed to demonstrate the efficacy and safety of edoxaban in the treatment of DVT and PE and in the prevention of recurrent DVT and PE.

The study established that edoxaban was non-inferior to warfarin for the primary efficacy endpoint — recurrent VTE.

Efficacy results in the pre-specified major subgroups (with dose reduction applied where necessary), including age, body weight, sex and renal function, were consistent with the primary efficacy results in the overall study population.

The primary safety endpoint was clinically relevant bleeding (major or non-major but clinically relevant).

In the edoxaban group, there was a significant reduction in the risk of clinically relevant bleeding, major bleeding, or clinically relevant non-major bleeding compared with warfarin.

Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and creatinine clearance (CrCL) > 100 mL/min

Taking into account the totality of data on NVAF patients with high CrCL (> 100 mL/min) treated with edoxaban 60 mg, the expected annual rate of ischaemic stroke / systemic embolism is ≤ 1 %. Increasing the edoxaban dose (above 60 mg) in NVAF patients with high CrCL (> 100 mL/min) does not provide greater protection against stroke and may be associated with increased adverse reactions. Therefore, edoxaban 60 mg once daily is recommended for these patients after careful assessment of the individual thromboembolic and bleeding risk.

Patients undergoing cardioversion

In the studies, a low incidence of major and clinically relevant non-major bleeding and thromboembolism was observed in patients who underwent cardioversion.

Paediatric population

The safety, efficacy, pharmacokinetics and pharmacodynamics of edoxaban in patients from birth to 18 years of age with VTE and with cardiac disease at risk of thrombotic events were evaluated in two studies (see section "Posology and method of administration").

The primary efficacy endpoint was a composite of symptomatic recurrent venous thromboembolic disease, death due to VTE, and no change or an increase in thrombotic burden during the first 3 months (planned treatment duration was 6 to 12 weeks for children from birth to less than 6 months of age).

Edoxaban doses were established according to age and body weight. Dose reduction was recommended on the basis of clinical factors, including renal function and concomitant use of P-glycoprotein (P-gp) inhibitors.

The hazard ratio for the edoxaban group compared with the standard-of-care control group was 1.01 (95 % CI 0.59–1.72). The upper limit of the 95 % CI (1.72) exceeded the pre-defined non-inferiority margin of 1.5; therefore, non-inferiority of edoxaban to standard of care was not confirmed.

Pharmacokinetics

Absorption. After absorption, peak plasma concentrations (Cmax) of edoxaban are reached within 1–2 hours. Absolute bioavailability is approximately 62 %. Food increases peak exposure to a variable extent but has minimal effect on total exposure. Edoxaban was taken with or without food in the studies. Edoxaban is poorly soluble at pH 6.0 or higher. Concomitant use of proton pump inhibitors has no significant effect on edoxaban exposure.

Distribution. Edoxaban has a biphasic distribution. The mean volume of distribution is 107 L (standard deviation 19.9 L).

In vitro plasma protein binding is approximately 55 %. There is no clinically significant accumulation of edoxaban (accumulation ratio 1.14) with once-daily dosing. Steady state is achieved within 3 days.

Biotransformation. Unchanged edoxaban is the predominant form in plasma. Edoxaban is metabolised via hydrolysis (mediated by carboxylesterase 1), conjugation or oxidation by CYP3A4/5 (< 10 %). Edoxaban has three active metabolites, the predominant one (M-4), formed by hydrolysis, is active and reaches less than 10 % of the exposure of the parent compound in healthy subjects. Exposure to the other metabolites is less than 5 %. Edoxaban is a substrate of the efflux transporter P-gp, but not a substrate of uptake transporters such as organic anion transporting polypeptide OATP1B1, organic anion transporters OAT1 or OAT3, or organic cation transporter OCT2. Its active metabolite is a substrate of OATP1B1.

Elimination. In healthy subjects, the estimated total clearance is 22 (± 3) L/h; 50 % is renal clearance (11 L/h). Renal clearance accounts for approximately 35 % of the administered dose. The remaining clearance is accounted for by metabolism and biliary/intestinal excretion. The terminal elimination half-life after oral administration is 10–14 hours.

Linearity. Edoxaban displays approximately dose-proportional pharmacokinetics for doses from 15 mg to 60 mg.

Special populations

Elderly

In the population pharmacokinetic analysis, after accounting for renal function and body weight, age had no additional clinically significant effect on the pharmacokinetics of edoxaban.

Renal impairment

The plasma AUC (area under the concentration–time curve) in patients with mild (CrCL > 50–80 mL/min), moderate (CrCL 30–50 mL/min) and severe (CrCL < 30 mL/min, not on dialysis) renal impairment was increased by 32 %, 74 % and 72 %, respectively, compared with patients with normal renal function. In patients with renal impairment, the metabolite profile changes and a greater number of active metabolites are formed.

There is a linear correlation between plasma edoxaban concentration and anti-FXa activity, regardless of renal function.

Patients with end-stage renal disease undergoing peritoneal dialysis had a 93 % higher total exposure compared with healthy volunteers.

Population pharmacokinetic modelling indicates that exposure approximately doubles in patients with severe renal impairment compared with patients with normal renal function.

Anti-FXa activity by creatinine clearance (CrCL)

Treatment with edoxaban does not require routine monitoring. The effect on anticoagulation can be assessed by a calibrated quantitative anti-FXa assay, which may be useful in exceptional situations where knowledge of edoxaban exposure may help in clinical decision-making, for example in cases of overdose and emergency surgery.

After a 4-hour haemodialysis session, total exposure to edoxaban was reduced by less than 9 %.

Hepatic impairment

In patients with mild or moderate hepatic impairment, pharmacokinetics and pharmacodynamics were comparable to those of the matched healthy control group. Edoxaban has not been studied in patients with severe hepatic impairment.

Sex

In the population pharmacokinetic analysis, sex had no additional clinically significant effect on the pharmacokinetics of edoxaban.

Ethnic origin

In the population pharmacokinetic analysis, peak and total exposure in Asian and non-Asian patients were comparable.

Body weight

The population pharmacokinetic analysis showed that in patients with low body weight (55 kg), Cmax and AUC were increased by 40 % and 13 %, respectively, compared with patients of median body weight (84 kg). In the study (for the NVAF and VTE indications), patients with body weight ≤ 60 kg who received a 50 % reduced dose of edoxaban had similar efficacy and fewer bleeding events compared with warfarin.

Pharmacokinetic/pharmacodynamic (PK/PD) relationship

PT, international normalised ratio (INR), aPTT and anti-FXa correlated linearly with edoxaban concentration. A linear correlation was also observed between anti-FXa activity and plasma edoxaban concentration in children from birth to 18 years of age. Overall, the PK/PD relationship was similar between paediatric patients from birth to 18 years and adult VTE patients; however, PD variability led to considerable uncertainty in the assessment of this relationship.

Clinical particulars

Indications

Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) and one or more risk factors, such as congestive heart failure, hypertension, diabetes mellitus, prior stroke or transient ischaemic attack (TIA), age ≥ 75 years.

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see section "Special warnings and precautions for use" for haemodynamically unstable PE patients).

Contraindications

Hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Clinically significant active bleeding.

Hepatic disease associated with coagulopathy and clinically relevant bleeding risk.

Lesions or conditions associated with a significant risk of major bleeding, including 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 arterial hypertension.

Concomitant use of any other anticoagulants, for example unfractionated heparin (UFH), low-molecular-weight heparins (LMWH) (enoxaparin, dalteparin), heparin derivatives (fondaparinux), oral anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban), except under the specific circumstances of switching anticoagulant therapy (see section "Posology and method of administration") or when UFH is given at doses necessary to maintain an open central venous or arterial catheter (see section "Interaction with other medicinal products and other forms of interaction").

Pregnancy or breast-feeding (see section "Use during pregnancy or breast-feeding").

Interaction with other medicinal products and other forms of interaction

Edoxaban is absorbed mainly in the upper gastrointestinal tract. Therefore, medicinal products or diseases that increase gastric emptying and intestinal motility may reduce the dissolution and absorption of edoxaban.

P-glycoprotein (P-gp) inhibitors

Edoxaban is a substrate of the efflux transporter P-gp. In pharmacokinetic studies, concomitant use 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 a dose reduction to 30 mg once daily.

Concomitant use of edoxaban with quinidine, verapamil or amiodarone does not require a dose reduction (see section "Posology and method of administration").

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

Edoxaban 30 mg once daily can be used concomitantly with the following P-gp inhibitors:

– Ciclosporin: concomitant administration of a single dose of ciclosporin 500 mg with a single dose of edoxaban 60 mg increased serum AUC and Cmax of edoxaban by 73 % and 74 %, respectively.

– 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: 500 mg four times daily for 8 days with a single concomitant dose of edoxaban 60 mg on Day 7 increased edoxaban AUC and Cmax by 85 % and 68 %, respectively.

– 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 can be used concomitantly with the following P-gp inhibitors:

– Quinidine: with quinidine 300 mg once daily on Days 1 and 4 and three times daily on Days 2 and 3, together with a single concomitant dose of edoxaban 60 mg on Day 3, the 24-hour AUC of edoxaban increased by 77 % and Cmax by 85 %, respectively.

– Verapamil: with verapamil 240 mg once daily for eleven days together with a single dose of edoxaban 60 mg on Day 10, edoxaban AUC and Cmax increased by approximately 53 %.

– Amiodarone: concomitant administration of amiodarone 400 mg once daily with edoxaban 60 mg once daily increased AUC by 40 % and Cmax by 66 %. This increase was not considered clinically significant. In the study in NVAF patients, efficacy and safety were similar in patients receiving concomitant amiodarone and in those not receiving concomitant amiodarone.

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

P-glycoprotein (P-gp) inducers

Concomitant use of edoxaban with the P-gp inducer rifampicin resulted in a decrease in mean edoxaban AUC and a shortened half-life, with a possible decrease in its pharmacodynamic effects. Concomitant use of edoxaban with other P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbital or St John's wort) may lead to reduced plasma concentrations of edoxaban. Edoxaban should be used with caution together with P-gp inducers.

P-glycoprotein (P-gp) substrates

Digoxin: when edoxaban 60 mg once daily was given for 1–14 days with concomitant multiple-dose digoxin 0.25 mg twice daily (Days 8 and 9) and 0.25 mg once daily (Days 10 and 14), edoxaban Cmax increased by 17 % with no significant effect on steady-state AUC or renal clearance. When the effect of edoxaban on digoxin pharmacokinetics was studied, digoxin Cmax increased by approximately 28 % and AUC by 7 %. This increase was not considered clinically significant. No dose adjustment is necessary when edoxaban is used concomitantly with digoxin.

Anticoagulants, antiplatelet agents, non-steroidal anti-inflammatory drugs (NSAIDs) and selective serotonin reuptake inhibitors / serotonin norepinephrine reuptake inhibitors (SSRIs/SNRIs)

Anticoagulants: concomitant use of edoxaban with other anticoagulants is contraindicated due to an increased risk of bleeding (see section "Contraindications").

Acetylsalicylic acid (ASA): concomitant use of ASA (100 mg or 325 mg) and edoxaban increases bleeding time compared with either drug alone. Concomitant use of high-dose ASA (325 mg) increased steady-state Cmax and AUC of edoxaban by 35 % and 32 %, respectively. Long-term concomitant use of high-dose ASA (325 mg) with edoxaban is not recommended. Concomitant use of ASA doses above 100 mg should be carried out only under medical supervision.

In the studies, concomitant use of ASA (low dose, ≤ 100 mg daily), other antiplatelet agents and thienopyridines was permitted, resulting in an approximately two-fold increase in major bleeding compared with monotherapy, with similar increases in both the edoxaban and warfarin groups (see section "Special warnings and precautions for use"). Concomitant use of low-dose ASA (≤ 100 mg) did not affect peak or total exposure to edoxaban after single-dose administration.

Edoxaban can be used concomitantly with low-dose ASA (≤ 100 mg daily).

Platelet aggregation inhibitors: in the study, concomitant use of thienopyridines as monotherapy (e.g. clopidogrel) led to an increased rate of clinically relevant bleeding, although the risk was relatively lower with edoxaban than with warfarin (see section "Special warnings and precautions for use").

Experience with edoxaban in combination with dual antiplatelet therapy or fibrinolytics is very limited.

Non-steroidal anti-inflammatory drugs (NSAIDs): concomitant use of naproxen and edoxaban results in prolonged bleeding time compared with either drug alone. Naproxen does not affect edoxaban Cmax and AUC. In clinical studies, concomitant use of NSAIDs was associated with an increased incidence of clinically relevant bleeding. Long-term use of NSAIDs with edoxaban is not recommended.

Selective serotonin reuptake inhibitors / serotonin norepinephrine reuptake inhibitors (SSRIs/SNRIs): as with other anticoagulants, there is a possibility that patients may be at increased risk of bleeding when co-administered with SSRIs or SNRIs, due to their reported effect on platelets (see section "Special warnings and precautions for use").

Effect of edoxaban on other medicinal products

Edoxaban increased the Cmax of concomitantly administered digoxin by 28 %, but this did not affect AUC. 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.

Special warnings and precautions for use

Edoxaban 15 mg is not indicated as monotherapy since this may result in decreased efficacy. It is indicated only during the switch from edoxaban 30 mg [with one or more clinical factors for increased exposure (see Table 1)] to a vitamin K antagonist (VKA) together with an appropriate VKA dose (see Table 2, section "Posology and method of administration").

Haemorrhage risk

Edoxaban increases the risk of bleeding and can cause serious, potentially life-threatening bleeding. As with other anticoagulants, edoxaban should be used with caution in patients with conditions associated with an increased risk of bleeding. If severe bleeding occurs, administration of the medicinal product must be discontinued (see sections "Overdose" and "Adverse reactions").

In clinical studies, mucosal bleeding (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, where appropriate, to detect occult bleeding.

Certain patient subgroups, as detailed below, are at increased risk of bleeding. These patients should be carefully monitored after initiation of treatment for signs and symptoms of bleeding complications and anaemia (see section "Adverse reactions"). 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. There is no specific antidote that reverses the anticoagulant effect of edoxaban (see section "Overdose").

Haemodialysis does not significantly contribute to edoxaban clearance (see subsection "Pharmacokinetics").

Elderly patients

Concomitant use of edoxaban and ASA in elderly patients should be done with caution because of the potentially higher bleeding risk (see section "Interaction with other medicinal products and other forms of interaction").

Renal impairment

Plasma AUC in patients with mild (CrCL > 50–80 mL/min), moderate (CrCL 30–50 mL/min) and severe (CrCL < 30 mL/min, not on dialysis) renal impairment was increased by 32 %, 74 % and 72 %, respectively, compared with patients with normal renal function (see section "Posology and method of administration").

Treatment with edoxaban is not recommended in patients with CrCL < 15 mL/min or in patients on dialysis (see subsection "Pharmacokinetics" and section "Posology and method of administration").

Renal function in non-valvular atrial fibrillation (NVAF)

A trend towards decreasing efficacy with increasing CrCL was observed for edoxaban compared with well-managed warfarin (see subsection "Pharmacodynamics"). Therefore, edoxaban should be used in NVAF patients with high CrCL only after careful evaluation of the individual thromboembolic and bleeding risk.

Assessment of renal function: CrCL should be monitored at the beginning of treatment in all patients and thereafter as clinically indicated (see section "Posology and method of administration").

Hepatic impairment

Edoxaban is not recommended in patients with severe hepatic impairment (see subsection "Pharmacokinetics" and section "Posology and method of administration").

Edoxaban should be used with caution in patients with mild or moderate hepatic impairment (see section "Posology and method of administration").

Patients with elevated liver enzymes (alanine aminotransferase/aspartate aminotransferase (ALT/AST) more than 2 times the upper limit of normal) or with total bilirubin 1.5 times the upper limit of normal or more were excluded from clinical studies. Therefore, edoxaban should be used with caution in this population (see subsection "Pharmacokinetics" and section "Posology and method of administration"). Liver function testing should be performed prior to initiation of edoxaban. Periodic liver function checks are recommended in patients treated with edoxaban for more than one 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.

If a procedure cannot be delayed, 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, bearing in mind that the onset of the anticoagulant effect of edoxaban occurs 1–2 hours after administration.

If oral medication cannot be taken during or after surgical intervention, consider administering a parenteral anticoagulant followed by a switch to once-daily oral edoxaban (see section "Posology and method of administration").

Interactions with other medicinal products that affect haemostasis

Concomitant use of medicinal products affecting haemostasis may increase the risk of bleeding. These include ASA, platelet aggregation inhibitors, other antiplatelet agents, fibrinolytic therapy, SSRIs or SNRIs, and NSAIDs when used long term (see section "Interaction with other medicinal products and other forms of interaction").

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, the use of edoxaban in these patients is not recommended.

Haemodynamically unstable PE patients or patients requiring thrombolysis or pulmonary embolectomy

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

Patients with active cancer

The 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 who 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 VKA therapy.

Laboratory parameters

Although treatment with edoxaban does not require routine monitoring, the effect on anticoagulation can be assessed by a calibrated quantitative anti-FXa assay, which may help inform clinical decisions in particular situations, for example overdose and emergency surgery (see subsection "Pharmacokinetics").

Edoxaban prolongs standard clotting tests such as PT, INR and aPTT as a result of factor Xa inhibition. However, changes in these clotting tests at the expected therapeutic dose are small, subject to a high degree of variability, and are not useful in monitoring the anticoagulant effect of edoxaban.

Excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains mannitol, which may have a mild laxative effect.

Use during pregnancy or breast-feeding

Effects on reproductive function. Women of childbearing potential should avoid becoming pregnant during treatment with edoxaban.

Pregnancy. The safety and efficacy of edoxaban in pregnant women have not been studied. Animal studies have shown reproductive toxicity. Due to the potential reproductive toxicity, the intrinsic risk of bleeding and the evidence that edoxaban passes across the placenta, Edoxacord is contraindicated during pregnancy (see section "Contraindications").

Breast-feeding. The safety and efficacy of edoxaban in breast-feeding women have not been studied. Data from animals indicate that edoxaban is secreted into milk. Therefore, Edoxacord is contraindicated during breast-feeding (see section "Contraindications"). A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy.

Fertility. No specific studies with edoxaban in humans have been performed to evaluate effects on fertility. In a study on male and female fertility in rats, no effects were seen.

Ability to influence reaction speed when driving or operating other machinery

Edoxacord has no or negligible influence on reaction speed when driving or operating other machinery.

Posology and method of administration

Prevention of stroke and systemic embolism

The recommended dose is 60 mg of edoxaban once daily.

Therapy with edoxaban in NVAF patients should be continued long term.

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

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

The duration of therapy for DVT and PE (VTE) and for the prevention of recurrent VTE should be individualised after careful assessment of the treatment benefit against the risk of bleeding (see section "Special warnings and precautions for use"). Short duration of therapy (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation), whereas longer durations should be based on permanent risk factors or idiopathic DVT or PE.

For NVAF and VTE, the recommended dose of edoxaban is 30 mg once daily in patients with one or more of the following clinical factors:

moderate or severe renal impairment (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 dosing recommendations for non-valvular atrial fibrillation and venous thromboembolism (deep vein thrombosis and pulmonary embolism)

Missed dose

If a dose of edoxaban is missed, the dose should be taken immediately and then continued the following day with once-daily intake as recommended. The dose should not be doubled within the same day to make up for a missed dose.

Switching to and from edoxaban

NVAF and VTE patients must receive continuous anticoagulant therapy. In some situations, it may be necessary to change anticoagulant therapy (Table 2).

Table 2

Switching of anticoagulant treatment in non-valvular atrial fibrillation and venous thromboembolism (deep vein thrombosis and pulmonary embolism)

Switching to edoxaban

Switching from edoxaban

Special patient populations

Elderly patients

No dose adjustment is required (see subsection "Pharmacokinetics").

Renal impairment

Renal function should be assessed in all patients by calculating CrCL prior to initiation of treatment with edoxaban, in order to exclude patients with end-stage renal disease (i.e. CrCL < 15 mL/min), to establish the correct edoxaban dose in patients with CrCL 15–50 mL/min (30 mg once daily) and in patients with CrCL > 50 mL/min (60 mg once daily), and to decide on the use of edoxaban in patients with increased CrCL (see section "Special warnings and precautions for use").

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

Renal function (CrCL in mL/min) is determined using the Cockcroft–Gault formula below:

To obtain creatinine values in µmol/L:

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To obtain creatinine values in mg/dL:

<![endif]> This method is recommended for estimating CrCL in patients before and during treatment with edoxaban.

This method is recommended for estimating CrCL in patients before and during treatment with edoxaban.

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

For patients with moderate or severe renal impairment (CrCL 15–50 mL/min), the recommended dose is 30 mg of edoxaban once daily (see subsection "Pharmacodynamics").

Use of this medicinal product is not recommended in patients with end-stage renal disease (CrCL <15 mL/min) or in patients undergoing dialysis (see subsection "Pharmacokinetics" and section "Special warnings and precautions for use").

Hepatic impairment

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

Edoxaban is not recommended in patients with severe hepatic impairment (see subsection "Pharmacokinetics" and section "Special warnings and precautions for use").

Edoxaban should be used with caution in patients with mild or moderate hepatic impairment (see section "Special warnings and precautions for use"); the recommended dose for these patients is 60 mg of edoxaban once daily (see subsection "Pharmacokinetics").

Patients with elevated liver enzymes (alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 2 times the upper limit of normal (ULN)) or total bilirubin (1.5 times ULN or more) were excluded from the studies. Therefore, Edoxacord should be used with caution in this group of patients (see subsection "Pharmacokinetics" and section "Special warnings and precautions for use"). Liver function testing should be performed prior to initiation of edoxaban.

Body weight

For patients with body weight ≤ 60 kg, the recommended dose is 30 mg of edoxaban once daily (see subsection "Pharmacokinetics").

Sex

No dose adjustment is required (see subsection "Pharmacokinetics").

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

For patients concomitantly receiving edoxaban and the P-gp inhibitors ciclosporin, dronedarone, erythromycin or ketoconazole, the recommended dose of edoxaban is 30 mg once daily (see section "Interaction with other medicinal products and other forms of interaction"). No dose reduction is required with concomitant use of amiodarone, quinidine or verapamil (see section "Interaction with other medicinal products and other forms of interaction").

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

Patients undergoing cardioversion

Edoxacord can be initiated or continued in patients who may require cardioversion.

For transoesophageal echocardiogram (TEE)-guided cardioversion in patients not previously treated with anticoagulants, treatment with Edoxacord should be started at least 2 hours before cardioversion to ensure adequate anticoagulation (see subsections "Pharmacodynamics" and "Pharmacokinetics"). Cardioversion should be performed no later than 12 hours after the dose of edoxaban on the day of the procedure.

For all patients undergoing cardioversion: confirmation should be sought prior to cardioversion that the patient has taken edoxaban as prescribed. Decisions on initiation and duration of treatment should take into account established guideline recommendations for anticoagulant treatment in patients undergoing cardioversion.

Method of administration

For oral use.

Edoxaban can be taken with or without food (see subsection "Pharmacokinetics").

Paediatric population

Edoxaban is not recommended for use in children from birth to 18 years of age with confirmed VTE (PE and/or DVT), as efficacy has not been established. Available data in patients with VTE are described in the subsections "Pharmacodynamics" and "Pharmacokinetics" and in the section "Adverse reactions".

Overdose

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

There is no specific antidote that reverses the pharmacodynamic effect of edoxaban.

In the event of edoxaban overdose, early administration of activated charcoal may be considered to reduce absorption. This recommendation is based on standard treatment of medicinal product overdose and on available data for similar compounds, as the use of activated charcoal to reduce edoxaban absorption has not been specifically studied.

Management of bleeding. If a bleeding complication arises, the next administration of edoxaban should be delayed or treatment should be discontinued as appropriate. The half-life of edoxaban is approximately 10–14 hours (see subsection "Pharmacokinetics"). Management should be individualised according to the severity and location of the haemorrhage. Appropriate symptomatic treatment may be used as needed, such as mechanical compression 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 measures such as transfusion or haemostasis, administration of a 4-factor prothrombin complex concentrate (PCC) at a dose of 50 IU/kg has been shown to reverse the effect of edoxaban 30 minutes after completion of the infusion.

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

Consultation with a haematologist may be required in the case of major bleeding.

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 systemic haemostatics (desmopressin, aprotinin) in individuals receiving edoxaban. Due to the high plasma protein binding, edoxaban is not expected to be dialysable.

Adverse reactions.

The safety profile of edoxaban is based on two phase 3 studies (21,105 patients with NVAF and 8,292 patients with DVT and PE), and on post-marketing experience.

The most frequently reported adverse reactions with edoxaban were epistaxis (7.7 %), haematuria (6.9 %) and anaemia (5.3 %). Bleeding may occur at any site and may be severe or even fatal (see section "Special warnings and precautions for use").

The list of adverse reactions is based on the two key phase 3 studies in DVT and NVAF patients, pooled for both indications, and on adverse drug reactions identified in the post-marketing period. The adverse reactions listed below are classified by system organ class (according to MedDRA) and by frequency: 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); not known (cannot be estimated from the available data).

Blood and lymphatic system disorders: common — anaemia; uncommon — thrombocytopenia.

Immune system disorders: rare — anaphylactic reactions, allergic oedema; uncommon — hypersensitivity.

Nervous system disorders: common — dizziness, headache; uncommon — intracranial haemorrhage; rare — subarachnoid haemorrhage.

Eye disorders: uncommon — intraocular haemorrhage, conjunctival/scleral haemorrhage.

Cardiac disorders: rare — pericardial haemorrhage.

Vascular disorders: uncommon — other haemorrhage.

Respiratory, thoracic and mediastinal disorders: common — epistaxis; uncommon — haemoptysis.

Gastrointestinal disorders: common — abdominal pain, lower and upper gastrointestinal haemorrhage, oral/pharyngeal haemorrhage, nausea; rare — peritoneal haemorrhage.

Hepatobiliary disorders: common — increased blood bilirubin and gamma-glutamyltransferase; uncommon — increased blood alkaline phosphatase and transaminases.

Skin and subcutaneous tissue disorders: common — cutaneous soft tissue haemorrhage; rash, pruritus; uncommon — urticaria.

Musculoskeletal and connective tissue disorders: rare — muscle haemorrhage (without compartment syndrome), intra-articular haemorrhage.

Renal and urinary disorders: common — macroscopic haematuria/urethral haemorrhage; not known – anticoagulant-related nephropathy.

Reproductive system and breast disorders: common — vaginal haemorrhage1.

General disorders and administration site conditions: common — puncture site haemorrhage.

Investigations: common — abnormal liver function tests.

Injury, poisoning and procedural complications: uncommon — surgical site haemorrhage; rare — subdural haemorrhage, procedural haemorrhage.

1 The reporting frequency is based on the female population in clinical studies. Vaginal haemorrhage was generally observed in women under 50 years of age and was uncommon in women over 50 years of age (according to study data).

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 possible fatal outcome) will vary according to the location and degree or extent of the bleeding and/or anaemia (see section "Overdose"). In clinical studies, mucosal bleeding (e.g. epistaxis, gastrointestinal, genitourinary) and anaemia were seen more frequently during long-term treatment with edoxaban compared with VKA treatment. Thus, in addition to adequate clinical surveillance, laboratory testing of haemoglobin/haematocrit could be of value, where appropriate, to detect occult bleeding. The risk of bleeding may be increased in certain patient groups, e.g. patients with uncontrolled severe arterial hypertension and/or patients concomitantly treated with a medicinal product that affects haemostasis (see section "Special warnings and precautions for use"). Menstrual bleeding may be intensified and/or prolonged. Haemorrhagic complications may present as weakness, pallor, 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. 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 studies in patients from birth to 18 years of age with VTE (286 patients, 145 of whom received edoxaban) and with cardiac disease at risk of thrombotic complications (167 patients, 109 of whom received edoxaban). Overall, the safety profile in children was similar to that in the adult population. 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, as well as patients or their legal representatives, are asked to report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years

Storage conditions.

Store in the original package at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Package. 10 tablets in a blister; 3 blisters in a carton.

Legal status. Prescription only.

Manufacturer. JSC "KYIV VITAMIN PLANT".

Manufacturer's location and address of the place of business.

38 Kopylivska St., Kyiv, 04073, Ukraine.

Date of last revision. 02.09.2026