Edoxadar

INSTRUCTIONS for medical use of the medicinal product Edoxadar (Edoxadar)

Composition:

Active substance: edoxaban;

1 film-coated tablet contains edoxaban 30.000 mg, equivalent to 40.410 mg of edoxaban tosylate monohydrate, or 60.000 mg, equivalent to 80.820 mg of edoxaban tosylate monohydrate.

Excipients: mannitol (E 421), hydroxypropylcellulose, crospovidone, pregelatinized starch (corn), colloidal anhydrous silicon dioxide, magnesium stearate; coating:

30 mg tablets: sodium carmellose; maltodextrin; glucose monohydrate; lecithin (soy); calcium carbonate; iron oxide red (E 172);

60 mg tablets: sodium carmellose; maltodextrin; glucose monohydrate; lecithin (soy); calcium carbonate; iron oxide yellow (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

30 mg tablets: pink, round-shaped, film-coated tablets, embossed with "30" on one side and smooth on the other;

60 mg tablets: yellow, round-shaped, film-coated tablets, embossed with "60" on one side and smooth on the other.

Pharmacotherapeutic group. Antithrombotic agents. Direct factor Xa inhibitors. Edoxaban. ATC code B01AF03.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Edoxaban is a highly selective, direct, reversible inhibitor of factor Xa, a serine protease that represents the final common pathway in the coagulation cascade. Edoxaban inhibits both free factor Xa and prothrombinase-bound factor Xa. Inhibition of factor Xa in the coagulation cascade leads to reduced thrombin generation, prolongs blood 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 the time of maximum plasma concentration (Cmax) of edoxaban. The pharmacodynamic effects, measured by anti-factor Xa activity assays, are predictable and correlate with the dose and concentration of edoxaban. As a result of factor Xa inhibition, edoxaban also prolongs clotting times measured by prothrombin time (PT) and activated partial thromboplastin time (aPTT). However, changes in clotting parameters observed with therapeutic doses are minor and variable; therefore, monitoring of coagulation parameters is not recommended for assessing the anticoagulant effect of edoxaban.

Effect of 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 60 mg dose of edoxaban on day 4. The effects on PT and other coagulation biomarkers (e.g., anti-factor Xa activity, aPTT) were assessed. On day 4 after switching to edoxaban, PT values were comparable to those observed on day 3 of rivaroxaban and apixaban treatment. aPTT values were higher after edoxaban administration following prior dabigatran treatment compared to edoxaban alone. This is considered attributable to residual effects of dabigatran, but it did not result in prolonged bleeding time.

Based on these data, when switching from these anticoagulants to edoxaban, the first dose of edoxaban can be administered in place of the next scheduled dose of the previous anticoagulant.

Clinical Efficacy and Safety

Prevention of Stroke and Systemic Embolism

The clinical trial program evaluating edoxaban in atrial fibrillation was designed to demonstrate the efficacy and safety of two edoxaban dose regimens compared to warfarin for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and moderate to high risk of stroke and systemic embolic events. The primary efficacy endpoint was a composite of stroke and systemic embolic events. Secondary efficacy endpoints included: composite of stroke, systemic embolic events, and cardiovascular death; major adverse cardiovascular events (MACE), defined as a composite of non-fatal myocardial infarction (MI), non-fatal stroke, non-fatal systemic embolic event, and death from cardiovascular causes or bleeding; and composite of stroke, systemic embolic event, and death from any cause.

The primary efficacy analysis aimed to demonstrate non-inferiority of edoxaban compared to warfarin regarding the primary endpoint of 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 demonstrated non-inferior efficacy compared to warfarin for the primary efficacy endpoint of stroke or systemic embolic event.

The primary safety endpoint was major bleeding.

A significant reduction in the risk of major bleeding, intracranial hemorrhage, and other types of bleeding was observed in the edoxaban 60 mg group compared to the warfarin group.

In the edoxaban 60 mg treatment group, a significant reduction in fatal bleeding was also observed compared to the warfarin group, primarily due to a reduction in fatal intracranial hemorrhages.

Treatment of Deep Vein Thrombosis (DVT) and Pulmonary Embolism (PE), and Prevention of Recurrent DVT and PE [Venous Thromboembolism (VTE)]

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

The study demonstrated that edoxaban is non-inferior to warfarin for the primary efficacy endpoint of recurrent VTE.

Efficacy results in pre-specified major subgroups (with dose reduction as needed), including age, body weight, sex, and renal function, were consistent with the overall efficacy results in the entire trial 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, and clinically relevant non-major bleeding compared to the warfarin group.

Prevention of Stroke and Systemic Embolism in Patients with NVAF and Creatinine Clearance (CrCl) > 100 mL/min

Based on data from patients with NVAF and high CrCl (> 100 mL/min) receiving edoxaban 60 mg, the expected annual rate of ischemic stroke/systemic embolism is ≤ 1%. Increasing the edoxaban dose (above 60 mg) in patients with NVAF and high CrCl (> 100 mL/min) does not provide additional protection against stroke and may be associated with increased adverse effects. Therefore, a dose of edoxaban 60 mg once daily is recommended for these patients after careful assessment of individual thromboembolic and bleeding risk.

Patients Undergoing Cardioversion

During clinical trials, a low incidence of major and clinically relevant non-major bleeding and thromboembolic events was observed in patients undergoing cardioversion.

Pediatric Population

The European Medicines Agency has deferred the obligation to submit the results of edoxaban studies in one or more pediatric subgroups for the prevention of arterial thromboembolism, treatment of thromboembolism, and prevention of thromboembolism (see section "Posology and Method of Administration").

Pharmacokinetics

Absorption. After administration, maximum plasma concentration of edoxaban is reached within 1–2 hours. Absolute bioavailability is approximately 62%. Food intake increases peak exposure unevenly but has minimal effect on overall exposure. Edoxaban was studied with and without food. Edoxaban has poor solubility at pH levels of 6.0 or higher. Concomitant use of proton pump inhibitors does not have a clinically significant effect on edoxaban exposure.

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

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

Metabolism. Edoxaban is predominantly present in unchanged form in plasma. It is metabolized via hydrolysis (mediated by carboxylesterase 1), conjugation, or oxidation by CYP3A4/5 (< 10%). Edoxaban has three active metabolites; the main one (M-4), formed via hydrolysis, is active and accounts for less than 10% of the parent drug concentration in healthy subjects. Concentrations of other metabolites are less than 5%. Edoxaban is a substrate of the efflux transporter P-glycoprotein (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 calculated total clearance is 22 (± 3) L/h; 50% of the drug is cleared renally (11 L/h). Renal clearance accounts for approximately 35% of the administered dose. The remainder is cleared via metabolism and biliary/intestinal excretion. The elimination half-life after oral administration is 10–14 hours.

Linearity. Edoxaban exhibits approximately dose-proportional pharmacokinetics over the dose range of 15 mg to 60 mg.

Special Populations

Elderly Patients

Population pharmacokinetic analysis, adjusted for renal function and body weight, showed that patient age has no additional clinically significant effect on edoxaban pharmacokinetics.

Renal Impairment

The 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 to patients with normal renal function. In patients with renal impairment, the metabolite profile is altered, with increased formation of active metabolites.

A linear correlation between plasma edoxaban concentration and anti-factor Xa activity was observed, independent of renal function.

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

Population pharmacokinetic modeling indicates that exposure is approximately doubled in patients with severe renal impairment compared to those with normal renal function.

Anti-Factor Xa Activity in Relation to CrCl

Edoxaban therapy does not require routine monitoring; however, anti-factor Xa activity can be assessed using a calibrated quantitative anti-factor Xa assay, which may be useful in exceptional situations where information on edoxaban exposure may assist clinical decision-making, such as in overdose or emergency surgery.

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

Hepatic Impairment

Pharmacokinetic and pharmacodynamic parameters in patients with mild or moderate hepatic impairment were similar to those observed in healthy control subjects. The use of edoxaban in patients with severe hepatic impairment has not been studied.

Sex

Population pharmacokinetic analysis showed that patient sex has no additional clinically significant effect on edoxaban pharmacokinetics.

Ethnic Origin

Population pharmacokinetic analysis showed that maximum and total exposure in patients from Asia and those from non-Asian countries were comparable.

Body Weight

Population pharmacokinetic analysis showed that in patients with low body weight (55 kg), Cmax and AUC were increased by 40% and 13%, respectively, compared to patients with average body weight (84 kg). In a clinical trial (for NVAF and VTE indications), patients with body weight ≤ 60 kg received a 50% reduced dose of edoxaban and demonstrated similar efficacy and fewer bleeding events compared to warfarin.

Pharmacokinetic/Pharmacodynamic Relationship

PT, INR (International Normalized Ratio), aPTT, and anti-factor Xa activity showed linear correlation with edoxaban concentration.

Clinical characteristics

Indications

• For the 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 ischemic attack (TIA), or age ≥75 years.
• For the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as for the prevention of recurrent DVT and PE in adults (see section "Special precautions for use" regarding patients with hemodynamically unstable PE).

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 significant bleeding risk.
• Lesions or conditions associated with a significant risk of bleeding, including active or recent gastrointestinal ulceration, presence of malignancies with high bleeding risk, recent trauma to the brain or spinal cord, recent surgery on the brain, spinal cord, or eyes, recent intracranial hemorrhage, diagnosed or suspected esophageal varices, arteriovenous malformations, aneurysms, or significant intraspinal or intracranial vascular anomalies.
• Uncontrolled severe hypertension.
• Concomitant use of any other anticoagulants, such as unfractionated heparin (UFH), low molecular weight heparins (LMWHs) (e.g., enoxaparin, dalteparin, etc.), heparin derivatives (e.g., fondaparinux, etc.), or oral anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, apixaban, etc.), except in specific cases of switching anticoagulant therapy (see section "Dosage and administration") or administration of UFH at doses required to maintain patency of a central venous or arterial catheter.
• Pregnancy or breastfeeding period (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction

Edoxaban is predominantly absorbed 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 administration of edoxaban with P-gp inhibitors such as cyclosporine, dronedarone, erythromycin, ketoconazole, quinidine, or verapamil resulted in increased plasma concentrations of edoxaban.

Concomitant use of edoxaban with cyclosporine, 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.

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

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

• Cyclosporine: concomitant administration of a single 500 mg dose of cyclosporine with a single 60 mg dose of edoxaban increased the AUC and Cmax of edoxaban.
• Dronedarone: 400 mg twice daily for 7 days with a single concomitant 60 mg dose of edoxaban on day 5 increased the AUC and Cmax of edoxaban.
• Erythromycin: 500 mg four times daily for 8 days with a single concomitant 60 mg dose of edoxaban on day 7 increased the AUC and Cmax of edoxaban.
• Ketoconazole: 400 mg once daily for 7 days with a single concomitant 60 mg dose of edoxaban on day 4 increased the AUC and Cmax of edoxaban.

Edoxaban 60 mg once daily may be used concomitantly with the following P-gp inhibitors:

• Quinidine: administration of quinidine 300 mg once daily on days 1 and 4, and three times daily on days 2 and 3, together with a single concomitant 60 mg dose of edoxaban on day 3, resulted in increased AUC of edoxaban over 24 hours.
• Verapamil: administration of verapamil 240 mg once daily for 11 days together with a single 60 mg dose of edoxaban on day 10 resulted in approximately a 53% increase in AUC and Cmax of edoxaban.
• Amiodarone: concomitant administration of amiodarone 400 mg once daily with edoxaban 60 mg once daily increased AUC and Cmax. This increase was not considered clinically significant. In a clinical trial in patients with NVAF, efficacy and safety were comparable between patients receiving concomitant amiodarone and those not receiving amiodarone.
• Clarithromycin: clarithromycin (500 mg twice daily) for 10 days with a single 60 mg dose of edoxaban on day 9 increased AUC and Cmax of edoxaban by approximately 53% and 27%, respectively.

P-gp inducers

Concomitant administration of edoxaban with the P-gp inducer rifampicin resulted in reduced mean AUC of edoxaban and shortened elimination half-life, potentially reducing pharmacodynamic effects. Concomitant use of edoxaban with other P-gp inducers (e.g., phenytoin, carbamazepine, phenobarbital, or St. John’s wort) may lead to decreased plasma concentrations of edoxaban. Concomitant use of edoxaban with P-gp inducers should be done with caution.

P-gp substrates

Digoxin: administration of edoxaban 60 mg once daily for 1–14 days together with multiple doses of digoxin 0.25 mg twice daily (on days 8 and 9) and 0.25 mg once daily (on days 10 and 11) resulted in a 17% increase in Cmax of edoxaban, without significant effect on AUC or renal clearance at steady state. In a study evaluating the effect of edoxaban on digoxin pharmacokinetics, Cmax of digoxin increased by approximately 28% and AUC by 7%. This increase was not considered clinically significant. No dose adjustment is required when edoxaban is used concomitantly with digoxin.

Anticoagulants, antiplatelet agents, nonsteroidal 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 increased bleeding risk (see section "Contraindications").

Acetylsalicylic acid (ASA): concomitant use of ASA (100 mg or 325 mg) with edoxaban prolongs bleeding time. Concomitant use of high-dose ASA (325 mg) increased steady-state Cmax and AUC values of edoxaban. Long-term concomitant use of high-dose ASA and edoxaban is not recommended. Concomitant use of ASA doses above 100 mg should be undertaken only under medical supervision.

In clinical trials, concomitant use of low-dose ASA (≤100 mg/day), other antiplatelet agents, and thienopyridines was permitted, resulting in approximately a two-fold increase in major bleeding compared to monotherapy, with similar increases observed in both edoxaban and warfarin treatment groups. Concomitant use of low-dose ASA did not affect the peak or overall anticoagulant effect of a single dose of edoxaban.

Edoxaban may be used concomitantly with low-dose ASA.

Antiplatelet agents: in clinical trials, concomitant use of thienopyridines (e.g., clopidogrel) as monotherapy increased the frequency of clinically significant bleeding, although the relative risk was lower with edoxaban than with warfarin.

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

NSAIDs: concomitant use of naproxen and edoxaban prolongs bleeding time compared to monotherapy with either agent. Naproxen does not affect Cmax or AUC of edoxaban. Clinical trials have shown that concomitant use of NSAIDs increases the incidence of clinically significant bleeding. Prolonged concomitant use of NSAIDs with edoxaban is not recommended.

SSRIs/SNRIs: as with other anticoagulants, the risk of bleeding increases in patients receiving concomitant SSRIs or SNRIs, due to the effect of these agents on platelet function (see section "Special precautions for use").

Special precautions for use

Edoxaban 15 mg should not be administered as monotherapy, as this may lead to reduced efficacy. It is indicated only during transition from edoxaban 30 mg [with one or more clinical factors increasing exposure (see Table 1)] to vitamin K antagonists (VKAs), together with an appropriate VKA dose (see Table 2, section "Dosage and administration").

Risk of bleeding

Edoxaban increases the risk of bleeding and may cause severe, potentially life-threatening hemorrhage. As with other anticoagulants, edoxaban should be used with caution in patients with conditions associated with an increased risk of bleeding. In case of serious bleeding, the drug should be discontinued.

Clinical trials have shown that mucosal bleeding (e.g., epistaxis, gastrointestinal bleeding, genitourinary bleeding) and anemia occur more frequently during long-term edoxaban therapy compared to treatment with VKAs. Therefore, in addition to appropriate clinical monitoring, laboratory testing for hemoglobin/hematocrit levels should be considered in relevant cases to detect occult bleeding.

Certain patient groups, as listed below, have an increased risk of bleeding. These patients should be closely monitored after initiation of treatment for signs of hemorrhagic complications and anemia. Any unexplained decrease in hemoglobin levels or arterial blood pressure requires identification of the bleeding source.

The anticoagulant effect of edoxaban cannot be reliably monitored using standard laboratory tests. There is no specific antidote to reverse the anticoagulant effect of edoxaban.

Hemodialysis has minimal effect on edoxaban clearance.

Elderly patients

Concomitant use of edoxaban and acetylsalicylic acid (ASA) in elderly patients requires caution due to an increased risk of bleeding.

Patients with renal impairment

The AUC values in plasma are increased 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 compared to patients with normal renal function (see section "Dosage and administration").

Edoxaban is not recommended in patients with CrCl < 15 mL/min or in patients on dialysis.

Renal function in non-valvular atrial fibrillation (NVAF)

When edoxaban is used, there is a trend toward reduced efficacy with increasing CrCl compared to appropriate warfarin use. Therefore, edoxaban should be used in patients with NVAF and high CrCl only after careful assessment of individual thromboembolic and bleeding risk.

Renal function assessment: CrCl should be monitored at the beginning of treatment in all patients and subsequently as clinically indicated.

Patients with hepatic impairment

Edoxaban is not recommended for patients with severe hepatic impairment.

Edoxaban should be used with caution in patients with mild to moderate hepatic impairment.

Patients with elevated liver enzymes (alanine aminotransferase/aspartate aminotransferase [ALT/AST] exceeding the upper limit of normal by more than 2 times) or total bilirubin levels exceeding the upper limit of normal by 1.5 times or more were not included in clinical trials. Therefore, edoxaban should be used with caution in this patient population. Liver function tests should be performed before initiating edoxaban therapy. Periodic monitoring of liver function is recommended in patients receiving edoxaban for more than one year.

Discontinuation of therapy for surgical or other procedures

If anticoagulant therapy needs to be discontinued to reduce the risk of bleeding during surgery or other procedures, edoxaban should be stopped as early as possible, at least 24 hours before the procedure.

If the procedure cannot be delayed, the presence of an increased bleeding risk and the urgency of the procedure should be assessed. Edoxaban therapy should be resumed after surgical or other procedures once adequate hemostasis has been achieved, keeping in mind that the anticoagulant effect of edoxaban occurs within 1–2 hours after administration.

If oral medication cannot be administered during or after surgery, parenteral anticoagulation should be considered, followed by transition to once-daily oral edoxaban.

Interactions with other medicinal products affecting blood coagulation

Concomitant use of medicinal products affecting blood coagulation increases the risk of bleeding. These include ASA, platelet aggregation inhibitors, other antiplatelet agents, fibrinolytics, selective serotonin reuptake inhibitors (SSRIs), and long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) (see section "Interaction with other medicinal products and other forms of interaction").

Prosthetic heart valves and moderate or severe mitral stenosis

The efficacy of edoxaban has not been studied in patients with prosthetic heart valves, within the first 3 months after bioprosthetic heart valve implantation (with or without atrial fibrillation), or in patients with moderate or severe mitral stenosis. Therefore, the use of edoxaban in these patients is not recommended.

Patients with pulmonary embolism (PE) and hemodynamic instability, or patients requiring thrombolysis or pulmonary embolectomy

Edoxaban is not recommended as an alternative to unfractionated heparin (UFH) in patients with PE and hemodynamic instability or in those undergoing thrombolysis or pulmonary embolectomy, as the safety and efficacy of edoxaban in these clinical situations have not been established.

Patients with active cancer

The efficacy and safety of edoxaban for treatment and/or prevention of venous thromboembolism (VTE) in patients with active cancer have not been established.

Patients with antiphospholipid syndrome

Direct oral anticoagulants, including edoxaban, are not recommended for patients with a history of thrombosis and diagnosed antiphospholipid syndrome. In particular, in patients with confirmed positive results for all three antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, anti-beta-2-glycoprotein I antibodies), direct oral anticoagulant therapy increases the risk of recurrent thrombotic events compared to vitamin K antagonist therapy.

Laboratory parameters

Although edoxaban therapy does not require routine monitoring, the anticoagulant effect can be assessed using calibrated quantitative anti-factor Xa assays, which may assist in clinical decision-making in certain situations, such as overdose or emergency surgery.

Edoxaban prolongs standard coagulation tests such as prothrombin time (PT), INR, and activated partial thromboplastin time (aPTT) due to factor Xa inhibition. However, changes in these coagulation tests within the expected therapeutic range are minimal, highly variable, and not useful for monitoring the anticoagulant effect of edoxaban.

Important information on excipients

The medicinal product contains glucose; therefore, patients with diagnosed sugar intolerance should consult their physician before taking this medicinal product.

Use during pregnancy or breastfeeding

Effect on reproductive function. Women of reproductive potential should avoid pregnancy during edoxaban therapy.

Pregnancy. The efficacy and safety of edoxaban use in pregnant women have not been studied. Animal studies have demonstrated reproductive toxicity. Due to the potential reproductive toxicity, high risk of bleeding, and placental transfer of edoxaban, the medicinal product Edoxadar is contraindicated during pregnancy (see section "Contraindications").

Breastfeeding period. The efficacy and safety of edoxaban use in breastfeeding women have not been studied. Animal studies have shown that edoxaban passes into breast milk. Therefore, Edoxadar is contraindicated during breastfeeding (see section "Contraindications"). A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from edoxaban therapy.

Fertility. Specific studies evaluating the effect of edoxaban on human fertility have not been conducted. Fertility studies in male and female rats revealed no effect.

Ability to influence reaction speed while driving or operating machinery

The medicinal product Edoxadar has no or negligible effect on reaction speed while driving or operating machinery.

Dosage and Administration

Prevention of stroke and systemic embolism

The recommended dose is 60 mg of edoxaban once daily.

Edoxaban therapy in patients with non-valvular atrial fibrillation (NVAF) is intended for long-term use.

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

The recommended dose is 60 mg of edoxaban once daily, initiated after at least 5 days of parenteral anticoagulant therapy. Edoxaban should not be used concomitantly with parenteral anticoagulants.

The duration of treatment for DVT and PE (VTE), as well as prevention of VTE recurrence, should be determined individually, following careful assessment of the benefits of treatment versus bleeding risk. Short-term therapy (for at least 3 months) is recommended in the presence of transient risk factors (e.g., recent surgery, trauma, immobilization), whereas extended therapy should be considered in the presence of persistent risk factors or in cases of idiopathic DVT or PE.

The recommended dose for NVAF and VTE is 30 mg of edoxaban once daily in patients with one or more of the following clinical factors (see also Table 1):

• moderate to severe renal impairment (creatinine clearance [CrCl] 15–50 mL/min);
• low body weight: ≤ 60 kg;
• concomitant use of P-glycoprotein (P-gp) inhibitors: cyclosporine, dronedarone, erythromycin, or ketoconazole.

Table 1

Summary of dosing recommendations for NVAF and VTE (DVT and PE)

Missed dose

If a dose of edoxaban is missed, this dose should be taken immediately, and the patient should continue with the once-daily regimen the following day as recommended. A double dose should not be taken within the same day to make up for the missed dose.

Transitioning to edoxaban and transitioning from edoxaban

Patients with NVAF and VTE should receive continuous anticoagulant therapy. In certain situations, switching anticoagulant therapy may be necessary (Table 2).

Table 2

Switching between anticoagulant treatments in NVAF and VTE (DVT and PE)

Transitioning to edoxaban

Edoxaban translation

Special patient groups

Elderly patients

Dose adjustment is not required (see section "Pharmacokinetics").

Renal impairment

Renal function should be assessed in all patients prior to initiating edoxaban therapy by determining creatinine clearance (CrCl) in order to avoid using edoxaban in patients with end-stage renal disease (CrCl < 15 mL/min), to establish the appropriate edoxaban dose for patients with CrCl 15–50 mL/min (30 mg once daily), for patients with CrCl > 50 mL/min (60 mg once daily), and to evaluate the appropriateness of edoxaban use in patients with elevated CrCl values.

Renal function assessment should also be performed whenever changes in renal function are expected during treatment (e.g., in cases of hypovolemia, dehydration, or concomitant use of certain medications).

Renal function (CrCl in mL/min) is determined using the Cockcroft-Gault formula:

To obtain creatinine levels in µmol/L:

To obtain creatinine levels in mg/dL:

This method is recommended for assessing CrCl levels in patients before and during edoxaban therapy.

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

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

Edoxaban is not recommended for patients with end-stage renal disease (CrCl < 15 mL/min) or for patients on dialysis.

Hepatic impairment

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

Edoxaban is not recommended for use in patients with severe hepatic impairment.

Edoxaban should be used with caution in patients with mild or moderate hepatic impairment; the recommended dose of edoxaban for such patients is 60 mg once daily.

Patients with elevated liver enzymes (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] more than twice the upper limit of normal [ULN]) or elevated total bilirubin (≥1.5 times ULN) were excluded from clinical trials. Therefore, Edoxadar should be used with caution in this patient group. Liver function tests should be performed before initiating edoxaban therapy.

Body weight

For patients with body weight ≤ 60 kg, the recommended dose is 30 mg edoxaban once daily.

Sex

Dose adjustment is not required (see section "Pharmacokinetics").

Concomitant use of Edoxadar and P-glycoprotein (P-gp) inhibitors

For patients receiving edoxaban concomitantly with P-gp inhibitors such as cyclosporine, dronedarone, erythromycin, or ketoconazole, the recommended dose of edoxaban is 30 mg once daily. Dose reduction is not required when edoxaban is used concomitantly with amiodarone, quinidine, or verapamil.

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

Patients undergoing cardioversion

Initiating or continuing treatment with Edoxadar is permitted in patients who may require cardioversion.

When performing cardioversion under transesophageal echocardiography guidance in patients who have not previously received anticoagulants, Edoxadar treatment should be started at least 2 hours before cardioversion to ensure adequate anticoagulation. Cardioversion should be performed no later than 12 hours after the dose of edoxaban on the day of the procedure.

For all patients who have undergone cardioversion: prior to cardioversion, it is necessary to confirm that they have been taking edoxaban as prescribed. Decisions regarding the initiation and duration of treatment should follow recommendations for anticoagulant use in patients undergoing cardioversion.

Method of administration

For oral use.

Edoxadar may be taken with or without food.

Children

Safety and efficacy of this medicinal product in children and adolescents under 18 years of age have not been established. Data are lacking.

Overdose

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

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

In case of edoxaban overdose, early administration of activated charcoal may be used to reduce absorption. This recommendation is based on standard overdose management and available data on similar compounds, as the use of activated charcoal to reduce edoxaban absorption has not been specifically studied.

Management of bleeding. In the event of bleeding complications, the next dose of edoxaban should be delayed or treatment discontinued. The elimination half-life of edoxaban is approximately 10–14 hours. Management should be individualized depending on the severity and site of bleeding. If necessary, appropriate symptomatic treatment should be initiated, such as mechanical compression for severe epistaxis, surgical hemostasis with bleeding control procedures, restoration of fluid and electrolyte balance and hemodynamic support, blood transfusion (packed red blood cells or fresh frozen plasma, depending on the condition—anaemia or coagulopathy), or platelet transfusion.

Since life-threatening bleeding cannot be controlled by measures such as transfusion or hemostasis, administration of a four-factor prothrombin complex concentrate (PCC) at a dose of 50 IU/kg has been shown to reverse the effect of edoxaban within 30 minutes after completion of infusion.

Recombinant factor VIIa (r-FVIIa) may also be considered. However, clinical experience with this agent in patients receiving edoxaban is limited.

In cases of significant bleeding, consultation with a hematologist may be required.

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

There is no experience with the use of antifibrinolytic agents (tranexamic acid, aminocaproic acid) in patients receiving edoxaban. There is no scientific rationale or clinical experience supporting the use of systemic hemostatic agents (desmopressin, aprotinin) in patients receiving edoxaban. Due to high plasma protein binding, edoxaban is not expected to be removed from the body by dialysis.

Side effects

The most commonly reported side effects of edoxaban were epistaxis, haematuria, and anaemia. Bleeding may occur at any site and can be severe, even fatal.

The side effects listed below are classified by system organ class (according to MedDRA) and frequency of occurrence: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

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

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

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

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

Cardiac disorders: rare — pericardial haemorrhage.

Vascular disorders: uncommon — other haemorrhages.

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-glutamyl transferase levels; uncommon — increased blood alkaline phosphatase and transaminase levels.

Skin and subcutaneous tissue disorders: common — skin haemorrhage in soft tissues; 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; frequency not known — anticoagulant nephropathy.

Reproductive system and breast disorders: common — vaginal bleeding¹.

General disorders and administration site conditions: common — bleeding at the site of administration.

Investigations: common — abnormal liver function test results.

Injury, poisoning and procedural complications: uncommon — bleeding at surgical sites; rare — subdural haemorrhage.

¹Vaginal bleeding was generally observed in women under 50 years of age and was uncommon in women over 50 years of age (based on clinical studies).

Description of selected side effects

Haemorrhagic anaemia

The use of edoxaban increases the risk of internal or overt bleeding in any tissues and organs, which may lead to post-haemorrhagic anaemia. Signs, symptoms, and severity (including potentially fatal outcomes) vary depending on the location and extent of bleeding and/or anaemia (see section "Overdose"). Clinical studies have shown that mucosal bleeding (e.g., epistaxis, gastrointestinal bleeding, genitourinary bleeding) and anaemia occur more frequently during long-term treatment with edoxaban than with vitamin K antagonists (VKAs). Therefore, in addition to appropriate clinical monitoring, laboratory testing of haemoglobin/hematocrit levels is recommended in appropriate cases to detect internal bleeding. The risk of bleeding may be higher in certain patient groups, for example, in patients with uncontrolled severe hypertension and/or in patients concurrently taking a medicinal product affecting blood coagulation. Menstrual bleeding may become more intense and/or prolonged. Manifestations of haemorrhagic complications may include weakness, pallor, dizziness, headache, unexplained swelling, dyspnoea, or shock of unknown origin.

Complications known to result from severe bleeding, such as compartment syndrome and renal failure due to hypoperfusion, have been reported. Therefore, when assessing patients prescribed anticoagulants, the risk of bleeding should be carefully considered.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and/or lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions

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

Keep out of reach of children.

Packaging

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

Prescription status. Prescription only.

Manufacturer

Pharos MT Limited

Pharos Pharmaceutical Oriented Services Ltd.

Manufacturer's address and location of operations

XF62EX, Casem Industries Hell Farr, Hell Farr, Birzebbuga, BBG 3000, Malta.

Lesvou Street End, Tese Loggos Industrial Zone, Metamorphosis, 144 52, Greece.

Marketing Authorisation Holder

JSC "Pharmaceutical Company "Darnitsya".

Address of the Marketing Authorisation Holder

13 Borispilska Street, Kyiv, 02093, Ukraine.