Lixiana^® (Tablets) Instructions for Use

ATC Code

B01AF03 (Edoxaban)

Active Substance

Edoxaban (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticoagulant – direct factor Xa inhibitor

Pharmacotherapeutic Group

Direct factor Xa inhibitors

Pharmacological Action

Edoxaban is a highly selective, direct, and reversible inhibitor of factor Xa (a serine protease involved in the final stage of blood coagulation).

Edoxaban inhibits free factor Xa, as well as prothrombinase activity. Inhibition of factor Xa in the coagulation cascade reduces thrombin generation, increases clotting time, and reduces the risk of thrombus formation.

Pharmacodynamic effects, measured by anti-Xa activity assays, are predictable and correlate with the dose and concentration of edoxaban.

Edoxaban is characterized by a rapid onset of pharmacodynamic effects – within 1-2 hours after administration, which corresponds to the peak exposure of edoxaban (C_max).

As a result of factor Xa (FXa) inhibition, Edoxaban increases clotting time according to tests such as prothrombin time (PT) and aPTT. Changes in these coagulation parameters are expected with therapeutic doses; however, they are small, highly variable, and thus do not have sufficient value for monitoring the anticoagulant effect of edoxaban.

Pharmacokinetics

After oral administration, Edoxaban is absorbed from the gastrointestinal tract, with C_max in plasma achieved within 1-2 hours. The absolute bioavailability is about 62%. Food intake increases peak exposure to varying degrees but minimally affects overall exposure.

Edoxaban is poorly soluble at pH 6.0 or higher. Concomitant use of proton pump inhibitors did not have a significant effect on edoxaban exposure. The distribution curve is biphasic. V_d is 107 (19.9) L (mean [standard deviation]). Plasma protein binding in vitro is about 55%.

With once-daily administration, no clinically significant accumulation of edoxaban was observed (accumulation factor 1.14). Steady-state concentrations are reached within 3 days. The main compound in plasma is unchanged Edoxaban.

Edoxaban is metabolized by hydrolysis (via carboxylesterase 1), conjugation, or oxidation by CYP3A4/5 (<10%). Edoxaban has 3 active metabolites; the main metabolite (M-4) is formed by hydrolysis, it is pharmacologically active, and its level in healthy volunteers was less than 10% of the exposure of the parent compound. The exposure of other metabolites is less than 5%.

Edoxaban is a substrate of the efflux transporter protein P-glycoprotein, but it is not a substrate of uptake transporter proteins, for example, the organic anion transporting polypeptide OATP1B1, organic anion transporters OAT1 or OAT3, or the organic cation transporter OCT2. Its active metabolite is a substrate of OATP1B1.

In healthy volunteers, the total clearance is 22 (±3) L/h; 50% of the drug is excreted by the kidneys (11 L/h). About 35% of the administered dose is excreted by the kidneys. The remainder is excreted via metabolism and biliary/intestinal excretion. T_1/2 after oral administration is 10-14 hours.

In healthy volunteers, Edoxaban demonstrated dose-dependent pharmacokinetics in the dose range from 15 to 60 mg.

Indications

Prevention of stroke and systemic thromboembolic complications in adult patients with non-valvular atrial fibrillation (NVAF) with one or more risk factors, such as chronic heart failure, arterial hypertension, age >75 years, diabetes mellitus, history of stroke or transient ischemic attack (TIA).

Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), prevention of recurrent DVT and PE in adult patients.

ICD codes

Dosage Regimen

Take tablets orally once daily.

Select the dose based on indication, renal function, body weight, and concomitant medications.

For non-valvular atrial fibrillation, the recommended dose is 60 mg once daily.

Reduce the dose to 30 mg once daily in patients with one or more of the following factors: creatinine clearance 15-50 mL/min, body weight ≤60 kg, or concomitant use of certain P-glycoprotein inhibitors (cyclosporine, dronedarone, erythromycin, ketoconazole).

For treatment of deep vein thrombosis and pulmonary embolism, initiate after 5-10 days of initial therapy with a parenteral anticoagulant.

The recommended dose for DVT/PE treatment and recurrence prevention is 60 mg once daily.

Reduce the dose to 30 mg once daily for DVT/PE in patients with creatinine clearance 15-50 mL/min or body weight ≤60 kg.

Do not use in patients with end-stage renal disease or on dialysis.

Assess renal function (CrCl) prior to initiation.

Take with or without food.

If a dose is missed, take it immediately on the same day and then continue the usual once-daily schedule.

Do not double the dose to make up for a missed dose.

Adverse Reactions

Blood and lymphatic system disorders common – anemia; uncommon – thrombocytopenia.

Immune system disorders uncommon – hypersensitivity; rare – anaphylactic reaction, allergic edema.

Nervous system disorders: common – dizziness, headache; uncommon – intracranial hemorrhage (ICH); rare – subarachnoid hemorrhage.

Eye disorders uncommon – subconjunctival/conjunctival hemorrhage, intraocular hemorrhage.

Cardiac and vascular disorders uncommon – bleeding of various locations; rare – pericardial hemorrhage.

Respiratory, thoracic and mediastinal disorders common – epistaxis; uncommon – hemoptysis.

Gastrointestinal disorders common – abdominal pain, gastrointestinal bleeding, oral/pharyngeal bleeding, nausea; rare – retroperitoneal bleeding.

Hepatobiliary disorders common – increased blood bilirubin concentration, increased GGT activity; uncommon – increased ALP, AST, ALT activity.

Skin and subcutaneous tissue disorders common – subcutaneous hemorrhage (into soft tissues), skin rash, skin itching; uncommon – urticaria.

Musculoskeletal and connective tissue disorders rare – intramuscular hemorrhage (without compartment syndrome), intra-articular hemorrhage.

Renal and urinary disorders common – macrohematuria/urethral bleeding.

Reproductive system and breast disorders common – vaginal bleeding

Local reactions bleeding at the injection site, bleeding in the area of the postoperative wound; rare – subdural hemorrhage, procedure-related bleeding.

Contraindications

Hypersensitivity to the active substance; clinically significant active bleeding; conditions or disorders associated with a significant risk of major bleeding (including existing or recent ulcerative lesions of the gastrointestinal tract, the presence of malignant neoplasms with a high risk of bleeding, recent trauma to the brain or spinal cord, recent surgery on the brain or spinal cord or eyes, recent intracranial hemorrhage, known or suspected esophageal varices, arteriovenous malformations, vascular aneurysms or significant intraspinal or intracranial vascular disorders); uncontrolled severe arterial hypertension; concomitant therapy with any other anticoagulants, for example, unfractionated heparin (UFH), low molecular weight heparins (including enoxaparin, dalteparin), heparin derivatives (including fondaparinux), oral anticoagulants (including warfarin, dabigatran, rivaroxaban, apixaban), except for situations of switching to another oral anticoagulant, or the use of UFH in doses necessary to maintain the patency of a central venous or arterial catheter; pregnancy, breastfeeding period; liver disease accompanied by coagulopathy and clinically significant risk of bleeding; age under 18 years.

With caution

Increased risk of bleeding, elderly patients when used concomitantly with acetylsalicylic acid; mild and moderate hepatic impairment with increased ALT or AST activity >2 ULN or with increased total bilirubin concentration ≥1.5 ULN; in patients with NVAF and high CrCl; when used concomitantly with P-glycoprotein inducers.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and breastfeeding.

Use in Hepatic Impairment

Contraindication: liver disease accompanied by coagulopathy and clinically significant risk of bleeding.

With caution: mild and moderate hepatic impairment with increased ALT or AST activity >2 ULN or with increased total bilirubin concentration >1.5 ULN.

Use in Renal Impairment

Use with caution in patients with NVAF and high CrCl.

In patients with end-stage renal disease, or on dialysis, the use of edoxaban is not recommended.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients when used concomitantly with acetylsalicylic acid.

Special Precautions

Edoxaban is not indicated for use as monotherapy, as this may lead to reduced efficacy.

It can only be used during the transition from edoxaban 30 mg (in patients with one or more clinical factors for increased exposure) to a vitamin K antagonist concurrently with the intake of an appropriate dose of the vitamin K antagonist.

Edoxaban increases the risk of bleeding; its use may lead to serious bleeding, potentially fatal. Like other anticoagulants, Edoxaban should be used with caution in patients with an increased risk of bleeding. If severe bleeding occurs, Edoxaban should be discontinued.

In clinical studies, bleeding from mucous membranes (e.g., epistaxis, gastrointestinal bleeding, urogenital bleeding) and anemia were observed more frequently in patients receiving long-term therapy with edoxaban compared to patients receiving vitamin K antagonists.

Thus, in addition to careful clinical monitoring, laboratory tests to determine hemoglobin/hematocrit can be performed if necessary to detect occult bleeding. The following patient subgroups have an increased risk of bleeding. After initiation of treatment, these patients should be closely monitored for signs or symptoms of hemorrhagic complications and anemia. In case of an unexplained decrease in hemoglobin or BP, a source of bleeding should be sought.

Reliable monitoring of the anticoagulant effect of edoxaban is not possible using standard laboratory tests. Currently, there is no specific agent available to reverse the anticoagulant effect of edoxaban. Hemodialysis does not significantly affect the clearance (elimination) of edoxaban.

When edoxaban is used concomitantly with acetylsalicylic acid in elderly patients, caution should be exercised due to a potentially higher risk of bleeding.

In patients with end-stage renal disease, or on dialysis, the use of edoxaban is not recommended. When using edoxaban, a trend towards reduced efficacy was observed with increasing CrCl compared to properly controlled warfarin therapy.

Therefore, Edoxaban should be used in patients with NVAF and high CrCl only after a careful assessment of the risk of thromboembolic and hemorrhagic complications in each individual case. Creatinine clearance should be determined at the start of treatment in all patients and thereafter as clinically indicated.

Liver function biochemical parameters should be analyzed before starting therapy with edoxaban. In patients taking Edoxaban for more than 1 year, periodic monitoring of liver function parameters is recommended.

Anticoagulant therapy should be discontinued if surgical or other interventions are necessary to reduce the risk of bleeding. In this case, edoxaban should be discontinued as soon as possible (recommended at least 24 hours before the procedure).

When deciding whether a procedure can be postponed until 24 hours after the last dose of edoxaban, the risk of bleeding should be weighed against the need for emergency intervention. After a surgical or other procedure, edoxaban should be resumed immediately after adequate hemostasis is achieved; it should be taken into account that the time to onset of the anticoagulant therapeutic effect of edoxaban is 1-2 hours.

If oral medication intake is not possible during or after surgery, the use of a parenteral anticoagulant followed by a switch to oral edoxaban once daily should be considered.

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

Edoxaban is not recommended as an alternative to unfractionated heparin in hemodynamically unstable patients with PE, or in patients with PE who may require thrombolysis or pulmonary embolectomy, as the safety and efficacy of edoxaban have not been studied in these clinical situations.

Direct oral anticoagulants, including Edoxaban, are not recommended for patients with a history of thrombosis and diagnosed antiphospholipid syndrome. In particular, for patients with triple positivity for antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies, and anti-β2-glycoprotein I antibodies), therapy with direct oral anticoagulants may be associated with an increased frequency of thrombotic recurrence compared with therapy with vitamin K antagonists.

Although no routine monitoring is required when using edoxaban, the anticoagulant effect can be assessed using a calibrated quantitative anti-FXa activity assay (activity against coagulation factor Xa), which may help in decision-making in specific situations, such as overdose or the need for emergency surgery.

As a result of factor Xa (FXa) inhibition, Edoxaban increases the values of standard coagulation tests, for example, prothrombin time, INR, and aPTT. Changes in these coagulation parameters with therapeutic doses are small, highly variable, and thus do not have sufficient value for monitoring the anticoagulant effect of edoxaban.

Effect on ability to drive vehicles and operate machinery

Edoxaban has no or negligible influence on the ability to drive vehicles and operate machinery.

Drug Interactions

Edoxaban is predominantly absorbed in the upper gastrointestinal tract.

Thus, drugs or conditions that accelerate gastric emptying and increase intestinal motility may potentially reduce the dissolution and absorption of edoxaban.

Edoxaban is a substrate of the efflux transporter protein P-glycoprotein. In pharmacokinetic studies, concomitant use of edoxaban with other P-glycoprotein inhibitors (cyclosporine, dronedarone, erythromycin, ketoconazole, quinidine, or verapamil) led to increased plasma concentrations of edoxaban.

When edoxaban is used concomitantly with cyclosporine, dronedarone, erythromycin, or ketoconazole, a dose reduction to 30 mg once daily is required for patients with NVAF and VTE.

Following a single dose of cyclosporine 500 mg with a single dose of edoxaban 60 mg, an increase in the AUC and C_max of edoxaban by 73% and 74%, respectively, was observed.
When dronedarone 400 mg twice daily was administered for 7 days in combination with a single dose of edoxaban 60 mg on day 5, an increase in the AUC and C_max of edoxaban by 85% and 46%, respectively, was observed.

When erythromycin 500 mg four times daily was administered for 8 days in combination with a single dose of edoxaban 60 mg on day 7, an increase in the AUC and C_max of edoxaban by 85% and 68%, respectively, was observed.
When ketoconazole 400 mg once daily was administered for 7 days in combination with a single dose of edoxaban 60 mg on day 4, an increase in the AUC and C_max of edoxaban by 87% and 89%, respectively, was observed.
When used concomitantly with the P-glycoprotein inhibitors quinidine, verapamil, amiodarone, the recommended dose of edoxaban is 60 mg once daily.

When quinidine 300 mg once daily on days 1 and 4 and three times daily on days 2 and 3 was administered in combination with a single dose of edoxaban 60 mg on day 3, an increase in the AUC and C_max of edoxaban by 77% and 85%, respectively, was observed.

When verapamil 240 mg once daily was administered for 11 days in combination with a single dose of edoxaban 60 mg on day 10, an increase in the AUC and C_max of edoxaban by approximately 53% was observed.
When amiodarone 400 mg once daily was used concomitantly with edoxaban 60 mg once daily, an increase in AUC and C_max by 40% and 66%, respectively, was observed. These changes were not considered clinically significant.

Concomitant use of edoxaban with the P-glycoprotein inducer rifampicin led to a decrease in the mean AUC of edoxaban and a decrease in T_1/2 with a potential reduction in its pharmacodynamic effects. Concomitant use of edoxaban with other P-glycoprotein inducers (e.g., phenytoin, carbamazepine, phenobarbital, or St. John’s wort) may lead to decreased plasma concentrations of edoxaban. Caution should be exercised when using edoxaban with P-glycoprotein inducers.

When edoxaban 60 mg once daily was administered for 14 days in combination with digoxin 0.25 mg twice daily (on days 8 and 9) and 0.25 mg once daily (from day 10 to 14), an increase in C_max of edoxaban by 17% was observed without a significant effect on AUC or renal clearance at steady state. The C_max and AUC values of digoxin increased by approximately 28% and 7%, respectively. These changes were not considered clinically significant. No dose adjustment is required when Edoxaban is used concomitantly with digoxin.

Anticoagulants: concomitant use of edoxaban with other anticoagulants is contraindicated due to an increased risk of bleeding.

When used concomitantly, ASA (100 mg or 325 mg) with edoxaban resulted in an increase in bleeding time compared to taking each of these drugs separately. With simultaneous use of edoxaban with high doses of ASA (325 mg), an increase in the steady-state values of C_max and AUC of edoxaban by 35% and 32%, respectively, was observed. Long-term use of ASA in high doses (325 mg) in combination with edoxaban is not recommended. Concomitant therapy with ASA in doses above 100 mg should be carried out only under medical supervision.

In clinical studies, simultaneous use of ASA (in low doses <100 mg) and other antiplatelet agents, including thienopyridines, was allowed; this was associated with an approximately two-fold increase in the frequency of major bleeding compared with monotherapy; the severity of this effect was similar in the edoxaban and warfarin groups. Concomitant use of ASA in low doses (<100 mg) did not affect the peak or total exposure of edoxaban after a single dose or at steady state. Edoxaban can be taken in combination with low doses of ASA (<100 mg/day).

Concomitant use of naproxen and edoxaban resulted in an increase in bleeding time compared to taking each of these drugs separately. Naproxen did not affect the C_max and AUC of edoxaban. In clinical studies, concomitant use of NSAIDs led to an increase in the frequency of clinically significant bleeding. Long-term use of NSAIDs in combination with edoxaban is not recommended.

As with other anticoagulants, concomitant use of edoxaban with SSRIs/SNRIs may lead to an increased risk of bleeding due to their effect on platelets.

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

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

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.