Apiksanta (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Combino Pharm Malta, Ltd. (Malta)

ATC Code

B01AF02 (Apixaban)

Active Substance

Apixaban (Rec.INN registered by WHO)

Dosage Forms

	Apiksanta	Film-coated tablets 2.5 mg
		Film-coated tablets 5 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

10 pcs. – blisters (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blisters (6 pcs.) – cardboard packs (60 pcs.) – By prescription
20 pcs. – blisters – cardboard packs (20 pcs.) – By prescription
20 pcs. – blisters (3 pcs.) – cardboard packs (60 pcs.) – By prescription
20 pcs. – blisters (9 pcs.) – cardboard packs (180 pcs.) – By prescription

Film-coated tablets

10 pcs. – blisters (3 pcs.) – cardboard packs (30 pcs.) – By prescription
10 pcs. – blisters (6 pcs.) – cardboard packs (60 pcs.) – By prescription
20 pcs. – blisters – cardboard packs (20 pcs.) – By prescription
20 pcs. – blisters (3 pcs.) – cardboard packs (60 pcs.) – By prescription
20 pcs. – blisters (9 pcs.) – cardboard packs (180 pcs.) – By prescription

Clinical-Pharmacological Group

Anticoagulant – direct factor Xa inhibitor

Pharmacotherapeutic Group

Antithrombotic agents; direct factor Xa inhibitors

Pharmacological Action

Apixaban is a direct-acting anticoagulant, a selective inhibitor of blood coagulation factor Xa.

The mechanism of action of apixaban involves inhibiting the activity of blood coagulation factor Xa, reversibly and selectively blocking the active site of the enzyme. The presence of antithrombin III is not required for the antithrombotic effect of apixaban to be realized. Apixaban inhibits both free and bound coagulation factor Xa, as well as prothrombinase activity. Apixaban does not have a direct effect on platelet aggregation, but indirectly inhibits thrombin-induced platelet aggregation. By inhibiting the activity of coagulation factor Xa, Apixaban prevents the formation of thrombin and blood clots. Apixaban alters the values of blood coagulation system parameters: it prolongs prothrombin time, INR, and aPTT.

Pharmacokinetics

After oral administration, Apixaban is rapidly absorbed from the gastrointestinal tract. C_max is reached within 3-4 hours. The absolute bioavailability of apixaban reaches 50% when used in doses up to 10 mg. Food intake does not affect the AUC or C_max of apixaban. The pharmacokinetics of apixaban for doses up to 10 mg is linear. When apixaban is taken in doses greater than 25 mg, a decrease in absorption is noted, which is accompanied by a decrease in bioavailability. Apixaban metabolism parameters are characterized by low to moderate inter- and intra-individual variability (corresponding coefficient of variation values are 20% and 30%).

The binding of apixaban to human plasma proteins is approximately 87%, V_ss is approximately 21 L.

About 25% of the administered dose is excreted as metabolites, mostly through the intestines. Renal excretion of apixaban accounts for approximately 27% of its total clearance.

The total clearance of apixaban is approximately 3.3 L/h, T_1/2 is about 12 hours. O-demethylation and hydroxylation at the 3-oxopiperidinyl residue are the main pathways of apixaban biotransformation. Apixaban is predominantly metabolized by the CYP3A4/5 isoenzyme, and to a lesser extent by the CYP1A2, 2C8, 2C9, 2C19, and 2J2 isoenzymes. Unchanged Apixaban is the main substance circulating in human plasma; there are no active circulating metabolites. Furthermore, Apixaban is a substrate for transport proteins, P-glycoprotein and breast cancer resistance protein (BCRP).

Indications

Prevention of venous thromboembolism in patients after elective hip or knee replacement surgery.

Prevention of stroke, systemic thromboembolism, and reduction of mortality in patients with atrial fibrillation (excluding patients with severe or moderate mitral stenosis or with prosthetic heart valves).

ICD codes

Dosage Regimen

Take Apiksanta orally, with or without food.

For stroke and systemic embolism prevention in non-valvular atrial fibrillation, the recommended dose is 5 mg twice daily.

Reduce the dose to 2.5 mg twice daily in patients with at least two of the following characteristics: age 80 years or older, body weight 60 kg or less, or serum creatinine 1.5 mg/dL or greater.

For prophylaxis of deep vein thrombosis (DVT) following hip or knee replacement surgery, the recommended dose is 2.5 mg twice daily.

Initiate therapy 12 to 24 hours postoperatively.

The recommended treatment duration is 35 days for hip replacement and 12 days for knee replacement surgery.

For treatment of DVT and pulmonary embolism (PE), and for reduction in risk of recurrence, the recommended dose is 10 mg twice daily for the first 7 days, followed by 5 mg twice daily long-term.

Discontinue all other oral and parenteral anticoagulants prior to initiation.

Do not crush or split tablets. Administer the missed dose immediately if remembered on the same day; otherwise, omit it and continue with the next scheduled dose. Do not double the dose to make up for a missed one.

Carefully assess renal and hepatic function prior to initiating therapy and periodically during treatment, as severe impairment is a contraindication.

Adverse Reactions

From the hematopoietic system: often – anemia (including postoperative and post-hemorrhagic, accompanied by corresponding changes in laboratory test results); infrequently – thrombocytopenia (including decreased platelet count).

Allergic reactions rarely – hypersensitivity.

From the organ of vision rarely – hemorrhages in the tissues of the eyeball (including conjunctival hemorrhage).

From the cardiovascular system: often – bleeding (including hematoma, vaginal and urethral bleeding); infrequently – arterial hypotension (including hypotension during a procedure).

From the respiratory system infrequently – nosebleed; rarely – hemoptysis.

From the digestive system often – nausea; infrequently – gastrointestinal bleeding (including vomiting with blood and melena), presence of unchanged blood in the stool, increased transaminase activity (including ALT, AST, GGT), alkaline phosphatase in the blood, increased bilirubin concentration in the blood; rarely – rectal bleeding, gum bleeding.

From the musculoskeletal system rarely – muscle hemorrhage.

From the urinary system infrequently – hematuria (including corresponding changes in laboratory test results).

Other often – closed trauma; infrequently – hemorrhages and bleeding after invasive procedures (including post-procedural hematoma, postoperative wound bleeding, hematoma at the vessel puncture site and catheter insertion site), presence of wound discharge, hemorrhage at the incision site (including hematoma at the incision site), bleeding during surgery.

Contraindications

Clinically significant active bleeding; severe liver dysfunction; renal impairment with CrCl <15 ml/min, as well as use in patients on dialysis; presence of a lesion or condition associated with a high risk of massive bleeding; pregnancy, lactation (breastfeeding) period; children and adolescents under 18 years of age; simultaneous use with other anticoagulants (except for cases where unfractionated heparin is administered in doses necessary to maintain the patency of a central venous or arterial catheter); hypersensitivity to apixaban.

Use in Pregnancy and Lactation

The use of apixaban is contraindicated during pregnancy and lactation (breastfeeding).

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

Apixaban should be used with caution during spinal or epidural anesthesia or punctures; in patients receiving systemic therapy with potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein, such as azole antifungals (including ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (e.g., ritonavir); in patients receiving potent inducers of the CYP3A4 isoenzyme and P-glycoprotein (including rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort preparations); in conditions characterized by an increased risk of bleeding, including congenital or acquired coagulation disorders, exacerbations of gastrointestinal ulcers, bacterial endocarditis, thrombocytopenia, thrombocytopathies; history of hemorrhagic stroke; recent surgery on the brain or spinal cord, as well as on the organ of vision; in severe uncontrolled arterial hypertension; in patients with mild and moderate hepatic impairment (Child-Pugh class A or B); with increased activity of liver enzymes (ALT, AST more than 2 times the ULN) or an increase in total bilirubin content by 1.5 times or more the ULN; in patients with renal impairment; concomitantly with NSAIDs (including acetylsalicylic acid), as these drugs increase the risk of bleeding; in elderly patients.

If severe bleeding develops, Apixaban should be discontinued. If hemorrhagic complications develop, Apixaban should be discontinued and an examination should be performed to identify the source of bleeding. If necessary, appropriate treatment should be prescribed, in particular, surgical hemostasis or transfusion of fresh frozen plasma.

When performing spinal or epidural anesthesia or diagnostic puncture of these areas in patients receiving antithrombotic agents for thromboembolism prophylaxis, there is a risk of developing epidural or spinal hematomas, which, in turn, can cause persistent or irreversible paralysis. This risk may be further increased with the use of an indwelling epidural catheter in the postoperative period or with the concomitant use of other drugs affecting hemostasis.

A similar increase in risk may be noted when performing traumatic or repeated punctures of the epidural or subarachnoid spaces. Frequent monitoring of patients for the development of manifestations of neurological dysfunction (in particular, numbness or weakness of the lower extremities, impaired bowel or bladder function) is necessary. If such disorders develop, emergency examination and treatment should be performed. Before performing interventions on the epidural or subarachnoid spaces in patients receiving anticoagulants, including for thrombosis prophylaxis, an assessment of the potential benefit-risk ratio is necessary.

Drug Interactions

With the simultaneous use of apixaban and ketoconazole (at a dose of 400 mg, once daily), which is a potent inhibitor of both the CYP3A4 isoenzyme and P-glycoprotein, an increase in the mean AUC of apixaban by 2 times and the mean C_max by 1.6 times was observed. With this combination, dose adjustment of apixaban is not required, but Apixaban should be used with caution in patients receiving systemic therapy with azole antifungals, in particular ketoconazole, or other potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein.

Drugs that moderately reduce the elimination rate of apixaban or inhibit the CYP3A4 isoenzyme and/or P-glycoprotein may lead to a lesser increase in the plasma concentration of apixaban. For example, diltiazem (a moderate inhibitor of the CYP3A4 isoenzyme and a weak inhibitor of P-glycoprotein) at a dose of 360 mg once daily led to an increase in the mean AUC of apixaban by 1.4 times and the mean C_max by 1.3 times. Naproxen (a P-glycoprotein inhibitor) when used at a dose of 500 mg in healthy volunteers caused an increase in the mean AUC and C_max of apixaban by 1.5 and 1.6 times, respectively. At the same time, an increase in the values of blood coagulation system parameters was noted.

The combination of apixaban with rifampicin (a potent inducer of the CYP3A4 isoenzyme and P-glycoprotein) led to a decrease in the mean AUC and C_max of apixaban by approximately 54% and 42%, respectively. It is likely that the combination of apixaban with other potent inducers of the CYP3A4 isoenzyme and P-glycoprotein (in particular, phenytoin, carbamazepine, phenobarbital, or St. John’s wort preparations) may also lead to a decrease in the plasma concentration of apixaban. Dose adjustment of apixaban when combined with drugs of this group is not required, but these drugs should be combined with caution.

After co-administration of enoxaparin (single dose, 40 mg) and apixaban (single dose, 5 mg), an additive effect of these agents on coagulation factor Xa activity was noted.

Combining apixaban with clopidogrel (at a dose of 75 mg, once daily) or a combination of clopidogrel (75 mg) and acetylsalicylic acid (162 mg, once daily), according to some data, did not lead to an increase in bleeding time, further inhibition of platelet aggregation, or an increase in blood coagulation system parameters (prothrombin time, INR, and aPTT) compared with the use of these antiplatelet agents in monotherapy. However, caution should be exercised when using apixaban concomitantly with NSAIDs (including acetylsalicylic acid), as these drugs increase the risk of bleeding.

Drugs whose action may be associated with the development of serious bleeding, such as thrombolytics, glycoprotein IIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dextran, sulfinpyrazone, should not be used simultaneously.

Combining apixaban (at a dose of 10 mg) with atenolol (at a dose of 100 mg) did not lead to clinically significant changes in the pharmacokinetic parameters of apixaban, but it was accompanied by a decrease in the mean AUC and C_max of apixaban by 15% and 18%, respectively, compared with the monotherapy regimen.

In in vitro studies, Apixaban caused weak suppression of CYP2C19 isoenzyme activity (IC50 > 20 µmol/L) by apixaban at a concentration significantly exceeding the C_max in plasma during its clinical use.

Taking activated charcoal reduces the exposure to apixaban.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.