Eliquis, 2.5mg 60 pcs.

The mechanism of action of apixaban is inhibition of FXa activity. As a result, apixaban changes the values of blood coagulation system parameters:

prolongs prothrombin time, MHO and activated partial thromboplastin time (APTB). The changes of these parameters when using the drug in a therapeutic dose are insignificant and individual.

Therefore, their use for the purpose of assessing the pharmacodynamic activity of apixaban is not recommended. Inhibition of FXa activity by apixaban has been proved by chromogenic test using heparin “Rotachrom. Change in anti-FXa activity is directly proportional to increase in plasma concentration of apixaban, with maximum activity values observed when maximum, plasma concentration of apixaban is reached.

Linear relationship between the concentration and anti-FXa activity of apixaban is registered in a wide range of therapeutic doses of the drug! Changes in anti-FXa activity with changes in dose and concentration, apixaban is more pronounced and less variable than clotting parameters.

. The expected maximum and minimum anti-FXa activity of apixaban at equilibrium, when administered at a dose of 2.5 mg-2 times daily, is 1.3 IU/ml (5/95 percentile – 0.67 IU/ml – 2,4 IU/ml) and 0.84 IU/ml (5/95 percentile -0.37 IU/ml – 1.8 IU/ml), respectively, which correlates with fluctuations in this index between doses of the drug (less than 1.6 times). Against the background of apixaban therapy, routine monitoring of its plasma concentrations is not required, but performance of anti-FXa Rotachrom activity test may be useful for making a decision on continuation of therapy.

Mechanism of action

Apixaban is a potent direct FXa inhibitor that reversibly and selectively blocks the active center of the enzyme, intended for oral use. Antithrombin III is not required for realization of the antithrombotic effect of apixaban. Apixaban inhibits free and bound FXa as well as prothrombinase activity.

Apixaban has no direct effect on, platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting the activity of FXa apixaban prevents thrombin and thrombus formation.

Indications

Prevention of thrombosis, Prevention of heart attacks and strokes

• prevention of venous thromboembolism in patients after elective hip or knee arthroplasty;
• prevention of strokes, systemic thromboembolism and reduction of mortality in patients with atrial fibrillation. Exceptions are patients with severe to moderate mitral stenosis or artificial heart valves.
  

Active ingredient

Apixaban

How to take, the dosage

Ingestion, regardless of meals.

If the drug is missed, it should be taken as soon as possible and thereafter continued twice daily according to the original regimen.

In patients after planned hip or knee arthroplasty: 1 tablet 2.5 mg 2 times daily (first administration 12-24 hours after surgery).

In patients who have undergone hip arthroplasty, the recommended duration of therapy is 32-38 days; in knee joints it is 10-14 days.

In patients with atrial fibrillation: 1 tablet of 5 mg twice daily.

Special patient groups

1. Patients with atrial fibrillation combined with two or more of the following characteristics – age over 80 years, body weight less than 60 kg, or plasma creatinine concentration ≥1.5 mg/dL (133 μmol/L) – the recommended dose of Eliquis is reduced to 1 tablet 2.5 mg 2 times daily.

2. patients with impaired renal function. In patients with mild, moderate or severe renal dysfunction with decreased Cl creatinine up to 15 ml/min, no dose adjustment of apixaban is required (except for patients from step 1). In patients with severe renal dysfunction with creatinine Cl less than 15 ml/min, as well as in patients on dialysis, the use of the drug Eliquis is not recommended.

3. patients with impaired liver function. Caution should be exercised when using Eliquis in patients with mild to moderate hepatic impairment (class A or B according to the Child-Pugh classification), and no dose adjustment is required. The use of the drug in patients with severe hepatic impairment is not recommended.

4. elderly patients. No dose adjustment is required in elderly patients (the only exceptions are the patients listed in p. 1).

5. Body weight. No dose adjustment is required for body weight (except in patients in p. 1).

6. gender. There is no need to adjust the dose depending on the gender of the patient.

7. Race and ethnicity. No adjustment of the drug dose according to the race or ethnicity of the patient is necessary.

Transition from or to parenteral anticoagulant therapy

Transition from parenteral anticoagulants to Eliquis and vice versa can be done at the time of the next scheduled dose of the discontinued drug (and the next dose of the discontinued drug is not taken).

Transfer from or to warfarin or other vitamin K antagonists

Transfer patients from therapy with warfarin or other vitamin K antagonists to therapy with Eliquis should be performed when the patient has an INR below 2.

If patients are switched from Eliquis to warfarin or other vitamin K antagonists, Eliquis therapy should be continued for 48 hours after the first dose of warfarin or other vitamin K antagonists.

Surgical and invasive procedures

Eliquis should be stopped 2-3 days before a planned surgery or invasive procedure. If the procedures cannot be postponed, special caution should be exercised given the increased risk of bleeding. The risks of bleeding and delayed surgery should also be evaluated.

Interaction

Influence of other drugs on apixaban pharmacokinetics CYP3A4 and P-glycoprotein isoenzyme inhibitors
Combination of apixaban with ketoconazole (in dose 400 mg, once daily), which is a potent inhibitor of both CYP3A4 isoenzyme and P-glycoprotein, resulted in 2-fold increase of mean AUC value of apixaban and 1.6-fold increase of mean C_max values.

Dose adjustment of apixaban in combination with ketoconazole is not required, but apixaban should be used with caution in patients receiving systemic therapy with azole antifungal agents, particularly ketoconazole, or other potent inhibitors of CYP3A4 isoenzyme and P-glycoprotein.

Drugs that moderately decrease the excretion rate of apixaban or inhibit the CYP3A4 isoenzyme and/or P-glycoprotein are expected to result in lower plasma concentrations of apixaban. For example, diltiazem (a moderate CYP3A4 isoenzyme inhibitor and a weak P-glycoprotein inhibitor) at a dose of 360 mg once daily resulted in a 1.4-fold increase in the mean AUC of apixaban and a 1.3-fold increase in mean C_max values. Naproxen (P-glycoprotein inhibitor) when administered in 500 mg dose in healthy volunteers caused 1.5 and 1.6 times increase of averaged AUC and C_max values of apixaban, respectively. At the same time, there was an increase in the values of clotting system parameters. However, against the background of this combination there was no effect of naproxen on platelet aggregation, associated with impaired arachidonic acid metabolism, and clinically significant prolongation of bleeding time.
Dose adjustment of apixaban when combining with moderate CYP3A4 isoenzyme and/or P-glycoprotein inhibitors is not required.

CYP3A4 and P-glycoprotein isoenzyme inducers

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

Antiplatelet agents, platelet aggregation inhibitors and NSAIDs

The additive effect of these agents on FXa activity was observed after coadministration of enoxaparin (singly, in dose of 40 mg) and apixaban (singly, in dose of 5 mg).

There were no signs of pharmacokinetic or pharmacodynamic interaction of apixaban with acetylsalicylic acid (in a dose of 325 mg, once daily) in healthy subjects.

. Combination of apixaban with clopidogrel (in dose 75 mg, once daily) or combination of clopidogrel (75 mg) and acetylsalicylic acid (162 mg, once daily) in phase I clinical trial did not result in increase of bleeding time, further inhibition of platelet aggregation or increase of parameters of blood clotting system (prothrombin time, MHO and PTC) in comparison with using these antiaggregants in monotherapy.

However, caution should be exercised when concomitant use of apixaban with NSAIDs (including acetylsalicylic acid), due to the fact that these drugs increase the risk of bleeding.

The concomitant use of drugs that may be associated with the development of serious bleeding, such as unfractionated heparin or heparin derivatives (including low molecular weight heparins), FXa-inhibiting oligosaccharides (such as fondaparinux), direct thrombin II inhibitors (such as desirudin), thrombolytic drugs, glycoprotein IIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists and other oral anticoagulants. It should be noted that unfractionated heparin may be used in doses necessary to support the patency of a venous or arterial catheter.

Combination with other medicinal products
No clinically significant pharmacokinetic or pharmacodynamic interaction of apixaban with atenolol or famotidine has been found. Combination of apixaban (in 10 mg dose) with atenolol (in 100 mg dose) did not result in development of clinically significant changes of apixaban pharmacokinetic parameters, but it was accompanied by 15% and 18% decrease in mean AUC and C_max values of apixaban, respectively, compared to monotherapy regimen. Administration of apixaban (10mg dose) with famotidine (40 mg dose) had no effect on, AUC or C_max values of apixaban.

The effect of apixaban on the pharmacokinetics of other drugs
In in vitro studies, apixaban did not inhibit the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4/ (inhibitory concentration (IC50) >45 μmol/L), but weak inhibition of CYP2C19 isoenzyme activity (IC50 > 20 μmol/L) by apixaban was found at a concentration significantly higher than the maximum plasma concentration of the drug during its clinical use. Apixaban is not an inducer of CYP1A2, CYP2B6, CYP3A4/5 isoenzymes at concentrations up to 20 μmol/l. In this regard, it is expected that when used together it will not affect clearance of drugs metabolized by these isoenzymes. In addition, apixaban does not significantly inhibit the activity of P-glycoprotein.

In studies in healthy volunteers, apixaban did not significantly alter the pharmacokinetics of digoxin, naproxen or atenolol.

Special Instructions

In patients with atrial fibrillation and conditions requiring monotherapy or therapy with a combination of two antiaggregant drugs, a careful assessment of the benefit/risk ratio should be performed before concomitant use with Eliquis. Eliquis is not recommended for use in patients with liver disease accompanied by bleeding disorders and clinically significant risk of bleeding.

It has been shown that in high-risk patients after acute coronary syndrome, with the presence of multiple both cardiac and noncardiac comorbidities, there was a significant increase in the risk of bleeding when apixaban and acetylsalicylic acid or a combination of acetylsalicylic acid and clopidogrel were used together compared to placebo.

As with other anticoagulants, patients taking Eliquis should be closely monitored for bleeding. If severe bleeding occurs, Eliquis should be discontinued. If hemorrhagic complications develop, it is necessary to cancel treatment with the drug and perform examination to identify the source of bleeding. If necessary, appropriate treatment, such as surgical stoppage of bleeding or transfusion of fresh frozen blood plasma, is indicated.

Stopping therapy with anticoagulants, including apixaban, for active bleeding before a planned surgical intervention or invasive procedure may lead to an increased risk of thrombosis. Prolonged discontinuation of therapy should be avoided, and if therapy with apixaban must be temporarily stopped, it should be resumed as soon as possible.

Performance of spinal, epidural anesthesia or punctures in patients receiving Eliquis

. When performing spinal or epidural anesthesia or diagnostic puncture of these areas in patients treated with antithrombotic agents to prevent thromboembolism, there is a risk of epidural or spinal hematoma, which in turn can cause permanent or irreversible paralysis. This risk may be further increased if an epidural catheter is used in the postoperative period or if other drugs affecting hemostasis are used in parallel. Installed epidural or subarachnoid catheters should be removed at least 5 h before the first dose of Eliquis. A similar increased risk may be noted with traumatic or multiple epidural or subarachnoid punctures. Frequent monitoring of patients for manifestations of nervous system dysfunction (e.g., numbness or weakness in the lower extremities, bowel or bladder dysfunction) is necessary.

If such abnormalities develop, an emergency examination and treatment should be performed. Prior to epidural or subarachnoid interventions in patients receiving anticoagulants, including for thrombosis prophylaxis, an assessment of the potential benefit-risk ratio should be performed.

Impact on the ability to drive vehicles and operate other mechanisms. Eliquis has no significant effect on the ability to drive vehicles and operate mechanisms.

Contraindications

• hypersensitivity to any component of Eliquis;
• clinically significant bleeding;
• severe hepatic impairment;
• hypersensitivity to any component of Eliquisrenal impairment with a creatinine Cl less than 15 ml/min, as well as use in patients on dialysis;
• pregnancy;
• breastfeeding;
• the age below 18 years.
• It is not recommended to use apixaban simultaneously with drugs the effect of which may be associated with the development of serious bleeding.

With caution: apixaban should be used with caution in patients with moderate to mild hepatic dysfunction (Child-Pugh grades A or B); performing spinal/epidural anesthesia or spinal/epidural puncture; in patients receiving systemic therapy with potent CYP3A4 and P-glycoprotein isoenzyme inhibitors, such as azole antifungals (in particular ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (such as ritonavir); when apixaban is used with potent CYP3A4 and P-glycoprotein isoenzyme inducers (particularly rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s wort preparations).

Side effects

The incidence of adverse reactions is understood as: often – ≥1/100,

Prevention of venous thromboembolism in patients after elective hip or knee arthroplasty

Undesired reactions have been reported in 11% of patients receiving apixaban at a dose of 2.5 mg 2 times daily. As with other anticoagulants, bleeding may occur in patients with risk factors such as organic lesions that may be accompanied by bleeding. The most common side effects were anemia, bleeding, hematomas, and nausea. The adverse reactions developed in patients who underwent orthopedic surgery against the background of apixaban therapy are presented below.

Blood and lymphatic system disorders: often – anemia (including postoperative and post-hemorrhagic, accompanied by corresponding changes in the results of laboratory tests), bleeding (including hematoma, vaginal and urethral bleeding); rarely – thrombocytopenia (including platelet count reduction).

Intrinsic system disorders: rarely – hypersensitivity.

An organ of vision: rarely – haemorrhage in the eyeball tissue (including conjunctival haemorrhage).

Systems: infrequent – arterial hypotension (including hypotension during the procedure).

Respiratory system disorders: infrequent – nasal bleeding; rarely – hemoptysis.

Gastrointestinal system disorders: frequently – nausea; infrequently – gastrointestinal bleeding (including vomiting with blood and melena), unchanged blood in stools; rarely – rectal bleeding, gingival bleeding.

Hepatic and biliary tract disorders: infrequent – increased transaminase activity, including ALT, AST, GGTP, abnormal changes of liver function tests, increased ALP activity in blood, increased bilirubin concentration in blood.

Musculoskeletal system disorders: rare – muscle haemorrhage.

Urinary system disorders: infrequent – hematuria (including corresponding changes in the results of laboratory tests).

Others: often – closed trauma; infrequent – hemorrhage and bleeding after invasive procedures (including hematoma after the procedure, bleeding from the postoperative wound, hematoma in the area of vessel puncture and catheter placement), presence of wound discharge, bleeding in the incision area (including hematoma in the incision area), bleeding during surgical intervention.

Prevention of strokes and systemic embolism in patients with atrial fibrillation

Immune system disorders: infrequent hypersensitivity (including drug hypersensitivity reactions such as skin rash and anaphylactic reactions, allergic edema).

Nervous system disorders: infrequent – intracranial hemorrhage, subarachnoid hemorrhage, subdural hematoma, cerebrospinal canal hemorrhage, spinal hematoma.

VIight: often – ocular hemorrhages (including conjunctival hemorrhages).

Systemic system disorders: frequently – other types of bleeding, hematoma; infrequently – abdominal bleeding.

Respiratory system: frequently – nasal bleeding; infrequently – hemoptysis; rarely – bleeding in the respiratory system (including pulmonary alveolar bleeding, laryngeal and pharyngeal bleeding).

Gastrointestinal system disorders: frequently – gastrointestinal bleeding (including vomiting with blood and melena), rectal bleeding, gingival bleeding; infrequently – hemorrhoidal bleeding, unchanged blood in stool, bleeding in the mouth; rarely – retroperitoneal bleeding.

Urinary system disorders: often – hematuria.

Reproductive system disorders: infrequent – intermenstrual vaginal bleeding, urogenital bleeding.

Reactions at the injection site: infrequent – bleeding at the injection site.

Laboratory indices: infrequent – positive reaction in fecal occult blood test.

Others: often – closed trauma; infrequent – traumatic bleeding, bleeding after the procedure, bleeding in the area of incision.

Overdose

Symptoms: increased risk of bleeding. In controlled clinical trials, apixaban was taken orally in healthy volunteers in doses up to 50 mg/day for 3-7 days (25 mg, twice daily for 7 days or 50 mg, once daily for 3 days); no clinically significant adverse effects were observed.

Treatment: the use of activated charcoal may be considered. The antidote to the drug is unknown.