Eliquis, 5 mg 20 pcs.

A direct-acting anticoagulant is a selective inhibitor of factor Xa clotting.

The mechanism of action of apixaban is inhibition of FXa activity. As a result, apixaban changes values of indexes of blood coagulation system: prolongs prothrombin time, MHO and activated partial thromboplastin time (APTB). Changes of these parameters when using the drug in a therapeutic dose are insignificant and individual. Therefore, their use to assess pharmacodynamic activity of apixaban is not recommended.

The inhibition of FXa activity by apixaban has been proven by a chromogenic test using Rotachrom heparin. The change in anti-FXa activity is directly proportional to the increase in plasma apixaban concentration, with maximum activity values observed when C_max apixaban in plasma 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 apixaban dose and concentration are more pronounced and less variable than blood 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/day, is 1.ZMe/ml (5/95 percentile – 0.67 IU/ml to 2.4 IU/ml) and 0.84 IU/ml (5/95th percentile -0.37 IU/ml to 1.8 IU/ml), respectively, which correlates with the variation in this index between doses of the drug (less than 1.6 times).

Apixaban therapy does not require routine monitoring of plasma concentrations, but performing a Rotachrom anti-FXa activity test may be helpful in deciding whether to continue therapy.

Indications

Active ingredient

Composition

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).

The conversion from or to warfarin or other vitamin K antagonists

The conversion of patients from 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® therapy 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 the pharmacokinetics of apixaban

CYP3A4 and P-glycoprotein inhibitors. Combination of apixaban with ketoconazole (in dose 400 mg, once daily), which is a potent inhibitor of both CYP3A4 isoenzyme and P-glycoprotein, led to increase of mean AUC of apixaban by 2 times and mean Cmax by 1.6 times. There is no dose adjustment of apixaban in combination with ketoconazole, however apixaban should be used with caution in patients receiving systemic therapy with azole antifungal agents, in particular ketoconazole, or other potent inhibitors of CYP3A4 isoenzyme and P-glycoprotein.

Drugs other than potent CYP3A4 and P-glycoprotein isoenzyme inhibitors (e.g. diltiazem, naproxen, amiodarone, verapamil, quinidine) are likely to result in lower plasma concentrations of apixaban. For example, diltiazem (moderate CYP3A4 isoenzyme inhibitor and weak P-glycoprotein inhibitor) at a dose of 360 mg once daily, resulted in a 1.4-fold increase in mean AUC values of apixaban and 1.3-fold increase in mean Cmax 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 Cmax values of apixaban, respectively. At the same time, there was an increase in the values of clotting system parameters (PV, INR and ACTV). However, there was no effect of naproxen on arachidonic acid-induced platelet aggregation, as well as clinically significant prolongation of bleeding time.

Dose adjustment of apixaban when combined 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 reduction of the mean AUC and Cmax 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 apixaban concentration. Dose adjustment of apixaban when combining it with agents of this group is not required, but these drugs should be combined with caution.

Anticoagulants, platelet aggregation inhibitors and NSAIDs. After coadministration of enoxaparin (singly, in dose of 40 mg) and apixaban (singly, in dose of 5 mg) the additive effect of these drugs on activity of FXa was observed.

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

The 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 lead to increase of bleeding time or further inhibition of platelet aggregation compared to use of these antiaggregants in monotherapy. Increase of clotting system parameters (PV, INR and ACTV) was consistent with the effects of apixaban when used in monotherapy.

. It is not recommended to use concomitantly drugs whose effects may be associated with the development of serious bleeding, such as unfractionated heparin or heparin derivatives (including low-molecular-weight heparins), oligosaccharides, FXa inhibitors (such as fondaparinux), direct thrombin II inhibitors (such as desirudin), thrombolytic drugs, glycoprotein IIb/IIIa receptor antagonists, 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 patency of a central venous or arterial catheter.

In patients after elective hip or knee arthroplasty, co-administration of apixaban with other antiaggregants or antithrombotic drugs is not recommended.

Combination with other drugs. No clinically significant pharmacokinetic or pharmacodynamic interaction of apixaban with atenolol or famotidine has been observed.

The combination of apixaban (10 mg dose) with atenolol (100 mg dose) did not result in development of clinically significant changes in apixaban pharmacokinetic parameters, but it was accompanied by 15 and 18% reduction in mean AUC and Cmax values of apixaban compared to monotherapy regimen, respectively. Administration of apixaban (10 mg dose) with famotidine (40 mg dose) had no effect on the AUC or Cmax values of apixaban.

The effect of apixaban on the pharmacokinetics of other drugs

. In in vitro studies, apixaban did not inhibit the activity of the CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 isoenzymes (inhibitory concentration (IC50) >45 μmol/L) and, at the same time, weakly inhibited the activity of the CYP2C19 isoenzyme (IC50 >20 μmol/L) at a concentration significantly higher than the Cmax of the drug in plasma 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 the clearance of drugs metabolized by these isoenzymes. In addition, apixaban does not significantly inhibit P-glycoprotein activity. 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 antiplatelet agents, a careful benefit/risk assessment should be performed prior to concomitant use with Eliquis.

Eliquis is not recommended for use in patients with liver disease accompanied by clotting abnormalities 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 bleeding risk 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.

In case of hemorrhagic complications, treatment with the drug should be stopped and an examination to determine the source of bleeding should be performed. If necessary, appropriate treatment, such as surgical stoppage of bleeding or transfusion of fresh frozen 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

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 were noted 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).

Systemic system disorders: 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 hemorrhage.

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.