Eliquis, 2.5mg 20 pcs.

Eliquis has antithrombotic effect.

Pharmacodynamics

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

prolongs prothrombin time, MHO and activated partial thromboplastin time (APTB). Changes in these parameters when using the drug in a therapeutic dose are insignificant and individual. Therefore, their use to assess 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, and maximum values of activity are observed when maximum, plasma concentration of apixaban is reached. A 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 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 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 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.

Pharmacokinetics

Absorption
Absolute bioavailability of apixaban reaches 50% when used in doses up to 10 mg. Apixaban is rapidly absorbed from the gastrointestinal tract, its maximum concentration (C_max) is reached within 3-4 hours after oral administration. Food intake has no effect on the values of area under the curve “concentration-time” (AUC) or C_max apixaban. Apixaban pharmacokinetics for doses up to 10 mg is linear. When apixaban is administered in doses above 25 mg, limited absorption of the drug is noted, which is accompanied by a decrease in its bioavailability. Metabolic parameters of apixaban are characterized by low to moderate inter- and intraindividual variability (the respective coefficient of variation values are ∼20% and ∼30%, respectively).

Distribution
The binding of apixaban to human plasma proteins is approximately 87%, the volume of distribution (V₈₅) is approximately 21L.

Metabolism and excretion
Approximately 25% of the dose taken is excreted as metabolites, most of it – through the intestine. Renal excretion of apixaban is about 27% of its total clearance.

The total clearance of apixaban is approximately 3.3 l/hour, the half-life (T1/2) is about 12 hours. O-demethylation and hydroxylation by 3-oxopiperidinyl residue are the main pathways of apixaban biotransformation. Apixaban is predominantly metabolized with participation of CYP3A4/5 isoenzyme, to a lesser extent – CYP1A2, 2C8, 2C9, 2C19 and 2J2 isoenzymes. Unchanged apixaban is the main substance circulating in human blood plasma, there are no active metabolites circulating in bloodstream. In addition, apixaban is a substrate of transport proteins, P-glycoprotein 70 and breast cancer resistance protein (BCRP).

Renal dysfunction
Renal dysfunction has no effect on the maximum concentration of apixaban. However, there was an increase in apixaban concentration that correlated with the degree of decrease in renal function as assessed by creatinine clearance values. In patients with mild (creatinine clearance – 51 ml/min to 80 ml/min), moderate (creatinine clearance – 30 ml/min to 50 ml/min) and severe (creatinine clearance – 15 ml/min to 29 ml/min) renal function disorders the AUC values of apixaban in plasma increased by 16%, 29% and 44%, respectively, compared to those patients who had normal creatinine clearance values. Moreover, impaired renal function had no apparent effect on the relationship between plasma concentrations of apixaban and its anti-FXa activity.No studies of apixaban in patients with creatinine clearance <15 ml/min or those on dialysis have been conducted.

Hepatic impairment
Studies of apixaban in severe hepatic impairment and active hepatobiliary pathology have not been performed.
In a study of pharmacokinetics and pharmacodynamics of apixaban at a single dose of 5 mg in patients with mild to moderate hepatic impairment (Child-Pugh grades A and B, respectively) and healthy volunteers it was shown that hepatic impairment has no effect on these parameters. Changes in anti-FXa activity and MHO in patients with moderate hepatic insufficiency and healthy volunteers were comparable.

Use in elderly patients
In elderly patients (over 65 years old) higher values of drug concentration in plasma were observed than in younger patients: the average AUC was approximately 32% higher. No adjustment of the drug dose in elderly patients is required.

Position
Apixaban exposure in women was 18% higher than in men.
No adjustment of the drug dose according to the patient’s gender is required.

Race and ethnicity
The results obtained in Phase I studies indicate that there are no significant differences in apixaban pharmacokinetics between Caucasoid, Mongoloid and Negroid races. The results of pharmacokinetic analyses in different populations performed in studies including patients receiving apixaban after elective hip or knee arthroplasty are consistent with the results of the phase studies. No dose adjustments are required based on the race or ethnicity of the patient.

Body weight
Patients with body weight greater than 120 kg had plasma apixaban concentrations approximately 30% lower than those of patients with body weight between 65 kg and 85 kg; patients with body weight less than 50 kg had approximately 30% higher concentrations. No dose adjustment is required depending on the patient’s body weight.

Dependence of pharmacokinetic and pharmacodynamic parameters
The relationship between pharmacokinetic and pharmacodynamic parameters (including anti-FXa activity, MHO, prothrombin time, ACTV) of apixaban and its plasma concentration has been studied for a wide range of drug doses (from 0.5 mg to 50 mg). It was shown that the relationship between apixaban concentration and FXa activity is best described using a linear model. The dependence of pharmacokinetic and pharmacodynamic parameters of apixaban evaluated in patients undergoing elective hip or knee arthroplasty was consistent with that observed in healthy volunteers.

Indications

Prevention of thrombosis, heart attacks and strokes

Prevention of venous thromboembolism in patients after planned hip or knee arthroplasty.

Active ingredient

Apixaban

Composition

1 film-coated tablet contains:

the active ingredient:

apixaban 2.5 mg.

Auxiliary substances:

lactose,

microcrystalline cellulose,

croscarmellose sodium,

sodium lauryl sulfate,

Magnesium stearate;

The Opadray II Yellow film jacket (hypromellose 15 cps, lactose monohydrate, titanium dioxide, triacetin, iron oxide yellow dye).

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 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, 1 time per day), which is a potent inhibitor of both CYP3A4 isoenzyme and P-glycoprotein, led to increasing of mean AUC value of apixaban by 2 times and mean C_max – 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 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 blood 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 decreased mean AUC and C_max 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.

Anticoagulants, platelet aggregation inhibitors and NSAIDs
After co-administration of enoxaparin (once, in a dose of 40 mg) and apixaban (once, in a dose of 5 mg) an additive effect of these agents on activity of FXa was observed.
No signs of pharmacokinetic or pharmacodynamic interaction of apixaban with acetylsalicylic acid (in a dose of 325 mg, once daily) were observed in healthy subjects.
Combination of apixaban with clopidogrel (in dose 75 mg, 1 time per day) or combination of clopidogrel (75 mg) and acetylsalicylic acid (162 mg, 1 time per day) in phase I of clinical study 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 of 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.
It is not recommended to use simultaneously the 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 prescribed.

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 defined as: frequently, ≥1/100, < 1/10; infrequently, ≥1/1000, < 1/100; rarely, ≥1/10000, < 1/1000.

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).

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.

Pregnancy use

There are only limited data on the use of Eliquis during pregnancy. The use of apixaban in pregnancy is not recommended.

There are no data on excretion of apixaban or its metabolites with breast milk in humans. If it is necessary to use the drug Eliquis during lactation, breastfeeding should be stopped.