Eliquis, 5 mg 60 pcs

Pharmgroup:

A direct acting anticoagulant is a selective factor Xa inhibitor.

Pharmic action:

Eliquis is a direct acting anticoagulant – a selective inhibitor of factor Xa blood 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 the maximum values of activity observed when the Cmax of apixaban in plasma 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 apixaban dose and concentration are more pronounced and less variable than blood clotting parameters. The expected maximal and minimal anti-FXa activity of apixaban at equilibrium, when administered at a dose of 2.5 mg 2 times/day, are 1.ZMe/ml (5/95 percentile – 0.67 ME/ml – 2.4 ME/ml) and 0.84 ME/ml (5/95 percentile -0.37 ME/ml – 1.8 ME/ml), respectively, which correlates with variation in this index between drug doses (less than 1.6 times). Routine monitoring of plasma concentrations is not required during therapy with apixaban, but performing an anti-FXaA activity Rotachrom test may be helpful in deciding whether to continue therapy.

Apixaban is a potent direct FXa inhibitor that reversibly and selectively blocks the active center of the enzyme for oral administration. 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:

Intake

The absolute bioavailability of apixaban reaches 50% when used in doses up to 10 mg. Apixaban is rapidly absorbed from the gastrointestinal tract, Cmax 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 Cmax of apixaban. Apixaban pharmacokinetics for doses up to 10 mg has a linear character. When administering apixaban in doses above 25 mg, limitation of 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% and the volume of distribution (Vss) is approximately 21 l.

Metabolism and excretion

About 25% of the dose taken is excreted as metabolites, most of it through the intestine. Renal excretion of apixaban is approximately 27% of its total clearance.

The total clearance of apixaban is approximately 3.3 L/hour, T1/2 is about 12 h. O-demethylation and hydroxylation at the 3-oxopiperidinyl residue are the main biotransformation pathways of apixaban. Apixaban is primarily 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 plasma, there are no active metabolites circulating in the bloodstream. In addition, apixaban is a substrate of transport proteins, P-glycoprotein 70 and breast cancer resistance protein (BCRP).

Kidney dysfunction

Kidney dysfunction has no effect on the Cmax of apixaban. However, there was an increase in apixaban concentrations correlated with the degree of renal function impairment as assessed by creatinine clearance (CK) values. In patients with mild renal dysfunction (CK – from 51 ml/min to 80 ml/min), moderate (CK – from 30 ml/min to 50 ml/min) and severe (CK – from 15 ml/min to 29 ml/min) apixaban AUC values in plasma increased by 16%, 29% and 44%, respectively, compared to those with normal CK values. However, impaired renal function had no apparent effect on the relationship between plasma apixaban concentrations and its anti-FXa activity.

There have been no studies of apixaban in patients with creatinine clearance < 15 ml/min or on dialysis.

Hepatic impairment

There have been no studies of apixaban in severe hepatic insufficiency and active hepatobiliary pathology.
In investigation of pharmacokinetics and pharmacodynamics of apixaban at a single dose of 5 mg in patients with mild to moderate hepatic insufficiency (Child-Pugh grades A and B, respectively) and healthy volunteers it was shown that hepatic insufficiency has no effect on these parameters. Changes in anti-FXa activity and MHO in patients with moderate hepatic impairment and healthy volunteers were comparable.

The use in elderly patients

Elderly patients (over 65 years) showed higher plasma concentrations of the drug than younger patients: the average AUC was approximately 32% higher. No dose adjustment is required in elderly patients.

Per sex

The exposure of apixaban in women was 18% higher than in men. No adjustment of the drug dose depending on the patient’s sex is required.
Race and ethnicity

The results obtained within the framework of the phase I trials testify to the absence of significant differences of apixaban pharmacokinetics among representatives of 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 phase I studies. No dose adjustments are required based on the race or ethnicity of the patient.

Body weight

Patients with a body weight greater than 120 kg had a plasma apixaban concentration approximately 30% lower than that of patients with a body weight between 65 kg and 85 kg; patients with a body weight less than 50 kg had a plasma apixaban concentration approximately 30% higher. No dose adjustment is required depending on patient weight.

The relationship between 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 05 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 venous thromboembolism in patients after planned hip or knee replacement.

Pharmacological effect

Pharmaceutical group:

Direct anticoagulant – selective inhibitor of factor Xa.

Pharmaceutical action:

Eliquis is a direct-acting anticoagulant – a selective inhibitor of blood coagulation factor Xa.

The mechanism of action of apixaban is the inhibition of FXa activity. As a result of this, apixaban changes the values ​​of the blood coagulation system: it lengthens prothrombin time, MHO and activated partial thromboplastin time (aPTT). Changes in these indicators 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.

The inhibition of FXa activity by apixaban has been demonstrated using the heparin Rotachrom chromogenic test. The change in anti-FXa activity is directly proportional to the increase in the concentration of apixaban in the blood plasma, with maximum activity values ​​​​observed when the Cmax of apixaban in the blood plasma is reached. A linear relationship between the concentration and anti-FXa activity of apixaban is recorded over 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 coagulation parameters. The expected maximum and minimum anti-FXa activity of apixaban at steady state, when used at a dose of 2.5 mg 2 times / day, is 1.3IU/ml (5/95th percentile – 0.67 IU/ml – 2.4 IU/ml) and 0.84 IU/ml (5/95th percentile -0.37IU/ml – 1.8 IU/ml), respectively, which correlates with fluctuations in this indicator in the interval between taking doses of the drug (less than 1.6 times). During apixaban therapy, routine monitoring of its plasma concentrations is not required, but the Rotachrom anti-FXa activity test may be useful in deciding whether to continue therapy.

Mechanism of action

Apixaban is a potent, direct FXa inhibitor that reversibly and selectively blocks the enzyme’s active site for oral administration. The antithrombotic effect of apixaban does not require the presence of antithrombin III. Apixaban inhibits free and bound FXa, as well as prothrombinase activity. Apixaban has no immediate direct effect on platelet aggregation, but indirectly inhibits thrombin-induced platelet aggregation. By inhibiting FXa activity, apixaban prevents the formation of thrombin and blood clots.

Pharmacokinetics:

Suction

The absolute bioavailability of apixaban reaches 50% when used in doses of up to 10 mg. Apixaban is rapidly absorbed from the gastrointestinal tract, Cmax is achieved within 3-4 hours after oral administration. Food intake does not affect the area under the concentration-time curve (AUC) or Cmax of apixaban. The pharmacokinetics of apixaban for doses up to 10 mg is linear. When taking apixaban in doses above 25 mg, limited absorption of the drug is observed, which is accompanied by a decrease in its bioavailability. Apixaban metabolism rates are characterized by low to moderate inter- and intra-individual variability (corresponding 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 (Vss) is approximately 21 L.

Metabolism and excretion

Approximately 25% of the dose taken is excreted as metabolites, most of it 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/hour, T1/2 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 metabolites circulating in the bloodstream. In addition, apixaban is a substrate of the transport proteins P-glycoprotein 70 and breast cancer resistance protein (BCRP).

Renal dysfunction

Impaired renal function does not affect the Cmax of apixaban. However, there was an increase in apixaban concentrations, which correlated with the degree of decrease in renal function, assessed by creatinine clearance (CC) values. In individuals with mild renal impairment (CK – from 51 ml/min to 80 ml/min), moderate (CK – from 30 ml/min to 50 ml/min) and severe (CK – from 15 ml/min to 29 ml/min), the AUC values ​​of apixaban in blood plasma increased by 16%, 29% and 44%, respectively, compared with individuals who had normal CK values. However, renal dysfunction did not have an obvious effect on the relationship between the concentration of apixaban in the blood plasma and its anti-FXa activity.

Apixaban has not been studied in patients with creatinine clearance <15 mL/min or on dialysis.

Liver dysfunction

Apixaban has not been studied in severe liver failure and active hepatobiliary pathology.
In a study of the pharmacokinetics and pharmacodynamics of apixaban at a single dose of 5 mg in patients with mild to moderate hepatic impairment (Child-Pugh classes A and B, respectively) and healthy volunteers, it was shown that liver failure does not affect these indicators. Changes in anti-FXa activity and MHO in patients with moderate hepatic impairment and healthy volunteers were comparable.

Use in elderly patients

Elderly patients (over 65 years of age) had higher plasma concentrations of the drug than younger patients: the mean AUC was approximately 32% higher. No dose adjustment is required in elderly patients.

Floor

Exposure to apixaban was 18% higher in women than in men. No dose adjustment is required depending on the patient’s gender.
Race and Ethnicity

The results obtained in phase I studies indicate that there are no significant differences in the pharmacokinetics of apixaban between representatives of the Caucasian, Mongoloid and Negroid races. Results from cross-population pharmacokinetic analyzes performed in studies involving patients receiving apixaban after elective hip or knee replacement were consistent with those from phase I studies. No dosage adjustment is required depending on the race or ethnic origin of the patient.

Body weight

In patients weighing more than 120 kg, plasma concentrations of apixaban were approximately 30% lower than in patients weighing between 65 kg and 85 kg; in patients weighing less than 50 kg, this figure was approximately 30% higher. No dose adjustment is required depending on the patient’s body weight.

Dependence of pharmacokinetics and pharmacodynamics parameters

The relationship between pharmacokinetics and pharmacodynamics parameters (including anti-FXa activity, MHO, prothrombin time, aPTT) of apixaban and its plasma concentrations was studied for a wide range of drug doses (from 0.5 mg to 50 mg). The relationship between apixaban concentration and FXa activity has been shown to be best described using a linear model. The relationship between the pharmacokinetics and pharmacodynamics of apixaban, assessed in patients undergoing elective hip or knee replacement, was consistent with that observed in healthy volunteers.

Special instructions

As with other anticoagulants, patients taking Eliquis should be closely monitored for bleeding. If severe bleeding develops, Eliquis should be discontinued. If hemorrhagic complications develop, it is necessary to discontinue treatment with the drug and perform an examination to identify the source of bleeding. If necessary, appropriate treatment is prescribed, in particular, surgical stop of bleeding or transfusion of fresh frozen blood plasma.

Performing spinal, epidural, or puncture in patients receiving Eliquis

When performing spinal or epidural anesthesia or diagnostic puncture of these areas in patients receiving antithrombotic agents to prevent thromboembolism, there is a risk of developing epidural or spinal hematomas, which, in turn, can cause persistent or irreversible paralysis. This risk may further increase when using an installed epidural catheter in the postoperative period or when concurrently using other drugs that affect hemostasis. Established epidural or subarachnoid catheters should be removed at least 5 hours before the first dose of Eliquis.

A similar increase in risk may be observed when performing traumatic or repeated punctures of the epidural or subarachnoid spaces. Frequent monitoring of patients for the development of manifestations of nervous system dysfunction (in particular, numbness or weakness of the lower extremities, bowel or bladder dysfunction) is necessary. If such disorders develop, emergency examination and treatment are necessary. Before performing interventions on the epidural or subarachnoid spaces in patients receiving anticoagulants, incl. In order to prevent thrombosis, an assessment of the ratio of potential benefits and risks is necessary.

Impact on the ability to drive vehicles and operate machinery

Eliquis does not have a significant effect on the ability to drive a car or operate machinery.

Active ingredient

Apixaban

Composition

1 tab.:
– apixaban 5 mg

Excipients:

lactose,

microcrystalline cellulose,

croscarmellose sodium,

sodium lauryl sulfate,

magnesium stearate.

Film shell composition:

Opadry II Yellow (hypromellose 15 cps, lactose monohydrate, titanium dioxide, triacetin, iron oxide yellow dye).

Pregnancy

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

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

Contraindications

– hypersensitivity to the active substance or auxiliary components of the drug Eliquis;
– clinically significant active bleeding;
– liver disease, accompanied by disturbances in the blood coagulation system and a clinically significant risk of bleeding;
– severe liver dysfunction;
– impaired renal function with CC less than 15 ml/min, as well as use in patients on dialysis;
— pregnancy;
– breastfeeding;
— age up to 18 years.
It is not recommended to use apixaban simultaneously with drugs that may be associated with the development of serious bleeding.
Caution: Apixaban should be used with caution when performing spinal, epidural anesthesia or punctures, as well as in patients receiving systemic therapy with potent inhibitors of CYP3A4 and P-glycoprotein, such as azole antifungals (in particular ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (for example, ritonavir). Caution should also be exercised when using apixaban with potent inducers of the CYP3A4 isoenzyme and P-glycoprotein (in particular, rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s wort preparations).

Risk of bleeding

The drug is recommended to be used with caution in conditions characterized by an increased risk of bleeding: congenital or acquired bleeding disorders; exacerbations of gastrointestinal ulcer; bacterial endocarditis; thrombocytopenia; thrombocytopathies; history of hemorrhagic stroke; recent surgery on the brain or spinal cord, as well as on the organs of vision; with severe uncontrolled arterial hypertension.

In addition, caution should be exercised when using apixaban simultaneously with NSAIDs (including acetylsalicylic acid), due to the fact that these drugs increase the risk of bleeding.

Surgical interventions associated with hip fracture

In clinical trials, Eliquis was not used in patients undergoing emergency surgery for a hip fracture, and therefore its effectiveness and safety in this category of patients was not studied.

Side Effects

Adverse reactions were noted in 11% of patients receiving apixaban at a dose of 2.5 mg 2 times a day. As with other anticoagulants, bleeding may occur in patients with risk factors such as organic lesions associated with bleeding. The most common side effects were anemia, bleeding, hematomas, and nausea. Adverse reactions that developed in patients undergoing orthopedic surgery during apixaban therapy are presented below.
Further, the frequency of adverse reactions is understood as: often – > 1/100, 1/1000, 1/10000, < 1/1000.

From the blood and lymphatic system: often – anemia (including postoperative and posthemorrhagic, accompanied by corresponding changes in laboratory test results); uncommon – thrombocytopenia (including decreased platelet count).

From the immune system: rarely – hypersensitivity.

From the organ of vision: rarely – hemorrhages in the tissue of the eyeball (including hemorrhage in the conjunctiva).

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

From the respiratory system: infrequently – nosebleeds; rarely – hemoptysis.

From the gastrointestinal tract: often – nausea; uncommon – gastrointestinal bleeding (including vomiting mixed with blood and melena), the presence of unchanged blood in the stool; rarely – rectal bleeding, bleeding from the gums.

From the liver and biliary tract: uncommon – increased transaminase activity (including increased ALT activity), increased AST, gamma-glutamyl transpeptidase activity, pathological changes in liver function tests, increased alkaline phosphatase activity in the blood, increased bilirubin concentration in the blood.

From the musculoskeletal system: rarely – muscle hemorrhage.

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

Other: often – closed injury; uncommon – hemorrhage and bleeding after invasive procedures (including hematoma after the procedure, bleeding from a postoperative wound, hematoma in the area of ​​​​vascular puncture and at the site of catheter installation), the presence of discharge from the wound, hemorrhage in the incision area (including hematoma in the incision area), bleeding during surgery.

Interaction

Effect of other drugs on the pharmacokinetics of apixaban
CYP3A4 and P-glycoprotein inhibitors

Combining apixaban with ketoconazole (at a dose of 400 mg, 1 time per day), which is a potent inhibitor of both CYP3A4 and P-glycoprotein, led to an increase in the average AUC value of apixaban by 2 times and the average Cmax by 1.6 times. No dosage adjustment of apixaban is required when combined with ketoconazole, but apixaban should be used with caution in patients receiving systemic therapy with azole antifungals, particularly ketoconazole, or other potent inhibitors of CYP3A4 and P-glycoprotein.
Drugs that moderately inhibit the elimination of apixaban, CYP3A4 and/or P-glycoprotein are expected to increase plasma concentrations of apixaban to a lesser extent. For example, diltiazem (at a dose of 360 mg, 1 time per day), considered a moderate CYP3A4 inhibitor and a weak P-glycoprotein inhibitor, provided an increase in mean apixaban AUC values ​​by 1.4 times and mean Cmax values ​​by 1.3 times.

Naproxen (500 mg), a P-glycoprotein inhibitor, increased the mean AUC and Cmax of apixaban by 1.5- and 1.6-fold, respectively. At the same time, there was an increase in the values ​​of blood coagulation parameters. However, against the background of this combination, there was no change in the effect of naproxen on platelet aggregation induced by arachidonic acid, and no clinically significant prolongation of bleeding time.

No dose adjustment of apixaban is required when combined with less active inhibitors of CYP3A4 and/or P-glycoprotein.
Inducers of CYP3A4 and P-glycoprotein

Combining apixaban with rifampicin (a strong inducer of CYP3A4 and P-glycoprotein) resulted in a decrease in the mean AUC and Cmax of apixaban by approximately 54% and 42%, respectively. Therefore, combining apixaban with other strong inducers of CYP3A4 and P-glycoprotein (in particular phenytoin, carbamazepine, phenobarbital or St. John’s wort) may also lead to a decrease in plasma concentrations of apixaban. However, no dose adjustment of apixaban is required when combined with drugs in this group; however, these drugs should be combined with caution.

Anticoagulants

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

Due to the increased risk of bleeding, apixaban should be combined with other anticoagulants with caution.
Platelet aggregation inhibitors and NSAIDs

There were no signs of pharmacokinetic or pharmacodynamic interaction of apixaban with acetylsalicylic acid (at a dose of 325 mg, 1 time per day).

Combining apixaban with clopidogrel (at a dose of 75 mg, 1 time per day) or a combination of clopidogrel (75 mg) and acetylsalicylic acid (162 mg, 1 time per day) did not lead to an increase in bleeding time, platelet aggregation or blood coagulation parameters (PT, INR and APTT) compared with the use of these antiplatelet agents in monotherapy.

Despite these data, it is possible that the pharmacodynamic response to antiplatelet therapy may be enhanced when used in combination with apixaban. Therefore, caution should be exercised when combining it with NSAIDs (including acetylsalicylic acid) and/or platelet aggregation inhibitors, since these drugs usually increase the risk of bleeding.

Combination with other drugs

There were no clinically significant pharmacokinetic or pharmacodynamic interactions of apixaban with atenolol or famotidine. Combining apixaban (at a dose of 10 mg) with atenolol (at a dose of 100 mg) did not lead to the development of clinically significant changes in the pharmacokinetic parameters of apixaban, but was accompanied by a decrease in the average AUC and Cmax values ​​of apixaban by 15 and 18% than when used in monotherapy. Combining apixaban (10 mg) with famotidine (40 mg) had no effect on the AUC or Cmax of apixaban.

The effect of apixaban on the pharmacokinetics of other drugs

In vitro studies did not reveal an inhibitory effect of apixaban on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (IC50 >45 μmol/L) and a weak inhibitory effect was found on the activity of CYP2C19 (IC50 >20 μmol/L) at concentrations significantly higher than the Cmax of the drug in plasma when used clinically.

Apixaban was not an inducer of CYP1A2, CYP2B6, or CYP3A4/5 at concentrations up to 20 μmol/L. Therefore, it is not expected to affect the metabolic clearance of drugs metabolized by these isoenzymes when administered together. 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.
Digoxin. The combination of apixaban (at a dose of 20 mg, once a day) and digoxin (at a dose of 0.25 mg, once a day), which is a P-glycoprotein substrate, did not affect the AUC or Cmax values ​​of digoxin. Therefore, apixaban does not inhibit the transport of P-glycoprotein substrates.

Naproxen. Combining apixaban (10 mg single dose) and naproxen (500 mg dose), a commonly used NSAID, had no effect on naproxen AUC or Cmax.

Atenolol. Combining apixaban (single dose 10 mg) and atenolol (100 mg), a commonly used beta-blocker, did not affect the pharmacokinetics of the latter.

Overdose

Symptoms: overdose may increase the risk of bleeding. In controlled clinical studies, apixaban was administered orally to healthy volunteers at doses up to 50 mg/day for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days), which is 10 times the maximum recommended human dose; There were no clinically significant undesirable effects.

Treatment: There is no known antidote for apixaban. In preclinical studies, oral administration of activated charcoal within 3 hours of oral administration of apixaban was shown to reduce apixaban exposure values; therefore, in case of overdose of this drug, the use of activated carbon may be considered.

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Manufacturer

Bristol-Myers Squibb Manufacturing Company, Puerto Rico