Eliquis pills 5mg, 60pcs

Composition

of 1 tab. : – apixaban 5 mg

Auxiliary substances:

lactose,

microcrystalline cellulose,

croscarmellose sodium,

sodium lauryl sulfate,

magnesium stearate.

Composition of the film shell:

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

Pharmacological action

of the pharmaceutical group:

Direct-acting anticoagulant-selective factor Xa inhibitor

:  

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

The mechanism of action of apixaban is to inhibit the activity of FXa. As a result, apixaban changes the values of blood clotting system parameters: it extends prothrombin time, MHO, and activated partial thromboplastin time (APTT). Changes in these parameters when using the drug in a therapeutic dose are insignificant and individual. Therefore, their use for the purpose of evaluating the pharmacodynamic activity of apixaban is not recommended.

Apixaban inhibition of FXa activity was demonstrated by a chromogenic test using Rotachrom heparin. The change in anti-FXa activity is directly proportional to the increase in the concentration of apixaban in blood plasma, while the maximum activity values are observed when the Cmax of apixaban in blood plasma is reached. A linear relationship between the concentration and anti-FXa activity of apixaban is recorded in a wide range of therapeutic doses of the drug.

Changes in anti-FXa activity with changes in the dose and concentration of apixaban are more pronounced and less variable than blood clotting 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. ZME/ml (5/95 percentiles-0.67 IU / ml-2.4 IU / ml) and 0.84 IU/ml (5/95 percentiles -0.37 IU/ml – 1.8 IU/ml), respectively, which correlates with fluctuations in this indicator in the interval between doses of the drug (less than 1.6 times). While apixaban therapy does not require routine monitoring of its plasma concentration, however, performing the Rotachrom anti-FXa reactivity test may be useful for deciding whether to continue therapy.

Mechanism of action

Apixaban is a potent direct FXa inhibitor that reversibly and selectively blocks the active site of the enzyme and is intended for oral use. 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 direct direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. 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 up to 10 mg. Apixaban is rapidly absorbed from the gastrointestinal tract, and Cmax is reached within 3-4 hours after oral use. Food intake does not affect the values of the area under the concentration-time curve (AUC) or Cmax of apixaban. The pharmacokinetics of apixaban for doses up to 10 mg are linear. When taking apixaban in doses higher than 25 mg, there is a restriction in the absorption of the drug, which is accompanied by a decrease in its bioavailability. Apixaban’s metabolic parameters are characterized by low or moderate inter-and intra-individual variability (the corresponding values of the coefficient of variation 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 liters.

Metabolism and elimination

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

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

Impaired renal function

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

Apixaban studies in patients with creatinine clearance

Impaired liver function

Apixaban has not been studied in patients with severe hepatic insufficiency and active pathology of the hepatobiliary system. In a study of the pharmacokinetics and Pharmacodynamics of apixaban at a single dose of 5 mg in patients with mild and moderate hepatic insufficiency (Child-Pugh class A and B, respectively) and healthy volunteers, it was shown that hepatic insufficiency does not affect these indicators. 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 of age) there were higher values of the drug concentration in blood plasma than in younger patients: the average AUC value was approximately 32% higher. Dose adjustment of the drug in elderly patients is not required.

Gender

Apixaban exposure in women was 18% higher than in men. No dose adjustment is required depending on the patient’s gender. Race and ethnic origin The results obtained in the Phase I studies indicate that there are no significant differences in the pharmacokinetics of apixaban between representatives of the Caucasian, Mongoloid and Negroid races. The results of pharmacokinetic analyses in different populations performed in studies that included patients receiving apixaban after elective hip or knee replacement surgery are consistent with the results of Phase I studies. No dose adjustment is required depending on the patient’s race or ethnic origin.

Body weight

In patients with a body weight of more than 120 kg, the plasma concentration of apixaban was approximately 30% lower than in patients with a body weight of 65 kg to 85 kg; in patients with a body weight of less than 50 kg, this indicator was approximately 30% higher. No dose adjustment is required depending on the patient’s body weight.

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

Indications

-prevention of venous thromboembolism in patients after elective hip or knee replacement.

Use during pregnancy and lactation

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

There is no data on the elimination of apixaban or its metabolites in human breast milk. If it is necessary to use Eliquis during lactation, breastfeeding should be discontinued.

Contraindications

-hypersensitivity to the Active ingredient or auxiliary components of the drug Eliquis;— clinically significant active bleeding; – liver disease accompanied by disorders in the blood coagulation system and a clinically significant risk of bleeding;- severe hepatic impairment; – impaired renal function with creatinine clearance less than 15 ml / min, as well as use in patients on dialysis;— pregnancy;— breast-feeding;— under 18 years of age. It is not recommended to simultaneously use apixaban 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 the CYP3A4 isoenzyme and P-glycoprotein, such as azole antifungal agents (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 blood clotting disorders; exacerbations of gastrointestinal ulcers; bacterial endocarditis; thrombocytopenia; thrombocytopathies; a history of hemorrhagic stroke; recently undergone surgery on the brain or spinal cord, as well as on the visual organs; with severe uncontrolled arterial hypertension.

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

Surgical procedures related to hip fracture

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

Side effects

Adverse reactions were observed in 11% of patients treated with apixaban 2.5 mg twice daily. As with other anticoagulants, bleeding may occur in patients with risk factors, such as organic damage associated with bleeding. The most common side effects were anemia, bleeding, bruising, and nausea. The 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, > < 1/10, infrequently – > 1/1000, < 1/10, infrequently – > < 1/100, rarely – > 1/10000, < 1/100, rarely – >

From the blood and lymphatic system: often-anemia (including postoperative and post-hemorrhagic, accompanied by corresponding changes in the results of laboratory tests); infrequently – thrombocytopenia (including a decrease in the number of platelets).

Immune system disorders: rarely-hypersensitivity.

From the side of the organ of vision: rarely-hemorrhages in the eyeball tissue (including conjunctival hemorrhage).

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; infrequently-gastrointestinal bleeding (including vomiting with an admixture of blood and melena), the presence of unchanged blood in the feces; rarely-rectal bleeding, bleeding from the gums.

From the liver and biliary tract: infrequently-increased transaminase activity (including increased ALT activity), increased AST activity, gamma-glutamyltranspeptidase, pathological changes in liver function tests, increased ALP activity in the blood, increased bilirubin concentration in the blood.

Musculoskeletal disorders: rarely-muscle hemorrhage.

From the urinary system: infrequently-hematuria (including corresponding changes in the results of laboratory tests).

Other: often-closed trauma; infrequently-hemorrhage and bleeding after performing invasive procedures (including post-procedure hematoma, bleeding from a postoperative wound, hematoma in the area of vessel puncture and at the site of catheter insertion), 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

Combination of apixaban with ketoconazole (400 mg, once daily), which is a potent inhibitor of both CYP3A4 and P-glycoprotein, resulted in a 2 — fold increase in the mean apixaban AUC and 1.6-fold increase in the mean Cmax. Dose adjustment of apixaban when combined with ketoconazole is not required, but apixaban should be used with caution in patients receiving systemic therapy with azole antifungal agents, in particular ketoconazole, or other potent CYP3A4 and P-glycoprotein inhibitors. Drugs that moderately inhibit the elimination of apixaban, CYP3A4, and / or P-glycoprotein are expected to increase apixaban plasma concentrations to a lesser extent. For example, diltiazem (at a dose of 360 mg, once a day), considered a moderate inhibitor of CYP3A4 and a weak inhibitor of P-glycoprotein, provided an increase in the average AUC of apixaban by 1.4 times and the average Cmax by 1.3 times.

Naproxen (500 mg), a P-glycoprotein inhibitor, increased the mean apixaban AUC and Cmax by 1.5 and 1.6 times, respectively. At the same time, an increase in the values of the blood coagulation system was noted. 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.

Dose adjustment of apixaban in combination with less active CYP3A4 and/or P-glycoprotein inhibitors is not required. CYP3A4 and P-glycoprotein inducers

Combining apixaban with rifampicin (a potent inducer of CYP3A4 and P-glycoprotein) resulted in a decrease in the average apixaban AUC and Cmax by approximately 54 and 42%, respectively. Therefore, the combination of apixaban with other potent inducers of CYP3A4 and P-glycoprotein (in particular, phenytoin, carbamazepine, phenobarbital or St. John’s wort preparations) may also lead to a decrease in the concentration of apixaban in blood plasma. However, dose adjustment of apixaban is not required when it is combined with drugs of this group, but these drugs should be combined with caution.

Anticoagulants

After co-use of enoxaparin (once, at a dose of 40 mg) and apixaban (once, at a dose of 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).

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

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

Combining with other medicinal products

There was no clinically significant pharmacokinetic or pharmacodynamic interaction between apixaban and atenolol or famotidine. The combination of 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 pharmacokinetics of apixaban, but it was accompanied by a decrease in the average AUC and Cmax values of apixaban by 15 and 18% compared to its use in monotherapy. The combination of apixaban (10 mg) with famotidine (40 mg) did not affect the AUC or Cmax values of apixaban.

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 mmol/L) and a weak inhibitory effect was found on the activity of CYP2C19 (IC50 >>20 mmol/L) at concentrations significantly higher than the Cmax of the drug in blood plasma during its clinical use.

Apixaban was not an inducer of CYP1A2, CYP2B6, or CYP3A4/5 at concentrations up to 20 mmol/l. Therefore, it is not expected to affect the metabolic clearance of drugs metabolized by these isoenzymes when used 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 (20 mg, once daily) and digoxin (0.25 mg, once daily), 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. The combination of apixaban (a single dose of 10 mg) and naproxen (a dose of 500 mg) – a commonly used NSAID — did not affect the AUC or Cmax values of naproxen.

Atenolol.The combination of apixaban (a single dose of 10 mg) and atenolol (a dose of 100 mg), a commonly used beta — blocker, did not affect the pharmacokinetic parameters of the latter.

How to take, course of use and dosage

Inside, regardless of food intake (the first intake is 12-24 hours after surgery),1 table. 2 times a day. In patients who have undergone hip replacement, the recommended duration of therapy is from 32 to 38 days, for the knee joint-from 10 to 14 days.

In case of missed admission, the drug should be taken as soon as possible, and then continue taking it 2 times a day in accordance with the original scheme.

Use in patients with impaired renal function. In patients with mild, moderate or severe renal impairment (creatinine clearance — from 15 to 29 ml/min), no dose adjustment is required. Since there are no data on the use of the drug in patients with Cl creatinine

Use in patients with impaired liver function. Eliquis® can be used with caution in patients with mild to moderate hepatic insufficiency (Child-Pugh Class A or B). In patients with mild or moderate hepatic impairment, no dose adjustment is required. The use of the drug in patients with severe hepatic insufficiency is not recommended.

Overdose

Symptoms: Overdose may increase the risk of bleeding. In controlled clinical trials, 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 higher than the maximum recommended dose for humans; no clinically significant adverse effects were observed.

Treatment: The antidote of apixaban is not known. In preclinical studies, it has been shown that oral use of activated carbon within 3 hours after oral use of apixaban reduced apixaban exposure values; therefore, in case of overdose of this drug, the use of activated carbon may be considered.

Special instructions

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

Performing spinal, epidural anesthesia or punctures in patients receiving Eliquis

When performing spinal or epidural anesthesia or diagnostic puncture of these areas in patients receiving antithrombotic agents for the prevention of thromboembolism, 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 when using an established epidural catheter in the postoperative period or when using other medications that affect hemostasis in parallel. Installed epidural or subarachnoid catheters should be removed at least 5 hours before the first dose of Eliquis is administered.

A similar increase in risk may occur when performing traumatic or multiple punctures of the epidural or subarachnoid spaces. Patients should be frequently monitored for signs of nervous system dysfunction (in particular, numbness or weakness of the lower extremities, bowel or bladder dysfunction). With the development of such disorders, it is necessary to perform an emergency examination and treatment. Before performing surgery on the epidural or subarachnoid spaces in patients receiving anticoagulants, including for the prevention of thrombosis, it is necessary to assess the ratio of potential benefits and risks.

Influence on the ability to drive motor vehicles and manage mechanisms

Eliquis does not significantly affect the ability to drive a car and work with mechanisms.

Storage conditions

At a temperature not exceeding 30 °C

Shelf life

3 years

Active ingredient

Apixaban

Conditions of release from pharmacies

By prescription

Dosage form

Tablets

Purpose

For adults as directed by your doctor

Indications

Prevention of thrombosis, Prevention of heart attacks and strokes