Eliquis pills 2.5mg, 60pcs

Pharmacological action

Pharmacotherapy group

Direct-acting anticoagulant-selective inhibitor of blood clotting factor Xa (FXa).

ATX Code: B01AF02

Pharmacological properties

Pharmacodynamics

Apixaban is a powerful direct FXa inhibitor that reversibly and selectively blocks the active site of the enzyme. The drug is intended for oral use. The antithrombotic activity 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. As a result of FXa suppression, the values of blood coagulation system parameters change: prothrombin time is lengthened, partial thromboplastin time (APTT) is activated, and the international normalized ratio (INR) increases. Changes in these parameters when using the drug in a therapeutic dose are insignificant and highly variable. Therefore, their use for the purpose of evaluating the pharmacodynamic activity of apixaban is not recommended. In the thrombin generation test, apixaban reduced the endogenous thrombin potential, an indicator of the formation of thrombin in human blood plasma.

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 values of activity are observed when the maximum concentration 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.

Table 1 shows the estimated steady-state concentrations and anti-FXa activity with apixaban for each indication. In patients receiving apixaban after elective hip or knee joint, the ratio of the maximum and minimum levels of anti-FXa activity in the interval between doses of the drug does not exceed 1.6. In patients receiving apixaban about the prevention of stroke and systemic thromboembolism in non-valve atrial fibrillation, this ratio is less than 1.7, and in patients receiving apixaban treatment of deep vein thrombosis and prevention of recurrent deep venous thrombosis of less than 2,2.

Table 1.

Estimated steady-state concentrations (ng / ml) and anti-FXa activity (IU / ml)

* Dose adjustment according to the dose reduction criteria in the ARISTOTLE study.

While apixaban therapy does not require routine monitoring of its anticoagulant effect, however, performing a calibrated quantitative test of anti-FXa activity may be useful in situations where information about the presence of apixaban in the blood may be useful for deciding whether to continue therapy. Compared to warfarin, apixaban has been associated with a lower number of bleeding events, including intracranial hemorrhage.

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 its maximum concentration (Cmax) is reached within 3 to 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).

After oral use of apixaban at a dose of 10 mg in the form of 2 crushed tablets of 5 mg diluted in 30 ml of water, the drug exposure was comparable to that after oral use of 2 whole tablets of apixaban 5 mg. After oral use of apixaban at a dose of 10 mg in the form of 2 crushed tablets of 5 mg with 30 g of applesauce, the Cmax and AUC values were 21% and 16%, respectively, lower than after taking 2 whole tablets of 5 mg.

After nasogastric tube use of a crushed 5 mg apixaban tablet diluted in 60 ml of 5% dextrose water solution (5 DV), apixaban exposure was comparable to that observed in other clinical trials involving healthy volunteers who received a single dose of apixaban 5 mg orally as a tablet.

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 is excreted as metabolites. The main route of elimination is 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, and the elimination half — life (T 1/2) is approximately 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, and breast cancer resistance protein (BCRP).

Impaired renal function

Impaired renal function does not affect the maximum concentration 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 values. 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 with 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 has not been studied in patients with creatinine clearance less than 15 ml/min or on dialysis.

Hepatic dysfunction apixaban has not been studied in patients with severe hepatic insufficiency and active pathology of the hepatobiliary system.

No significant changes in pharmacokinetic and pharmacodynamic parameters were observed with a single dose of apixaban 5 mg in patients with mild and moderate hepatic insufficiency (Child-Pugh class A and B, respectively) compared with healthy volunteers. Changes in anti-FXa activity and INR in patients with mild to 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.

Gender

Apixaban exposure in women was 18% higher than in men.

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. The results of pharmacokinetic analyses in various populations performed as part of the apixaban clinical trial program, which included patients receiving apixaban after elective hip or knee replacement surgery, generally correspond to the results of phase 1 studies.

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.

The relationship between the pharmacokinetic and pharmacodynamic parameters (including anti-FXa activity, INR, 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. Dependence of apixaban pharmacokinetic and pharmacodynamic parameters. The evaluation rate in patients treated with apixaban in phase II and III clinical trials was similar to that in healthy volunteers.

Indications

• Prevention of venous thromboembolism in patients after elective hip or knee replacement surgery.
• Prevention of stroke and systemic thromboembolism in adult patients with non-valvular atrial fibrillation who have one or more risk factors (such as stroke or a history of transient ischemic attack, age 75 years and older, arterial hypertension, diabetes mellitus, symptomatic chronic heart failure (NYHA functional class II and higher)). The exception is patients with severe to moderate mitral stenosis or artificial heart valves.
• Treatment of deep vein thrombosis( DVT), pulmonary embolism (PE), and prevention of recurrent DVT and PE.

Use during pregnancy and lactation

Use in pregnancy There are no data on the use of apixaban in pregnant women. During preclinical studies, no direct or indirect negative effects on reproductive function were found. The use of apixaban during pregnancy is contraindicated.

Use during breast-feeding There is no information on the elimination of apixaban or its metabolites in human breast milk. According to available data from animal studies, apixaban is excreted in breast milk. In rat studies, the concentration of the drug in breast milk was many times higher than that in blood plasma (Cmax is about 8 times higher, AUC is about 30 times higher), which may indicate active transport of the drug into breast milk. The risk to breastfed children cannot be excluded. If the use of Eliquis® is necessary, a decision should be made to discontinue taking the drug or stop breastfeeding.

Effects on fertility Apixaban did not affect fertility in animal studies.

Recommendations for use

The most common adverse reactions were bleeding, bruising, nosebleeds and hematoma (see the profile of adverse reactions and their frequency according to indications below). The frequency of adverse reactions is defined as: often – ≥ 1/100, < 1/10, infrequently – ≥ 1/1000, < 1/100, rarely – ≥ 1/10000,

* There were no cases of generalized pruritus in CV185057 (long-term prevention of VTE).

The use of Eliquis® may be associated with an increased risk of bleeding (including hidden) from any organ or tissue, which in turn can lead to the development of post-hemorrhagic anemia. Symptoms, signs, and severity will vary depending on the source of the bleeding and the extent or prevalence of the bleeding.

Contraindications

• Hypersensitivity to apixaban or any other component of the drug.
• Active clinically significant bleeding.
• Liver diseases associated with disorders in the blood coagulation system and a clinically significant risk of bleeding.
• A disease or condition characterized by a significant risk of a large bleeding: current or recent exacerbation of peptic ulcer of the gastrointestinal tract, the presence of malignant neoplasms at high risk of bleeding; recent damage to the brain or spinal cord; recent surgery on the brain or spinal cord, as well as on the body: recent hemorrhagic stroke; known or suspected varicose veins of the esophagus; arteriovenous malformation; vascular aneurysm or severe vnutrispinalnaya or intracerebral vascular changes.
• Impaired renal function with creatinine clearance less than 15 ml / min, as well as use in patients on dialysis.
• Age up to 18 years (data on the use of the drug are not available).
• Pregnancy (there are no data on the use of the drug).
• Breast-feeding period (data on the use of the drug are not available).
• Concomitant use with any other anticoagulant medications, including unfractionated heparin (UFH), low-molecular-weight heparins (LMWH) (enoxaparin, dalteparin, etc. ), heparin derivatives (fondaparinux, etc. ), oral anticoagulants (warfarin, rivaroxaban, dabigatran, etc. ), except in situations where the patient is transferred to or from apixaban therapy or if unfractionated heparin is prescribed at the doses necessary to maintain patency of the central venous or arterial catheter (see the section “Interaction with other drugs”).
• Congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

With caution at the risk of bleeding, the drug is not recommended for liver diseases that are accompanied by disorders in the blood coagulation system and a clinically significant risk of bleeding. It is necessary to stop using the drug if severe bleeding occurs.

If there is a complication in the form of bleeding, therapy with the drug should be stopped; it is also necessary to determine the source of bleeding. Among the possible options for stopping bleeding, surgical hemostasis or transfusion of freshly frozen plasma can be considered, and for life-threatening conditions that cannot be controlled using the above methods, the possibility of introducing prothrombin complex concentrate (CPC) or recombinant blood clotting factor VIIa can be considered. In healthy volunteers, the reversibility of the pharmacodynamic effects of Eliquis® according to the results of the thrombin generation test was observed after an infusion of COCs containing 4 clotting factors. However, there is no experience with the clinical use of COCs containing 4 clotting factors to stop bleeding in patients receiving Eliquis®. There is currently no experience of using recombinant factor VIIa in patients receiving apixaban therapy.

Caution should be exercised when using apixaban concomitantly with nonsteroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid) due to the fact that these drugs increase the risk of bleeding.

Concomitant use of Eliquis and acetylsalicylic acid (ASA) in elderly patients requires caution due to the potentially higher risk of bleeding. In patients with atrial fibrillation and conditions requiring mono or dual antiplatelet therapy, a thorough risk and benefit assessment should be performed before prescribing apixaban.

Side effects

Common adverse reactions were bleeding, bruising, nosebleeds, and hematoma (see the profile of adverse reactions and their frequency according to indications below). The frequency of adverse reactions is defined as: often – ≥ 1/100, < 1/10, infrequently – ≥ 1/1000, < 1/100, rarely – ≥ 1/10000,

* There were no cases of generalized pruritus in CV185057 (long-term prevention of VTE).

The use of Eliquis® may be associated with an increased risk of bleeding (including hidden) from any organ or tissue, which in turn can lead to the development of post-hemorrhagic anemia. Symptoms, signs, and severity will vary depending on the source of the bleeding and the extent or prevalence of the bleeding.

Interaction

CYP3A4 and P-glycoprotein inhibitorscombination of apixaban with ketoconazole (at a dose of 400 mg, once a day), which is a powerful inhibitor of both CYP3A4 and P-glycoprotein, resulted in a 2 – fold increase in the average apixaban AUC and 1.6-fold increase in the average Cmax.

The use of Eliquis® is not recommended in patients receiving simultaneous systemic treatment with potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein, such as azole antimycotics (for example, ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (for example, ritonavir) (see the section “Special instructions”).

Drugs that are not considered potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein (for example, diltiazem, naproxen, clarithromycin, amiodarone, verapamil, quinidine) are likely to lead to an increase in the concentration of apixaban in blood plasma to a lesser extent. Dose adjustment of apixaban in combination with other drugs that are not potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein is not required. For example, diltiazem (a moderate inhibitor of the CYP3A4 isoenzyme and a weak inhibitor of P-glycoprotein) at a dose of 360 mg 1 time per day, led to an increase in the average AUC of apixaban by 1.4 times and the average Cmax by 1.3 times. Naproxen (a P-glycoprotein inhibitor, but not a CYP3A4 isoenzyme) when administered at a dose of 500 mg caused an increase in the average AUC and Cmax of apixaban by 1.5 and 1.6 times, respectively. Clarithromycin (a P-glycoprotein inhibitor and a potent inhibitor of the CYP3A4 isoenzyme) at a dose of 500 mg twice daily increased the average AUC and Cmax of apixaban by 1.6 and 1.3 times, respectively.

CYP3A4 and P-glycoprotein inducers Combining apixaban with rifampicin (a potent inducer of the CYP3A4 and P-glycoprotein isoenzymes) resulted in a decrease in the average apixaban AUC and Cmax by approximately 54% and 42%, respectively.Apparently, the combination of apixaban with other powerful inducers of the CYP3A4 isoenzyme and P-glycoprotein (in particular, phenytoin, carbamazepine, phenobarbital or St. John’s wort preparations) can also lead to a decrease in the concentration of apixaban in blood plasma (by about 50%). Dose adjustment of apixaban when combined| with the drugs of this group is not required when prescribed according to the indications: prevention of thromboembolism after joint replacement, prevention of strokes and systemic thromboembolism in non-valvular atrial fibrillation and prevention of relapses of deep vein thrombosis, pulmonary embolism, however, these drugs should be combined with caution. When used for the treatment of deep vein thrombosis and PE, the combined use of apixaban and powerful inducers of the CYP3A4 isoenzyme and P-glycoprotein is not recommended, since the effectiveness may be reduced (see the section “Special instructions”).

Anticoagulants, platelet aggregation inhibitors and NSAIDs due to the high risk of bleeding, concomitant use with any other anticoagulants is contraindicated (see the section “Contraindications”). 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 FXa activity was noted.

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

The combination of apixaban with clopidogrel (75 mg, once daily) or a combination of clopidogrel (75 mg) and acetylsalicylic acid (162 mg, once daily) or prasugrel (60 mg followed by a dose of 10 mg once daily) in a phase I clinical study did not lead to an increase in bleeding time or a more pronounced inhibition of platelet aggregation compared to the use of these antiplatelet agents in monotherapy. Increased blood clotting parameters (prothrombin time, INR, and APTT) were consistent with the effects of apixaban alone.

Naproxen (500 mg), which is a P – glycoprotein inhibitor, increases the average AUC and Cmax of apixaban by 1.5 and 1.6 times, respectively. When taking apixaban, a corresponding increase in blood clotting parameters was observed. There were no changes in the effect of naproxen on platelet aggregation induced by arachidonic acid, and there was no clinically significant increase in the duration of bleeding after the combined use of apixaban and naproxen. Despite these data, individual patients may experience a more pronounced pharmacodynamic response after co-use of apixaban with other antiplatelet agents. Eliquis® should be used with caution in combination with NSAIDs (including acetylsalicylic acid), as these medications usually increase the risk of bleeding. There was a statistically significant increase in the risk of major bleeding according to the criteria of the International Society on Thrombosis and Hemostasis (ISTH) when using triple therapy with apixaban, acetylsalicylic acid (ASA) and clopidogrel in a clinical study in patients with acute coronary syndrome with a high risk of thrombosis and several concomitant cardiac and non— cardiac diseases.

It is not recommended to use concomitantly drugs that may be associated with the development of serious bleeding, such as: thrombolytic drugs, antagonists of glycoprotein IIb/IIIa receptors, thienopyridines (for example, clopidogrel), dipyridamole, dextran and sulfinpyrazone.

Combination with other medicinal products: no clinically significant pharmacokinetic or pharmacodynamic interaction of apixaban with atenolol or famotidine was observed. The combination of apixaban (at a dose of 10 mg) with atenolol (at a dose of 100 mg) did not lead to 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%, respectively, compared with the monotherapy regimen. use of apixaban (10 mg) with famotidine (40 mg) had no effect on apixaban AUC or Cmax values.

Effect of apixaban on the pharmacokinetics of other drugs

In vitro studies, apixaban did not inhibit the activity of the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (inhibitory concentration (IC50) > 45 mmol / L) and at the same time weakly suppressed the activity of the isoenzyme CYP2C19 (IC50 >> 20 mmol/L) at a concentration significantly exceeding the maximum concentration of the drug in blood plasma during its clinical use the application. Apixaban is not an inducer of CYP1A2, CYP2B6, or CYP3A4/5 isoenzymes at concentrations up to 20 mmol/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 the activity of P-glycoprotein.

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

Digoxin With simultaneous use of apixaban (20 mg once daily) and digoxin (0.25 mg once daily), which is a P-gp substrate, the AUC or Cmax of digoxin did not change. Thus, apixaban does not inhibit the transport of P-glycoprotein substrates.

Naproxen Simultaneous use of single doses of apixaban (10 mg) and naproxen (500 mg), commonly used NSAIDs, did not affect the AUC and Cmax of naproxen.

ATENOLOL Simultaneous use of a single dose of apixaban (10 mg) and atenolol (100 mg), a widely used beta-blocker, did not alter the pharmacokinetics of atenolol.

Activated carbon Intake of activated carbon reduces the effect of apixaban (see section “Overdose”).

How to take, course of use and dosage

Eliquis® is taken orally regardless of food intake. 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.

For patients who cannot swallow the tablet whole, the Eliquis ® tablet can be crushed and diluted in water or 5% aqueous dextrose (5 DV) or apple juice, or mixed with applesauce and immediately taken orally (see section “Pharmacological properties”). Alternatively, a tablet of Eliquis® can be crushed and diluted in 60 ml of water or 5 ML and the resulting suspension can be immediately administered through a nasogastric tube (see section “Pharmacological properties”).

The drug substance in crushed tablets of Eliquis ® remains stable in water,5 DV, apple juice and applesauce for up to 4 hours.

1. In patients after elective hip or knee replacement: 2.5 mg 2 times a day (first dose 12-24 hours after surgery). When deciding when to start therapy, doctors should take into account the potential positive effect of early anticoagulant therapy in preventing venous thromboembolism, along with the risk of postoperative bleeding. 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.

2. In patients with atrial fibrillation: 5 mg twice daily. In patients with atrial fibrillation, the dose of the drug is reduced to 2.5 mg twice a day: – In the presence of a combination of two or more of the following characteristics: age 80 years or older, body weight 60 kg or less, or plasma creatinine concentration ≥ 1.5 mg / dl (133 mmol / l). Therapy should be continued for a long time.

3. Treatment of deep vein thrombosis, pulmonary embolism (PE):10 mg twice a day for 7 days, then 5 mg 2 times a day. The duration of treatment is determined individually, taking into account the ratio of expected benefit and risk of clinically significant bleeding. The decision on the duration of therapy should be based on an assessment of the presence and reversibility of factors predisposing to relapse (i. e., previous surgery, trauma, period of immobilization, etc. ), as well as manifestations of DVT and/or PE, at least 3 months.

4. Prevention of recurrent deep vein thrombosis, pulmonary embolism (PE):2.5 mg twice daily after at least 6 months of treatment for deep vein thrombosis or PE with apixaban at a dose of 5 mg twice daily or another anticoagulant, as indicated in table 2.

Table 2

	Dosages	Maximum daily dose
Treatment of deep vein thrombosis, PE	10 mg twice daily for the first 7 days	20 mg
	Then 5 mg twice a day	10 mg
Prevention of recurrent deep vein thrombosis, PE after 6 months of treatment for deep vein thrombosis or PE.	2.5 mg twice daily	5 mg

The total duration of therapy should be selected individually after careful evaluation of the ratio of the benefit of taking the drug and the risk of bleeding (see the section “Special instructions”).

Use in patients with impaired renal functionfor patients with mild or moderate renal impairment, the following recommendations apply:- no dose adjustment is required when using apixaban for the prevention of deep vein thrombosis in patients after elective hip or knee replacement, for the treatment of deep vein thrombosis, for the treatment of PE and for the prevention of relapses of deep vein thrombosis, PE (see the section “Pharmacological properties”). – when using apixaban in patients with atrial fibrillation and a creatinine concentration of ≥ 1.5 mg / dl (133 mmol/l) in blood plasma, in combination with an age of ≥ 80 years or a body weight of ≤ 60 kg, a dose reduction of the drug is required, as described above. In the absence of compliance with other criteria for dose reduction (age, body weight), correction of NS therapy is required (see the section “Pharmacological properties”).

In patients with severe renal impairment (with a creatinine clearance of 15-29 ml / min), the following recommendations apply (see sections “Special instructions” and “Pharmacological properties”):- apixaban should be used with caution for the prevention of deep vein thrombosis in patients after elective hip or knee replacement, for the treatment of deep vein thrombosis, for the treatment of PE, and for the prevention of relapses of deep vein thrombosis, PE;- in patients with atrial fibrillation, apixaban 2.5 mg should be administered twice daily.

There are no data on the use of apixaban in patients with creatinine clearance Therefore, the use of Eliquis® in such patients is contraindicated (see the section “Special instructions” and “Pharmacological properties”).

Use in patients with impaired liver function Eliquis® is contraindicated in patients with liver diseases associated with disorders in the blood coagulation system and a clinically significant risk of bleeding (see the section “Contraindications”). The use of the drug in patients with severe hepatic insufficiency is contraindicated (see the section “Contraindications”).

Caution should be exercised when taking Eliquis® in patients with mild to moderate hepatic insufficiency (Child-Pugh class A or B), and no dose adjustment is required (see the sections “Special Instructions” and “Pharmacological properties”).

Patients who had an increase in the activity of liver enzymes alanine aminotransferase (ALT)/aspartate aminotransferase (ACT) twice the upper limit of normal or total bilirubin one and a half or more times higher than the upper limit of normal were excluded from clinical studies. Therefore, apixaban should be used with caution in patients of this group (see sections “Special instructions” and “Pharmacological properties”). Liver function should be evaluated prior to initiation of Eliquis therapy.

Use in elderly patientsc Orrection of the drug dose in elderly patients is not required (except for the patients indicated in clause 2-use in atrial fibrillation).

Body weight Dose adjustment depending on the patient’s body weight is not required (except for the patients listed in item 2 – use for atrial fibrillation).

Half-correction of the drug dose depending on the patient’s gender is not required.

Race and ethnicity No dose adjustment is required depending on the patient’s race or ethnicity.

Switching from or to parenteral anticoagulant therapy, switching from parenteral anticoagulants to Eliquis® and vice versa can be performed at the time of the next scheduled intake of the drug to be discontinued (the next dose of the drug to be discontinued is not taken).

Switching from or to warfarin or other vitamin K antagonists Patients should switch from warfarin or other vitamin K antagonists to Eliquis if the patient’s INR is below 2.0. When transferring patients from Eliquis® therapy to warfarin or other vitamin K antagonists, Eliquis® therapy should be continued for 48 hours after taking the first dose of warfarin or other vitamin K antagonists. After 48 hours, INR should be monitored before taking the next dose of Eliquis®. Co-use of warfarin (or another vitamin K antagonist) and Eliquis® should be continued until the INR is ≥ 2.0. If the INR is > 2.0, Eliquis® should be discontinued.

Cardioversion Patients with atrial fibrillation who require cardioversion may start or continue using Eliquis®.

In patients who have not been treated with anticoagulants, cardioversion should be prescribed at least. 5 doses of Eliquis® 5 mg twice daily (2.5 mg twice daily for patients who need a dose reduction (see point 2 of the section “Dosage and use”)) to achieve adequate anticoagulation.

If cardioversion is required prior to the appointment of 5 doses of Eliquis®, a loading dose of 10 mg should be taken, followed by 5 mg twice a day. The loading dose should be reduced to 5 mg, followed by 2.5 mg twice daily, if the patient fits the category for dose reduction (see point 2 of the section “Dosage and use”). It is necessary to take a loading dose at least 2 hours before performing cardioversion.

Before performing cardioversion, it is necessary to obtain confirmation of the proper use of Eliquis®. When deciding on the appointment and duration of treatment, it is necessary to rely on the established recommendations for the use of anticoagulants in patients who require cardioversion.

If there is a temporary interruption in treatment with the drug (accidental or intentional), the risk of thrombosis increases. Patients should be instructed to avoid interruptions in treatment with the drug. If anticoagulant therapy is temporarily discontinued for any reason, it should be resumed as soon as possible.

Overdose

The antidote is not known. Overdose increases the risk of bleeding. It is not expected that the use of hemodialysis for an overdose of apixaban will be an effective measure.

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,2 times a day, for 7 days or 50 mg,1 time a day, for 3 days); no clinically significant adverse effects were observed.

In case of overdose of this drug, you can consider using activated carbon.

When activated charcoal was administered to healthy volunteers 2 and 6 hours after taking apixaban at a dose of 20 mg, the area under the concentration-time curve (AUC) for apixaban decreased by 50% and 27%, respectively (Cmax did not change). The elimination half-lives of apixaban decreased from 13.4 to 5.3 and 4.9 hours, respectively.

Special instructions

Risk of bleeding As with other anticoagulants, patients receiving Eliquis® should be carefully monitored for signs of bleeding. In conditions with a high risk of bleeding, the drug is recommended to be used with caution. The use of Eliquis® should be discontinued if severe bleeding develops (see the sections “Side effects” and “Overdose”).

Although apixaban therapy does not require continuous monitoring of its concentration in the blood, it may sometimes be appropriate to conduct a calibrated quantitative analysis of anti-Xa-factor activity in exceptional cases where data on the effects of apixaban may contribute to clinical decision-making, for example, in case of overdose and emergency surgery (see the section “Pharmacological properties”).

Interaction with other drugs that affect hemostasis due to the high risk of bleeding, concomitant use with any other anticoagulants is contraindicated (see the section “Contraindications”).

Concomitant use of Eliquis® with antiplatelet agents increases the risk of bleeding (see section “Interaction with other medications”).

Patients receiving concomitant NSAIDs, including ASA, should be treated with caution.

After surgery, it is not recommended to use other platelet aggregation inhibitors simultaneously with Eliquis® (see the section “Interaction with other drugs”).

In patients with atrial fibrillation and conditions requiring antiplatelet therapy with one or two drugs, a careful assessment of the potential benefit-risk ratio should be made before starting concomitant therapy with Eliquis®.

In a clinical study involving patients with atrial fibrillation, the concomitant use of ASA resulted in an increased risk of major bleeding both while taking apixaban and while taking warfarin. In this clinical study, combined therapy with two antiplatelet agents was rarely used.

The use of thrombolytic agents for the treatment of acute ischemic stroke The experience of using thrombolytic agents for the treatment of acute ischemic stroke in patients receiving apixaban is very limited.

Patients with artificial heart valvesthe safety and efficacy of the drug in patients with artificial heart valves with and without atrial fibrillation have not been studied. The use of Eliquis® in this group of patients is not recommended.

Surgical and invasive procedures The use of Eliquis® should be discontinued at least 48 hours before elective surgery or an invasive procedure with a moderate or high risk of bleeding.This includes interventions in which the possibility of clinically significant bleeding is not excluded or for which the risk of bleeding is unacceptable.

Eliquis® should be discontinued at least 24 hours prior to elective surgery or an invasive procedure with a low risk of bleeding. This includes interventions where minimal, non-critical, or easily controlled bleeding is expected.

If surgery or an invasive procedure cannot be delayed, it should be performed with appropriate caution, given the increased risk of bleeding. The risk of bleeding should be correlated with the need for emergency intervention. Nonvalvular atrial fibrillation usually does not require the use of “bridge therapy” within 24-48 hours after discontinuation of apixaban before surgery.

After an invasive procedure or surgical intervention, the use of Eliquis® should be resumed as soon as possible, provided that the clinical situation allows it and sufficient hemostasis is established (for information on cardioversion, see the section “Dosage and use”).

Temporary discontinuation of anticoagulants, including Eliquis®, due to active bleeding, elective surgery, or an invasive procedure increases the patient’s risk of thrombosis. Interruptions in treatment should be avoided, and if for any reason it is necessary to temporarily stop anticoagulant therapy with Eliquis®, it should be resumed as soon as possible.

Treatment of deep vein thrombosis and TELANe it is recommended to replace therapy with unfractionated heparin with Eliquis® during initiation of therapy in patients with PE with unstable hemodynamics, possible thrombolysis or pulmonary artery thrombectomy, since the safety and efficacy of apixaban in these clinical situations have not been established.

Patients with oncological diseasesthe efficacy and safety of apixaban in the treatment of DVT, PE, and prevention of recurrent DVT and PE (lVTE) in patients with actively progressive malignancy have not been established.

Patients with renal insufficiency Limited clinical data indicate that in patients with severe renal impairment! renal function (creatinine clearance 15-29 ml/min) increases apixaban plasma concentrations, which may increase the risk of bleeding. For the treatment of DVT, PE, and prevention of recurrent DVT and PE (lVTE), apixaban should be used with caution in patients with severe renal impairment (creatinine clearance 15-29 ml/min) (see sections “Dosage and use” and “Pharmacological properties”).

For the prevention of stroke and systemic embolism in patients with NAFLD, patients with severe renal impairment (creatinine clearance 15-29 ml/min), and patients with serum creatinine levels ≥ 1.5 mg/dl (133 mmol/L) in combination with age ≥ 80 years or body weight ≤ 60 kg, the dose of apixaban should be reduced to 2.5 mg twice daily (see section “Dosage and use”).

Due to the lack of experience with clinical use of apixaban in patients with creatinine clearance

Elderly patients The risk of bleeding may increase with age (see section “Pharmacological properties”). Also, the concomitant use of Eliquis and ASA in elderly patients requires caution due to the potentially higher risk of bleeding.

Body mass at low body mass (

Patients with hepatic insufficiency Eliquis® is contraindicated in patients with liver disease associated with coagulopathy and a clinically significant risk of bleeding (see section “Contraindications”).

The drug is not recommended for patients with severe hepatic impairment (see the section “Pharmacological properties”).

The drug should be used with caution in patients with mild to moderate hepatic impairment (stage A or B according to the Child — Pugh classification) (see sections “Dosage and use” and “Pharmacological properties”).

Patients with elevated levels of hepatic enzymes ALT/AST > 2 x ULN or total bilirubin > 1.5 x ULN were excluded from clinical trials. Therefore, Eliquis® should be used with caution in this population (see section “Pharmacological properties”). Before starting the use of Eliquis®, it is necessary to check the biochemical parameters of liver function.

Interaction with cytochrome P 450 inhibitors and P-drNe inhibitors the use of Eliquis® is recommended in patients receiving simultaneous systemic treatment with potent inhibitors of the CYP3A4 isoenzyme and P-glycoprotein, such as azole antimycotics (for example, ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (for example, ritonavir). These drugs may increase apixaban exposure by a factor of two (see section “Interactions with other drugs”) or higher in the presence of additional factors that also increase apixaban exposure (for example, severe renal impairment).

Interaction with inducers of the CYP3A4 and P-gp isoenzymes Simultaneous use of Eliquis® with powerful inducers of the CYP3A4 isoenzyme and P-gp inducers (for example, rifampicin, phenytoin, carbamazepine, phenobarbital and St. John’s wort preparations) may also lead to a decrease in the concentration of apixaban in blood plasma (by approximately 50%). In a clinical study involving patients with atrial fibrillation, there was a decrease in efficacy and an increased risk of bleeding with simultaneous use of apixaban and powerful inducers of the CYP3A4 and P-gp isoenzymes compared to the use of apixaban in monotherapy.

The following recommendations apply to patients receiving systemic therapy with potent inhibitors of the CYP3A4 isoenzyme and P-gp (see section “Interaction with other drugs”):

– in order to prevent venous thromboembolism in patients after elective hip or knee replacement, to prevent stroke and systemic thromboembolism in non-valvular atrial fibrillation, as well as to prevent relapses of DVT and PE, apixaban should be used with caution:- for the treatment of DVT and PE, apixaban should not be used, as the effectiveness may be reduced.

Surgical interventions related to hip fracture The efficacy and safety of apixaban in clinical trials in patients after surgery for hip fracture have not been evaluated. Therefore, it is not recommended for these patients.

Laboratory parametersthe effect of the mechanism of action of apixaban on blood clotting parameters (for example, prothrombin time (PV), INR, and activated partial thromboplastin time (APTT)) matched what was expected. The observed changes in these blood clotting parameters at the intended therapeutic dose were small and had significant variability (see the section “Pharmacological properties”).

Information on excipients Eliquis ® contains lactose. Patients with rare hereditary problems such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take Eliquis®.

Performing spinal, epidural, or puncture procedures 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. The risk may also increase with traumatic or repeated epidural or spinal punctures. Patients should be checked frequently for signs and symptoms of neurological deficits (for example, numbness or weakness in the legs, bowel or bladder dysfunction). If a neurological deviation from the norm is detected, urgent diagnosis and treatment is necessary. Prior to neuroaxial intervention, the physician should evaluate the potential benefit – risk ratio for patients who are receiving anticoagulant therapy or will be receiving it for the prevention of thrombosis.

There is no clinical experience with apixaban in patients with an installed intrathecal or epidural catheter. If this situation is necessary, based on the pharmacokinetic characteristics of apixaban, an interval of 20-30 hours (i. e. 2 half-lives) should be observed between the last dose of apixaban taken and catheter removal, so at least one dose of apixaban should be skipped before catheter removal. The next dose of apixaban can be administered no earlier than 5 hours after catheter removal. As is the case with all new anticoagulant medications, there is limited experience with apixaban in neuroaxial blockade, and therefore extreme caution should be exercised in this situation.

Influence on the ability to drive vehicles and mechanisms

The drug Eliquis® does not affect or does not significantly affect the ability to drive vehicles and work with mechanisms.

Storage conditions

Store at a temperature not exceeding 30 °C. Keep out of reach of children!

Shelf

life is 3 years. Do not use after the expiration date.

Active ingredient

Apixaban

Conditions of release from pharmacies

By prescription

Dosage form

Tablets