Instruction for use: Eliquis

Dosage form: film-coated tablets

Active substance: Apixabanum

ATX

B01AF02 Apixaban

Pharmacological groups

Anticoagulant direct action - a selective inhibitor of the coagulation factor Ha (FXa) [Anticoagulants]

The nosological classification (ICD-10)

I48 Atrial fibrillation and flutter: Permanent atrial tachyarrhythmias; Relief frequent ventricular rate during atrial flutter or blink; atrial fibrillation; Paroxysm of atrial fibrillation and flutter; Paroxysm of atrial fibrillation; Paroxysmal atrial fibrillation; Atrial premature beats; Tahiaritmicheskoy atrial fibrillation; Tahisistolicheskoy atrial fibrillation; auricular flutter; Life-threatening ventricular fibrillation; Atrial fibrillation; Chronic atrial fibrillation; supraventricular arrhythmia; Paroxysmal atrial fibrillation and flutter; Paroxysmal fibrilloflutter; Atrial premature beats

I64 Unspecified Stroke as a bleeding or heart attack: Primary stroke; Stroke; Stroke in the course of; microstroke; stroke; The completed stroke

I82 Embolism and thrombosis of other veins: Recurrent venous thrombosis; Postoperative thrombosis; Venous thrombosis; Acute venous thromboembolism; Recurrent vein thrombosis; Venous thrombosis; Thrombosis of veins of internal organs; Venous thrombosis; Deep vein thrombosis; Thrombosis of blood vessels; Vascular thrombosis; Thrombosis of veins; Deep vein thrombosis; Thromboembolic diseases; Thromboembolism of veins; Severe venous thrombosis; Embolism; Embolism of veins; Thromboembolic complications

T84 Complications associated with internal orthopedic prosthetic devices, implants and transplants

Composition

active substance: Apixaban 2.5 mg, 5 mg

Auxiliary substances: lactose - 50.25 / 100.5 mg; MCC - 41/82 mg; Croscarmellose sodium - 4/8 mg; Sodium lauryl sulfate - 1/2 mg; Magnesium stearate 1.25 / 2.5 mg

Film membrane: Opadry II yellow / pink (hypromellose 15 cps - 1.48 / 2.96 mg, lactose monohydrate - 1.24 / 2.48 mg, titanium dioxide - 0.8 / 1.87 mg, triacetin - 0, 32 / 0.64 mg, iron dye oxide yellow - 0.16 / - mg, iron oxide red oxide - - / 0.046 mg) - 4/8 mg

Description of dosage form

Tablets, 2.5 mg: round, biconvex, covered with a film coating of yellow color, engraved "893" on one side and "2½" on the other side.

Tablets, 5 mg: oval, biconcave, film-coated pink, engraved "894" on one side and "5" on the other side.

Pharmachologic effect

Mode of action - antithrombotic.

Pharmacodynamics

Apixaban is a powerful direct inhibitor of FXa, reversibly and selectively blocking the active center of the enzyme. The drug is intended for oral use. To realize the antithrombotic activity of apixaban, the presence of antithrombin III is not required. Apixaban inhibits free and bound FXa, as well as prothrombinase activity. Apixaban has no direct direct effect on platelet aggregation, but it indirectly inhibits platelet aggregation induced by thrombin. By inhibiting the activity of FXa, apixaban prevents the formation of thrombin and thrombi. As a result of FXa suppression, the values of blood coagulation system values change: the PV, APTT is extended and the INR increases.

Changes in these parameters when the drug is administered in a therapeutic dose are insignificant and highly variable. Therefore, their use to assess the pharmacodynamic activity of apixaban is not recommended.

Inhibition of FXa activity by apixaban has been demonstrated using a chromatin test using Rotachrom heparin. The change in anti-FXa activity is directly proportional to the increase in the concentration of apixaban in the blood plasma, while the maximum values of activity are observed when Cmax apixaban is reached in the blood plasma. The 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 dose changes and apixaban concentrations are more pronounced and less variable than blood coagulation.

The table shows the expected Css and anti-FXa activity with apixaban for each of the indications. In patients receiving apixaban after planned hip or knee arthroplasty, the ratio of maximum and minimum levels of anti-FXa activity in the interval between doses is not more than 1.6. In patients receiving apixaban for stroke prevention and systemic thromboembolism in patients with non-valvular atrial fibrillation, this ratio is less than 1.7, and in patients receiving apixaban for the treatment of deep vein thrombosis and prevention of recurrence of deep vein thrombosis, less than 2.2.

Assumed equilibrium concentrations (ng / ml) and anti-FXa activity (IU / ml)

* Correction of dose according to the criteria for dose reduction in the ARISTOTLE study.

Against the backdrop of apixaban therapy, routine monitoring of its anticoagulant effect is not required, but the performance of a calibrated quantitative test of anti-FXa activity may be useful in situations where information on the presence of apixaban in the blood can be useful for deciding whether to continue therapy. In comparison with warfarin on the background of apixaban, there are fewer bleeding, including intracranial hemorrhage.

Pharmacokinetics

Suction. Absolute bioavailability of apixaban reaches 50% when administered in doses up to 10 mg.

Apixaban is rapidly absorbed from the digestive tract, Cmax is reached within 3-4 hours after oral administration. The intake of food does not affect the values of the AUC or Cmax indices of apixaban.

The pharmacokinetics of apixaban for doses up to 10 mg is linear. When taking apixaban in doses above 25 mg, there is a restriction of absorption of the drug, which is accompanied by a decrease in its bioavailability.

The metabolic parameters of apixaban are characterized by low or moderate inter- and intra-individual variability (the corresponding coefficient of variation is 20 and 30%, respectively).

Distribution. The association of apixaban with human plasma proteins is approximately 87%, Vss is approximately 21 liters.

Metabolism and excretion. Approximately 25% of the accepted dose is excreted in the form of metabolites. The main way of excretion is through the intestine. Renal excretion of apixaban is approximately 27% of its total clearance.

The total clearance of apixaban is approximately 3.3 l / h, T1 / 2 is about 12 hours. O-demethylation and hydroxylation of the 3-oxo-piperidinyl residue are the main pathways of the biotransformation of apixaban. Apixaban is predominantly metabolized with the participation of the CYP3A4 / 5 isoenzyme, to a lesser extent - the isoenzymes CYP1A2, 2C8, 2C9, 2C19 and 2J2. Unchanged apixaban is the main substance circulating in human blood plasma, 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 Cmax apixaban. However, there was an increase in the concentration of apixaban, which correlated with the degree of decrease in renal function, as measured by Cl creatinine. In individuals with renal dysfunction of light (Cl creatinine - 51 to 80 ml / min), medium (Cl creatinine - 30 to 50 ml / min) and severe (Cl creatinine - 15 to 29 ml / min), values AUC of apixaban in blood plasma increased by 16, 29 and 44%, respectively, compared with those who had normal values of creatinine clearance. At the same time, 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.

Studies of apixaban in patients with creatinine clearance less than 15 ml / min or those on dialysis have not been performed.

Violation of the function of the liver. Studies of apixaban in severe hepatic insufficiency and active pathology of the hepatobiliary system were not conducted.

There were no significant changes in the parameters of pharmacokinetics and pharmacodynamics in a single dose of apicaban at a dose of 5 mg in patients with mild to moderate hepatic insufficiency (Child-Pugh classes A and B, respectively) compared with healthy volunteers.

Changes in anti-FXa activity and INR in patients with mild and moderate hepatic insufficiency and healthy volunteers were comparable.

Use in elderly patients. Older patients (over 65 years of age) had higher blood plasma concentrations than younger patients: the mean AUC was approximately 32% higher.

Floor. The exposure of apixaban in women was 18% higher than that of men.

Race and ethnic origin. The results obtained in the Phase I studies indicate that there is no significant difference in the pharmacokinetics of apixaban between representatives of the Caucasoid, Mongoloid and Negroid races. The results of pharmacokinetics analyzes in various populations performed within the framework of the clinical trials program of apixaban, including patients receiving apixaban after planned hip or knee replacement, generally correspond to the results of phase I studies.

Body mass. In patients with a body weight of more than 120 kg, the concentration of apicaban in the blood plasma was approximately 30% lower than in patients with a body weight of 65 to 85 kg; In patients with a body weight of less than 50 kg, this figure was approximately 30% higher.

Dependence of pharmacokinetics and pharmacodynamics. The dependence between the parameters of pharmacokinetics and pharmacodynamics (including anti-FXa activity, MNO, PV, APTTV) of apixaban and its concentration in plasma was studied for a wide range of doses (0.5 to 50 mg). It was shown that the relationship between the concentration of apixaban and FXa activity is best described using a linear model. The dependence of pharmacokinetic parameters and pharmacodynamics of apixaban, evaluated in patients receiving apixaban in clinical studies of II and III phases, corresponded to that of healthy volunteers.

Indications for Eliquis

Prevention of venous thromboembolism in patients after planned endoprosthetics of the hip or knee joint;

Prevention of stroke and systemic thromboembolism in adult patients with non-valvular atrial fibrillation who have one or more risk factors (such as a stroke or transient ischemic attack in the anamnesis, age 75 and older, hypertension, diabetes, symptomatic chronic heart failure (functional class II and higher by the NYHA classification)). The exception is patients with severe and moderately expressed mitral stenosis or with artificial heart valves;

Treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), as well as the prevention of relapses of DVT and PE.

Contraindications

Hypersensitivity to any component of the drug;

Clinically significant bleeding;

At conditions characterized by an increased risk of bleeding: congenital or acquired bleeding disorders; Exacerbations of gastrointestinal ulcer; Bacterial endocarditis; Thrombocytopenia; Thrombocytopathy; A hemorrhagic stroke in the anamnesis; Recently transferred surgical intervention on the brain or spinal cord, as well as on the organ of vision; With severe uncontrolled arterial hypertension;

Severe violations of liver function, liver disease, accompanied by violations in the blood clotting system and clinically significant risk of bleeding;

Impaired renal function with Cl creatinine less than 15 mL / min, as well as use in patients on dialysis;

Simultaneous application with drugs, the effect of which can be associated with the development of serious bleeding, such as any anticoagulant drugs, unfractionated heparins, low molecular weight heparins (enoxaparin, dalteparin), heparin derivatives (fondaparinux), oral anticoagulants (warfarin, rivaroxaban, dabigatran) Those situations where the patient is transferred to therapy or with apixaban therapy, or if unfractionated heparin is given at the doses necessary to maintain the permeability of the central venous or arterial catheter (see "Interaction");

Congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

Pregnancy (there is no data on the use of the drug);

The period of breastfeeding (there are no data on the use of the drug);

Age under 18 years (no data on the use of the drug).

Carefully

The experience of using the drug with thrombolytic agents for the relief of acute ischemic stroke is limited;

Apixaban should be used with caution in patients with moderate or mild liver disease (class A or B in the Child-Pugh classification);

Apixaban should be used with caution in performing spinal / epidural anesthesia or spinal / epidural puncture (see "Specific guidance"), as well as in patients receiving systemic therapy with potent inhibitors of the isoenzyme CYP3A4 and P-glycoprotein, such as azole antifungal agents (in particular , Ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (eg ritonavir);

When using apixaban with powerful inducers of the isoenzyme CYP3A4 and P-glycoprotein (in particular, rifampicin, phenytoin, carbamazepine, phenobarbital or preparations of St. John's wort perfume), care must be taken.

Risk of bleeding. It is not recommended to use the drug in liver diseases accompanied by disorders in the blood coagulation system and clinically significant risk of bleeding. It is necessary to stop using the drug when heavy bleeding occurs.

If complications occur in the form of bleeding, therapy with the drug should be stopped; Also need to establish a source of bleeding. Among the possible options for stopping bleeding, surgical hemostasis or transfusion of freshly frozen plasma can be considered, in life-threatening conditions that cannot be controlled by the above methods, the possibility of introducing a recombinant coagulation factor VIIa can be considered, although experience with this coagulation factor in patients receiving apixaban therapy , not at the moment.

Caution should be exercised while using apixaban with NSAID (including with acetylsalicylic acid) because these drugs increase the risk of bleeding.

Operative interventions related to hip fracture. In clinical trials, Eliquis® was not used in patients who underwent emergency surgeries for a hip fracture, so efficacy and safety in this category of patients were not studied.

Pregnancy and breast-feeding

During preclinical studies there was no toxicity of the drug in relation to the reproductive function. There is limited information on the use of Eliquis ® during pregnancy. The use of apixaban in pregnancy is not recommended.

In studies on rats, 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 an active transport of the drug into breast milk. The risk to infants who are breastfed cannot be ruled out. There is no information on excretion of apixaban or its metabolites with human breast milk. If you need Eliquis® during lactation, breastfeeding should be discontinued.

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

Side effects

The frequency of adverse reactions is understood: often - ≥1 / 100, <1/10; Infrequently - ≥1 / 1000, <1/100; Rarely - ≥1 / 10000, <1/1000.

Prevention of venous thromboembolism in patients after planned endoprosthetics of the hip or knee joint

Undesirable 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, which may be accompanied by bleeding. The most common side effects were anemia, bleeding, bruising, nausea. Undesirable reactions that have developed in patients who underwent orthopedic surgery, against apyxaban therapy are presented below.

On the part of the blood and lymphatic system: often - anemia (including postoperative and posthemorrhagic, accompanied by appropriate changes in the results of laboratory tests), bleeding (including hematoma, vaginal and urethral bleeding); Infrequently - thrombocytopenia (including a decrease in the number of platelets).

From the immune system: rarely - hypersensitivity.

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

From the CVS: infrequently - arterial hypotension (including hypotension during the procedure).

From the respiratory system: infrequently - epistaxis; Rarely - hemoptysis.

From the digestive tract: often - nausea; Infrequently - gastrointestinal bleeding (including vomiting with an admixture of blood and melena), the presence of unchanged blood in the stool; Rarely - rectal bleeding, bleeding from the gums.

From the liver and bile ducts: infrequently - increased activity of transaminases, incl. Increased ALT, AST, GGTP, pathological changes in functional liver samples, increased activity of the alkaline phosphatase in the blood, increased bilirubin concentration in the blood.

From the musculoskeletal system: rarely - muscle hemorrhage.

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

Other: often - closed trauma; Infrequently - hemorrhages and bleeding after performing invasive procedures (including hematoma after the procedure, bleeding from the postoperative wound, hematoma in the area of the vascular puncture and at the site of the catheter installation), the presence of a discharge from the wound, hemorrhage in the incision area (including Hematoma in the region of the incision), bleeding during surgery.

Prevention of strokes and systemic embolism in patients with atrial fibrillation

From the immune system: infrequently - hypersensitivity (including drug hypersensitivity reactions, such as skin rash and anaphylactic reactions, allergic edema).

From the side of the nervous system: infrequently - intracranial hemorrhages, subarachnoid hemorrhage, subdural hematomas, hemorrhages in the spinal canal, spinal hematoma.

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

From the CVS: often - other types of bleeding, bruising; Infrequently - bleeding into the abdominal cavity.

On the part of the respiratory system: often - nosebleeds; Infrequently - hemoptysis; Rarely - bleeding to the respiratory system (including pulmonary alveolar bleeding, guttural and pharyngeal bleeding).

From the gastrointestinal tract: often - gastrointestinal bleeding (including vomiting with an admixture of blood and melena), rectal bleeding, bleeding from the gums; Infrequently - hemorrhoidal bleeding, the presence of unchanged blood in the stool, bleeding into the mouth; Rarely - retroperitoneal hemorrhage.

From the urinary system: often - hematuria.

On the part of the reproductive system: infrequently - intermenstrual vaginal bleeding, urogenital bleeding.

Reactions at the injection site: infrequent - bleeding at the site of injection.

Laboratory indicators: infrequently - a positive reaction in the analysis of feces for latent blood.

Other: often - closed trauma; Infrequently - traumatic bleeding, bleeding after the procedure, hemorrhage in the region of the incision.

Treatment of DVT, PE

On the part of the blood and lymphatic system: rarely - hemorrhagic anemia, hemorrhagic diathesis, spontaneous occurrence of hematomas.

From the nervous system: rarely - craniocerebral hemorrhage, hemorrhagic stroke.

From the side of the organ of vision: infrequently - hemorrhage in the conjunctiva; Rarely - bleeding in the tissue of the eyeball, hemorrhage in the retina, sclera, vitreous.

From the organs of hearing: rarely - ear bleeding.

From the CVS side: often - hematomas; Rarely - pericardial bleeding, other types of bleeding, bleeding into the abdominal cavity, hemorrhagic shock.

On the part of the respiratory system: often - nosebleeds; Infrequently - hemoptysis; Rarely - pulmonary alveolar bleeding.

From the gastrointestinal tract: often - bleeding from the gums; Infrequently - rectal bleeding, the presence of unchanged blood in the stool, hemorrhoidal bleeding, gastrointestinal bleeding, bloody vomiting; Rarely - melena, anal bleeding, bleeding from stomach and duodenal ulcers, bleeding into the oral cavity, abdominal wall bruising, Mallory-Weiss syndrome, gastric bleeding, bleeding in the small intestine.

From the skin: rarely - bruising, bleeding from the skin; Rarely - petechiae, purpura, increased tendency to bleeding, corn, bleeding from skin ulcers.

From the side of the musculoskeletal system: rarely - a hemorrhage into the muscles.

From the urinary system: often - hematuria; Rarely bleeding of the urinary system.

From the side of the reproductive system: often - hypermenorrhea; Infrequently - vaginal bleeding, metrorrhagia; Rarely - menometrorrhagia, uterine bleeding, genital bleeding, hemorrhages in the mammary gland, hematospermia, uterine bleeding after the onset of menopause.

Reactions at the site of injection and other reactions: infrequently - hematoma at the site of injection, hematoma at the site of the vascular puncture, bleeding from the wound, traumatic hematoma; Rarely - bleeding at the injection site, hematoma at the site of infusion, periorbital hematoma, vascular pseudoaneurysm, subcutaneous hematoma, hematoma during and after the procedure, hematuria after the procedure, extradural hematoma, subdural bleeding, hematoma of the kidney.

Laboratory indicators: infrequent - the presence of blood in the urine, a positive reaction in the analysis of feces for latent blood; Rarely - hidden blood, the presence of erythrocytes in the urine.

Interaction

The effect of other drugs on the pharmacokinetics of apixaban

Inhibitors of CYP3A4 and P-glycoprotein. The combination of apixaban with ketoconazole (400 mg once a day), a potent inhibitor of both the CYP3A4 isoenzyme and the P-glycoprotein, resulted in a 2-fold increase in the mean AUC of apixaban and a 1.6-fold increase in the mean Cmax. Correction of the dose 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 inhibitors of the isoenzyme CYP3A4 and P-glycoprotein.

Preparations that do not relate to potent inhibitors of the isoenzyme CYP3A4 and P-glycoprotein (eg diltiazem, naproxen, amiodarone, verapamil, quinidine), apparently, will lead to an increase in the concentration of apixaban in the blood plasma to a lesser degree. For example, diltiazem (a moderate inhibitor of the isoenzyme CYP3A4 and a weak inhibitor of P-glycoprotein) at a dose of 360 mg once a day led to an increase in the average values of AUC apixaban by 1.4 times and average values of Cmax by 1.3 times. Naproxen (P-glycoprotein inhibitor) when applied at a dose of 500 mg in healthy volunteers caused an increase in the average values of AUC and Cmax apixaban by 1.5 and 1.6 times, respectively. At the same time there was an increase in the values of the parameters of the blood coagulation system (PV, MNO and APTTV). However, there was no effect of naproxen on arachidonic acid-induced platelet aggregation, as well as clinically significant prolongation of bleeding time.

Correction of the dose of apixaban when combined with moderate inhibitors of the isoenzyme CYP3A4 and / or P-glycoprotein is not required.

Inductors of the isoenzyme CYP3A4 and P-glycoprotein. The combination of apixaban with rifampicin (a powerful inducer of the isoenzyme CYP3A4 and P-glycoprotein) led to a decrease in the average values of AUC and Cmax apixaban by approximately 54 and 42%, respectively. It seems that the combination of apixaban with other potent inducers of the isoenzyme CYP3A4 and P-glycoprotein (in particular phenytoin, carbamazepine, phenobarbital or preparations of St. John's wort) can also lead to a decrease in the concentration of apicaban in blood plasma (by approximately 50%). Correction of the dose of apixaban when combined with this group is not required for prescribing: prophylaxis of thromboembolism after arthroplasty of joints, prevention of strokes and systemic thromboembolism in non-valvular atrial fibrillation and prevention of relapses of DVT and PE, however, these agents should be combined with caution. During the application for the treatment of DVT and PE, the joint use of apixaban and powerful inducers of the isoenzyme CYP3A4 and P-glycoprotein is not recommended.

Anticoagulants, inhibitors of platelet aggregation and NSAIDs. After the combined administration of enoxaparin (once, at a dose of 40 mg) and apixaban (once, at a dose of 5 mg), the additive effect of these drugs on FXa activity was noted.

Symptoms of pharmacokinetic or pharmacodynamic interaction of apixaban with acetylsalicylic acid (at a dose of 325 mg, once a day) were not observed in healthy people.

Despite the results obtained in healthy volunteers, some sensitive patients may have a more pronounced pharmacokinetic interaction between apixaban and platelet aggregation inhibitors.

Combination of apixaban with clopidogrel (75 mg once daily) or a combination of clopidogrel (75 mg) and acetylsalicylic acid (162 mg, once a day) or prasugrel (60 mg followed by a dose of 10 mg once daily) in Phase I clinical study did not lead to an increase in bleeding time or more severe inhibition of platelet aggregation compared with the use of these antiplatelet agents in monotherapy.

The increase in the parameters of the blood coagulation system (PV, MNO and APTTV) corresponded to the effects of apixaban when used in monotherapy.

It is not recommended at the same time to use drugs that may be associated with the development of serious bleeding, such as unfractionated heparin or heparin derivatives (including low molecular weight heparins), oligosaccharides inhibiting FXa (eg fondaparinux), direct thrombin II inhibitors (eg, desandin), thrombolytic drugs, Receptor antagonists for glycoproteins IIb / IIIa, dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists and other oral anticoagulants. It should be noted that unfractionated heparin can be used in doses necessary to support the permeability of the central venous or arterial catheter.

In patients after planned endoprosthetics of the hip or knee joint co-administration of apixaban with other antiplatelet agents or antithrombotic drugs is not recommended.

There was a statistically significant increase in the risk of bleeding when using a combination of apixaban with acetylsalicylic acid or triple antithrombotic therapy (a combination of apixaban, acetylsalicylic acid and clopidogrel) in patients with acute coronary syndrome who have multiple cardiac and noncardiac co-morbidities.

With the use of atrial fibrillation, the simultaneous use of apixaban with one or two antiplatelet agents led to an increased risk of bleeding, so it is necessary to conduct both benefit-risk analysis in the appointment of such therapy and to monitor patients.

The use of the drug together with powerful inducers of CYP3A4 and P-glycoprotein (such as rifampicin, phenytoin, carbamazepine, phenobarbital and preparations of St. John's wort) can lead to a 50% decrease in the plasma concentration of the drug, so these combinations should be used with caution. It is not recommended to use apixaban jointly with powerful inducers of CYP3A4 and P-glycoprotein when apixaban is used to treat DVT and PE.

Combination with other drugs. There was no clinically significant pharmacokinetic or pharmacodynamic interaction of apixaban with atenolol or famotidine.

Combination of apixaban (10 mg dose) 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 mean values of AUC and Cmax apixaban by 15 and 18%, respectively, compared with the monotherapy regimen. The administration of apixaban (at a dose of 10 mg) with famotidine (at a dose of 40 mg) did not affect the values of AUC or Cmax apixaban.

Effect of apixaban on the pharmacokinetics of other drugs

In studies in vitro, apixaban did not inhibit the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, or CYP3A4 (inhibitory concentration (IC50)> 45 μmol / L) isozymes and at the same time slightly suppressed the activity of the CYP2C19 isoenzyme (IC50> 20 μmol / L) at a concentration significantly higher than the Cmax of the drug in blood plasma for its clinical application. Apixaban is not an inducer of the isoenzymes CYP1A2, CYP2B6, CYP3A4 / 5 in concentrations up to 20 μmol / l. In this regard, it is expected that, when combined, 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.

Dosing and Administration

Inside, regardless of food intake.

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

1. In patients after planned endoprosthetics of the hip or knee joint: 1 tab. 2.5 mg 2 times a day (the first reception 12-24 hours after surgery).

In patients undergoing hip replacement, the recommended duration of therapy is 32-38 days, the knee joint is 10-14 days.

2. In patients with atrial fibrillation. According to 1 table. 5 mg 2 times a day.

Dosage of the drug is reduced to 2.5 mg (2.5 mg tablet) 2 times a day in the presence of a combination of two or more of the following characteristics: age 80 years and older, body weight 60 kg or less, or creatinine concentration in blood plasma ≥1, 5 mg / dL (133 μmol / L).

3. Treatment of DVT, PE. 10 mg twice a day for 7 days, then 5 mg twice a day.

Duration of treatment is determined individually, taking into account the ratio of expected benefits and the 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 recurrence (ie, previous surgical intervention, trauma, immobilization period, etc.), as well as manifestations of DVT and / or PE, 3 months

4. Prevention of recurrence of DVT, PE. 2.5 mg 2 times a day after at least 6 months of treatment with DVT or PE.

Special patient groups

Patients with impaired renal function. If the renal function is mild, moderate or severe with a decrease in Cl creatinine to 15 ml / min, dose adjustment of apixaban is not required. In patients with impaired renal function of severe degree with Cl creatinine less than 15 ml / min, as well as in patients on dialysis, the use of Eliquis ® is not recommended.

Patients with impaired liver function. Caution should be exercised when taking Eliquis® with patients with mild to moderate hepatic insufficiency (class A or B according to Child-Pugh classification), with no dose adjustment required. The use of the drug in patients with severe hepatic insufficiency is not recommended.

Elderly patients. Correction of the dose of the drug in elderly patients is not required (the exception is the patients specified in clause 2 - use in atrial fibrillation).

Body mass. Correction of the dose in relation to the patient's body weight is not required (the exception is the patients specified in clause 2 - application in atrial fibrillation).

Gender. Correction of the dose of the drug depending on the sex of the patient is not required.

Race and ethnic origin. Correction of the dose of the drug depending on the race or ethnic origin of the patient is not required.

Transition from or to therapy with parenteral anticoagulants

The translation from parenteral anticoagulants to Eliquis® and vice versa can be performed at the time of the next scheduled admission of the withdrawn drug (with the next dose of the drug being withdrawn not taken).

Transition from or to warfarin or other antagonists of vitamin K. Transfer of patients with therapy with warfarin or other vitamin K antagonists to Eliquis therapy should be performed with the INR value in the patient below 2.

When transferring patients with Elqiuis® therapy to warfarin or other vitamin K antagonists, continue therapy with Eliquis® for 48 hours after taking the first dose of warfarin or other vitamin K antagonists. After 48 hours, the INR should be monitored before taking the next dose of Eliquis®. The simultaneous administration of warfarin (or another vitamin K antagonist) and Eliquis® should be continued until the INR is achieved ≥2. When reaching INR ≥2, Elicvis® should be discontinued.

Surgical and invasive procedures. Eliquis® should be discontinued at least 48 hours before a scheduled operation or an invasive procedure with an estimated average or high risk of life-threatening or clinically significant bleeding. Eliquis® should be discontinued at least 24 hours before the planned operation or invasive procedure if a low risk of bleeding is suspected or bleeding of uncritical localization is possible which can be easily controlled. In the event that procedures cannot be postponed, special care should be taken, given the increased risk of bleeding. It is also necessary to assess the ratio of bleeding risks and the timing of the operation.

With non-valvular atrial fibrillation, it usually does not require the use of "bridge therapy" within 24-48 hours after the abolition of apixaban before surgical interventions.

The therapy with apixaban after the intervention should be resumed immediately upon the achievement of adequate hemostasis.

Patients can continue taking Eliqus® during cardioversion.

With a temporary break in treatment with the drug (accidental or deliberate), the risk of thrombosis increases. Patients should be instructed about the need to avoid interruptions in drug treatment. If the anticoagulation therapy is temporarily stopped for any reason, it should be resumed as soon as possible.

Overdose

Symptoms: an overdose increases the risk of bleeding. In the framework of controlled clinical trials, apixaban was taken orally by healthy volunteers at doses up to 50 mg / day for 3 to 7 days (25 mg twice a day for 7 days or 50 mg once a day for 3 days); Clinically significant adverse effects were not observed.

Treatment: consideration should be given to the use of activated carbon. When healthy volunteers were injected with activated carbon 2 and 6 hours after taking apixaban at a dose of 20 mg, the AUC for apixaban decreased by 50 and 27%, respectively (Cmax did not change). T1 / 2 apixaban decreased from 13.4 to 5.3 and 4.9 hours, respectively. The antidote is not known. It is not expected that the use of hemodialysis in case of an overdose of apixaban will be an effective measure.

Precautionary measures

Risk of bleeding. In patients with atrial fibrillation and conditions requiring monotherapy or therapy with a combination of two antiplatelet agents, a careful assessment of the benefit / risk relationship should be conducted prior to the simultaneous use with the Eliquis® preparation.

Eliquis ® is not recommended for patients with liver disease, accompanied by disorders in the blood coagulation system and clinically significant risk of bleeding.

In patients at high risk after acute coronary syndrome with multiple cardiac and noncardiac comorbidities, there was a significant increase in the risk of bleeding with the combined use of apixaban and acetylsalicylic acid or a combination of acetylsalicylic acid and clopidogrel compared with placebo.

As with the use of other anticoagulants, careful monitoring of patients taking Eliquis® should be considered for bleeding. When developing severe bleeding, Eliquis® should be withdrawn.

With the development of hemorrhagic complications, it is necessary to cancel the treatment with the drug and perform a check for the source of bleeding. If necessary, appropriate treatment is prescribed, in particular, surgical stopping of bleeding or transfusion of fresh-frozen blood plasma. The abolition of therapy with anticoagulants, including apixaban, with active bleeding, before routine surgery or an invasive procedure can lead to an increased risk of thrombosis. Long-term cessation of therapy should be avoided and, if apyxaban therapy should be temporarily stopped, then it must be resumed as soon as possible.

Operative interventions related to hip fracture. In clinical trials, Eliquis® was not used in patients who underwent emergency surgery for a hip fracture, thus, efficacy and safety in this category of patients were not studied.

Performing spinal, epidural anesthesia or puncture 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 lead to persistent or irreversible paralysis. This risk can be further increased by using an established epidural catheter in the postoperative period or with the parallel application of other drugs that affect hemostasis. The established epidural or subarachnoidal catheters should be removed at least 5 hours before the first dose of Eliquis®. Clinical experience with apixaban in patients with an established intrathecal or epidural catheter is absent. If this situation is necessary, based on the pharmacokinetic characteristics of apixaban, an interval of 20-30 h (ie 2 T1 / 2) should be observed between the last dose of apixaban taken and the catheter removed, so at least 1 dose of apixaban should be omitted Before removal of the catheter. A similar increase in risk may be noted when performing traumatic or multiple punctures of the epidural or subarachnoid spaces. Frequent monitoring of patients for the development of manifestations of disorders of the nervous system (in particular, numbness or weakness of the lower limbs, bowel or bladder function disorder) is necessary. With the development of such violations, it is necessary to perform emergency screening and treatment. Before performing interventions on epidural or subarachnoid spaces in patients receiving anticoagulants, incl. With the purpose of prophylaxis of thromboses, it is necessary to estimate the ratio of potential benefits and risks.

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

Treatment of DVT and PE. It is not recommended to replace unfractionated heparin therapy with Eliquis® during the initiation of therapy for patients with PE with unstable hemodynamics, possible thrombolysis or pulmonary thrombectomy.

Influence on ability to drive vehicles, mechanisms. Eliquis® does not significantly affect the ability to drive vehicles and work with machinery.

Release form

When packing at the Bristol-Myers plant, Squibb Sr.L., Italy

Tablets, film-coated, 2.5 mg. For 10 tab. In a blister of PVC / PVDH film and aluminum foil. For 1, 2 or 6 blisters in a cardboard box.

For 10 tab. In a perforated blister of PVC / PVDH film and aluminum foil. For 6 or 10 blisters in a cardboard box.

Tablets, film-coated, 5 mg. By 10 or 14 tablets. In a blister of PVC / PVDH film and aluminum foil. For 2, 6 or 10 blisters for 10 tab. In a cardboard box. 4 blisters on 14 tables. In a cardboard box.

For 10 tab. In a perforated blister of PVC / PVDH film and aluminum foil. By 2, 6 or 10 perforated blisters in a cardboard bundle.

OJSC "Akrihin", Russia

Film-coated tablets, 2.5 mg. For 10 tab. In a blister of PVC / PVDH film and aluminum foil. 2 blisters in a cardboard box.

For 10 tab. In a perforated blister of PVC / PVDH film and aluminum foil.

6 perforated blisters in a cardboard bundle.

Film-coated tablets, 5 mg. For 10 tab. In a perforated blister of PVC / PVDH film and aluminum foil.

For 2 or 6 perforated blisters in a cardboard bundle.

Manufacturer

Bristol-Myers Squibb Manning Company, Puerto Rico. State Road # 3, km. 77.5, Humacao, Puerto Rico, 00791.

Name and address of the legal entity in whose name the registration certificate was issued: Bristol-Myers Squibb Company, USA. 345, Park Avenue, New York, New York, USA.

Packaging (primary, secondary), issuing quality control: Bristol-Myers Squibb Sr.L., Italy. Lokalita Fontana del Cerrazo, 03012, Anagni (FR), Italy.

Or packer (secondary packaging) that issues quality control: open joint-stock company "Chemical-Pharmaceutical Plant" Akrihin "(OJSC" Akrihin "), Russia.

The claims of consumers should be sent to the representative office of the company in the Russian Federation: Bristol-Myers Squibb LLC. 105064, Moscow

The name and address of the legal entity in whose name the registration certificate was issued: Bristol-Myers Squibb Company, USA, 345, Park Avenue, New York, New York, USA.

Conditions of supply of pharmacies

On prescription.

Storage conditions of the drug Eliquis

At a temperature no higher than 30 ° C.

Keep out of the reach of children.

The shelf life of the drug Eliquis

3 years.

Do not use beyond the expiration date printed on the package.