Indications
Prevention of venous thromboembolism in patients after elective hip or knee replacement surgery.
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Active ingredient: | |
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Dosage form: | |
Indications for use: | Heart attack prevention, Prevention of thrombosis, Stroke prevention |
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Prevention of venous thromboembolism in patients after elective hip or knee replacement surgery.
With caution: apixaban should be used with caution in patients with moderate to mild hepatic impairment (Child-Pugh class A or B); during spinal/epidural anesthesia or spinal/epidural puncture; 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, etc. posaconazole), HIV protease inhibitors (for example, ritonavir); when using apixaban with powerful inducers of the CYP3A4 isoenzyme and P-glycoprotein (in particular, rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s wort preparations).
1 film-coated tablet contains:
active substance:
apixaban 2.5 mg.
excipients:
lactose,
microcrystalline cellulose,
croscarmellose sodium,
sodium lauryl sulfate,
magnesium stearate;
Opadray II Yellow film shell (hypromellose 15 cps, lactose monohydrate, titanium dioxide, triacetin, iron oxide yellow dye).
1 film-coated tablet contains:
Active ingredient:
apixaban 2.5 mg
. excipients:
lactose,
microcrystalline cellulose,
croscarmellose sodium,
sodium lauryl sulfate,
magnesium stearate;
Opadray II Yellow film shell (hypromellose 15 cps, lactose monohydrate, titanium dioxide, triacetin, iron oxide yellow dye).
Eliquis has an antithrombotic effect.
Pharmacodynamics
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. they 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 proved by a chromogenic test using heparin ” Rotachrom.
The change in anti-FXa activity is directly proportional to the increase in the concentration of apixaban in plasma, blood, 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. The expected maximum and minimum anti-FXa activity of apixaban at steady state, when used at a dose of 2.5 mg-2 times a day, is 1.3 IU / 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 concentration in blood plasma, however, performing the Rotachrom anti-FXa activity 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
Absorption 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 3-4 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 (V85) is approximately 21 liters.
Metabolism and excretion 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, with a half-life (T1 / 2) of 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 70, 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 studies in patients with creatinine clearance
Hepatic dysfunction 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 and 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.
The sex exposure of apixaban 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 II 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 concentration in blood plasma 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.
Prevention of venous thromboembolism in patients after elective hip or knee replacement surgery.
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.
With caution: apixaban should be used with caution in patients with moderate to mild hepatic impairment (Child-Pugh class A or B); during spinal/epidural anesthesia or spinal/epidural puncture; 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, etc. posaconazole), HIV protease inhibitors (for example, ritonavir); when using apixaban with powerful inducers of the CYP3A4 isoenzyme and P-glycoprotein (in particular, rifampicin, phenytoin, carbamazepine, phenobarbital or St. John’s wort preparations).
The frequency of adverse reactions is defined as: often – ≥1/100, <1/10; infrequently – ≥1/1000, <1/100; rarely – ≥1/10000,
Prevention of venous thromboembolism in patients after elective hip or knee replacement surgery
Adverse reactions were reported 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 lesions that may be accompanied by 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.
From the blood and lymphatic system: often-anemia (including postoperative and post-hemorrhagic, accompanied by corresponding changes in the results of laboratory tests), bleeding (including hematoma, vaginal and urethral bleeding); 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: 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, AST, GGTP activity, 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.
Prevention of strokes and systemic embolism in patients with atrial fibrillation
Immune system disorders: Infrequently — hypersensitivity (including drug-induced hypersensitivity reactions such as skin rash and anaphylactic reactions, allergic edema).
From the nervous system: infrequently-intracranial hemorrhages, subarachnoid hemorrhages, subdural hematomas, hemorrhages in the spinal canal, spinal hematoma.
From the side of the organ of vision: often — hemorrhages in the eyeball tissue (including conjunctival hemorrhage).
From the cardiovascular system: often-other types of bleeding, hematomas; infrequently-bleeding in the abdominal cavity.
From the respiratory system: often-nosebleeds; infrequently-hemoptysis; rarely-bleeding in the respiratory system (including pulmonary alveolar bleeding, laryngeal 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 feces, bleeding into the oral cavity; rarely-retroperitoneal hemorrhage.
From the urinary system: often-hematuria.
From the reproductive system: infrequently-intermenstrual vaginal bleeding, urogenital bleeding.
Reactions at the injection site: infrequently – bleeding at the injection site.
Laboratory parameters: infrequently-a positive reaction when analyzing feces for hidden blood.
Other: often-closed trauma; infrequently-traumatic bleeding, bleeding after the procedure, hemorrhage in the incision area.
Effect of other drugs on the pharmacokinetics of apixaban Inhibitors of CYP3A4 and P-glycoproteinoses of apixaban with ketoconazole (at a dose of 400 mg 1 time per day), a potent inhibitor of both CYP3A4 and P-glycoprotein, resulted in increases in the mean AUC values of apixaban 2 times and the average value Withmax – 1.6 times. Dose adjustment of apixaban in combination 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 CYP3A4 isoenzyme and P-glycoprotein.
Drugs that modestly reduce the rate of apixaban elimination or inhibit the CYP3A4 isoenzyme and/or P-glycoprotein are expected to increase the concentration of apixaban in blood plasma to a lesser extent. 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 values ofcmax – by 1.3 times. Naproxen (a P-glycoprotein inhibitor), when administered at a dose of 500 mg in healthy volunteers, caused an increase in the average values of apixaban AUC andcmax 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 effect of naproxen on platelet aggregation associated with impaired arachidonic acid metabolism, and no clinically significant prolongation of bleeding time. Dose adjustment of apixaban in combination with moderate inhibitors of the CYP3A4 isoenzyme and/or P-glycoprotein is not required.
Inducers of the CYP3A4 and P-glycoprotein isoenzymes Combining apixaban with rifampicin (a potent inducer of the CYP3A4 and P-glycoprotein isoenzymes) resulted in a decrease in the mean apixaban AUC andCMAX values 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. No dose adjustment of apixaban is required when it is combined with drugs of this group, but these drugs should be combined with caution.
Anticoagulants, platelet aggregation inhibitors, and NSAIDs After co-use of enoxaparin (a single dose of 40 mg) and apixaban (a single dose of 5 mg), an additive effect of these agents on FXa activity was observed. 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) in a phase I clinical study did not lead to an increase in bleeding time, further inhibition of platelet aggregation, or an increase in blood clotting system parameters (prothrombin time, MHO, and APTT) compared to the use of these antiplatelet agents in monotherapy. However, 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. It is not recommended to use concomitantly drugs that may be associated with the development of serious bleeding, such as: unfractionated heparin or heparin derivatives (including low-molecular-weight heparins), FXa-inhibiting oligosaccharides (for example, fondaparinux), direct thrombin II inhibitors (for example, desirudin), thrombolytic drugs, glycoprotein IIb/IIIa receptor antagonists, thienopyridines (for example, clopidogrel), 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 patency of a venous or arterial catheter.
Combination with other medicinal products: no clinically significant pharmacokinetic or pharmacodynamic interaction of apixaban with atenolol or famotidine was observed. 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 values of AUC andcmaxapixaban increased by 15% and 18%, respectively, compared to the monotherapy regimen. use of apixaban (10 mg) with famotidine (40 mg) had no effect on apixaban AUC orcmax values.
Effect of apixaban on the pharmacokinetics of other medicinal products In vitro studies, apixaban did not inhibit the activity of the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4/ (inhibitory concentration (IC50) >45 µmol/L), but weak suppression of the activity of the isoenzyme CYP2C19 (IC50 >> 20 µmol/L) was found apixaban at a concentration significantly higher than the maximum concentration of the drug in blood plasma during its clinical use. 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.
Inside, 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.
In patients after elective hip or knee replacement surgery: 2.5 mg 2 times a day (the first dose 12-24 hours after surgery).
In patients who have undergone hip replacement, the recommended duration of therapy is 32-38 days, for the knee joint-10-14 days.
In patients with atrial fibrillation: 1 tablet of 5 mg 2 times a day.
Special patient groups
1. Patients with atrial fibrillation in combination with two or more of the following characteristics: age over 80 years, body weight less than 60 kg, or plasma creatinine concentration ≥1.5 mg / dl (133 mmol / L) – the recommended dose of Eliquis is reduced to 1 table 2.5 mg 2 times a day.
2. Patients with impaired renal function. In patients with mild, moderate or severe renal impairment with a decrease in creatinine clearance of up to 15 ml / min, no dose adjustment of apixaban is required (with the exception of the patients indicated in paragraph 1). In patients with severe renal impairment with a creatinine clearance of less than 15 ml/min, as well as in patients on dialysis, the use of Eliquis is not recommended.
3. Patients with impaired liver function. 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. The use of the drug in patients with severe hepatic insufficiency is not recommended.
4. Elderly patients. Dose adjustment of the drug in elderly patients is not required (except for the patients indicated in clause 1).
5. Body weight. Dose adjustment depending on the patient’s body weight is not required (except for the patients listed in clause 1).
6. Gender. No dose adjustment is required depending on the patient’s gender.
7. Race and ethnic origin. No dose adjustment is required depending on the patient’s race or ethnic origin.
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 canceled (the next dose of the drug to be canceled is not taken).
Switching from or to warfarin or other vitamin K antagonists
Patients should be transferred from warfarin or other vitamin K antagonists to Eliquis if the patient’s INR is below 2.
When transferring patients from Eliquis therapy to warfarin or other vitamin K antagonists, Eliquis therapy should be continued for 48 hours after the first dose of warfarin or other vitamin K antagonists
. Surgical and invasive procedures
Eliquis should be discontinued 2-3 days before elective surgery or an invasive procedure. If it is not possible to postpone the procedure, special care should be taken, given the increased risk of bleeding. It is also necessary to assess the ratio of the risks of bleeding and delaying the operation.
Symptoms: the risk of bleeding increases. In controlled clinical trials, apixaban was administered orally to healthy volunteers at doses up to 50 mg / day for 3-7 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.
Treatment: The use of activated carbon may be considered. The antidote of the drug is unknown.
In patients with atrial fibrillation and conditions requiring the use of monotherapy or therapy with a combination of two antiplatelet drugs, the benefit/risk ratio should be carefully evaluated before starting concomitant use with Eliquis. Eliquis is not recommended for use in patients with liver disease associated with disorders in the blood coagulation system and a clinically significant risk of bleeding.
It has been shown that high-risk patients after acute coronary syndrome, with multiple cardiac and non-cardiac comorbidities, experienced a significant increase in the risk of bleeding when apixaban and acetylsalicylic acid were co-administered or a combination of acetylsalicylic acid and clopidogrel compared to placebo.
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.
Discontinuation of anticoagulant therapy, including apixaban, with active bleeding before elective surgery or an invasive procedure may lead to an increased risk of thrombosis. Long-term discontinuation of therapy should be avoided and, if apixaban therapy needs to be temporarily discontinued, it should be resumed as soon as possible.
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 increase even more with the use of an established epidural catheter in the postoperative period or with the simultaneous use of other drugs that affect hemostasis. 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, impaired bowel or bladder function).
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 vehicles and work with other mechanisms. Eliquis does not significantly affect the ability to drive a car and work with mechanisms.
Film-coated tablets
At a temperature not exceeding 30 °C
3 years
Apixaban
By prescription
Tablets
For adults as directed by your doctor
Prevention of thrombosis, Prevention of heart attacks and strokes
Out of stock
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