Description
Latin name
Eliquis
Release form
Film-coated tablets.
Packing
60 tablets.
Pharmacological action of
The mechanism of action of apixaban is the inhibition of FXa activity. As a result of this, apixaban changes the values of the indicators of the blood coagulation system:
lengthens the prothrombin time, MHO and activated partial thromboplastin time (APTT). Changes in these parameters when using the drug in a therapeutic dose are insignificant and individual. Therefore, their use in order to assess the pharmacodynamic activity of apixaban is not recommended.
Inhibition of FXa activity by apixaban was proved using a chromogenic test using Rotachrom heparin. Change in anti-FXa activity is directly proportional to an increase in the concentration of apixaban in plasma, blood, while the maximum activity values are observed when the maximum concentration of apixaban in the 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 dose and concentration, apixaban are more pronounced and less variable than blood coagulation. The expected maximum and minimum anti-FXa activity of apixaban in equilibrium, when applied at a dose of 2.5 mg-2 times a day, is 1.3 IU / ml (5/95 percentile – 0.67 IU / ml – 2 , 4 IU / ml) and 0.84 IU / ml (5/95 percentile -0.37 IU / ml – 1.8 IU / ml), respectively, which correlates with the fluctuations of this indicator in the interval between doses of the drug (less than 1.6 times). Against the background of apixaban therapy, routine monitoring of its concentration in blood plasma is not required, 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 an enzyme for oral use. To implement the antithrombotic effect of apixaban, the presence of antithrombin III is not required. Apixaban inhibits free and bound FXa, as well as prothrombinase activity. Apixaban does not have a direct direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting the activity of FXa, apixaban prevents the formation of thrombin and blood clots.
Indications
prophylaxis of venous thromboembolism in patients after planned hip or knee arthroplasty
prophylaxis of strokes, systemic thromboembolism and reduction of mortality in patients with atrial fibrillation. The exception is patients with severe to moderate mitral stenosis or artificial heart valves.
Contraindications
hypersensitivity to any component of the drug Elikvis
clinically significant bleeding
severe impaired liver function
impaired renal function with Cl creatinine less than 15 ml / min, as well as use in patients undergoing
dialysis pregnancy 18 srd years.
It is not recommended to simultaneously use apixaban with drugs whose action may be associated with the development of serious bleeding.
Caution: Apixaban should be used with caution in patients with moderate to mild hepatic impairment (Child-Pugh Class A or B) undergoing spinal / epidural anesthesia or spinal / epidural puncture 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 (for example ritonavir) with apixaban with potent inducers of isoenzyme P4 and isoenzyme 3 in particular rifampicin, phenytoin, carbamazepine, phenobarbital or perforated hypericum preparations).
Use during pregnancy and lactation
There is only limited information on the use of Elikvis during pregnancy. The use of apixaban during pregnancy is not recommended.
There is no information on the excretion of apixaban or its metabolites with human milk. If it is necessary to use the drug Elikvis during lactation, breastfeeding should be discontinued.
Composition
1 film-coated tablet contains:
active substance:
apixaban 2.5 mg.
excipients:
lactose,
microcrystalline cellulose,
croscarmellose sodium,
sodium lauryl sulfate,
magnesium stearate
film coat Opadry II Yellow (hypromellose 15 cps, lactose monohydrate, lactose monohydroxide, lactose monoxide)
Dosage and administration
Inside, regardless of food intake.
If you miss a dose, you should take the drug as soon as possible, and continue to take it 2 times a day in accordance with the original scheme.
In patients after planned endoprosthetics of the hip or knee joint: 1 tab. 2.5 mg 2 times a day (first dose 12-24 hours after surgery).
In patients having undergone hip replacement, the recommended duration of therapy is 32 38 days, of the knee – 10-14 days.
In patients with atrial fibrillation: 1 tab. 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 μmol / L) – the recommended dose of the drug Elikvis is reduced to 1 table. 2.5 mg 2 times a day.
2. Patients with impaired renal function. In case of impaired renal function of mild, moderate or severe degree with a decrease in Cl creatinine to 15 ml / min, dose adjustment of apixaban is not required (the exception is the patients indicated in paragraph 1). In patients with severe renal impairment with Cl creatinine less than 15 ml / min, as well as in patients undergoing dialysis, the use of Elikvis is not recommended.
3. Patients with impaired liver function. Caution should be exercised when taking Elikvis in patients with mild to moderate hepatic insufficiency (class A or B according to the Child-Pugh classification), with no dose adjustment required. The use of the drug in patients with severe hepatic insufficiency is not recommended.
4. Elderly patients. Correction of the dose of the drug in elderly patients is not required (the exception is the patients indicated in paragraph 1).
5. Body weight. Dose adjustment depending on the patient s body weight is not required (the exception is the patients specified in paragraph 1).
6. Paul No dose adjustment depending on the patient s gender is required.
7. Race and ethnicity. Correction of the dose of the drug depending on the race or ethnic origin of the patient is not required.
Switching from or to parenteral anticoagulant therapy
Switching from parenteral anticoagulants to Elikvis and vice versa can be done at the time of the next scheduled administration of the drug being canceled (the next dose of the drug being canceled is not taken).
Switching from or to warfarin or other vitamin K antagonists
Transfer patients with warfarin therapy or other vitamin K antagonists to therapy with Elikvis should be performed with an INR value of less than 2 in the patient.
When transferring patients with therapy with Elikvis to warfarin or other vitamin K antagonists, continue therapy with Elikvis for 48 hours after taking the first dose of warfarin or other vitamin K antagonists.
Surgical and invasive procedures
Elikvis should be canceled 2-3 days before planned surgery or invasive procedure. In case it is impossible to postpone the procedure, special care should be taken, given the increased risk of bleeding. You should also evaluate the ratio of the risks of bleeding and the delay of surgery.
Side effects
The frequency of adverse reactions is understood as: often – 1/100,
Prevention of venous thromboembolism in patients after planned joint replacement of the hip or knee joint
Adverse reactions were observed in 11% of patients treated with apixaban 2 once a day. As with other anticoagulants, bleeding can 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, and nausea. Adverse reactions developed in patients undergoing orthopedic surgery, on the background of apixaban therapy are presented below.
On the part of the blood and lymphatic system: often – anemia (including postoperative and posthemorrhagic, accompanied by corresponding changes in laboratory results), bleeding (including hematoma, vaginal and urethral bleeding) infrequently – thrombocytopenia (including including a decrease in platelet count).
On the part of the immune system: rarely – hypersensitivity.
From the side of the organ of vision: rarely – hemorrhage in the tissue of the eyeball (including hemorrhage in the conjunctiva).
From the CCC side: 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 mixed with blood and melena), the presence of unchanged blood in the feces is rare – rectal bleeding, bleeding from the gums.
From the liver and biliary tract: infrequently – increased activity of transaminases, incl. increased activity of ALT, AST, GGTP, pathological changes in functional liver samples, increased activity of 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 tests).
Other: often – closed trauma infrequently – hemorrhages and bleeding after performing invasive procedures (including hematoma after the procedure, bleeding from a postoperative wound, a hematoma in the area of the puncture of the vessel and at the place of installation of the catheter), 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
From the immune system: infrequently – hypersensitivity (including drug hypersensitivity reactions such as skin rash and anaphylactic reactions, allergic edema).
From the nervous system: infrequently – intracranial hemorrhage, subarachnoid hemorrhage, subdural hematoma, hemorrhage 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 CCC: often – other types of bleeding, hematomas infrequently – bleeding in the abdominal cavity.
From the respiratory system: often – nosebleeds infrequently – hemoptysis rarely – bleeding into the organs of the respiratory system (including pulmonary alveolar bleeding, laryngeal and pharyngeal bleeding).
From the gastrointestinal tract: often – gastrointestinal bleeding (including vomiting mixed with blood and melena), rectal bleeding, bleeding from the gums infrequently – hemorrhoidal bleeding, the presence of unchanged blood in the feces, bleeding in 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 indicators: infrequently – a positive reaction in the analysis of feces for occult blood.
Other: often – closed trauma infrequently – traumatic bleeding, bleeding after the procedure, hemorrhage in the incision area.
Drug Interaction
Effect of Other Drugs on the Pharmacokinetics of Apixaban Isoenzyme Inhibitors CYP3A4 and P-Glycoprotein
Combination of apixaban with ketoconazole (400 mg, once daily), which is potent and CYP raising the mean AUC of apixaban 2-fold and the mean Cmax – 1.6-fold. No dose adjustment of apixaban when combined with ketoconazole is required, however, apixaban should be used with caution in patients receiving systemic therapy with azole antifungal agents, in particular ketoconazole, or other potent CYP3A4 isoenzyme inhibitors and P-glycoproteins.
Drugs that moderately reduce the rate of apixaban excretion or inhibit the CYP3A4 isoenzyme and / or P-glycoprotein are expected to result in a lower plasma apixaban concentration. For example, diltiazem (a moderate CYP3A4 isoenzyme inhibitor and a weak P-glycoprotein inhibitor) at a dose of 360 mg once daily resulted in a 1.4-fold increase in the mean AUC of apixaban and a 1.3-fold mean Cmax. Naproxen (a P-glycoprotein inhibitor), when administered at a dose of 500 mg in healthy volunteers, increased the mean AUC and Cmax of apixaban 1.5 and 1.6 times, respectively. At the same time, there was an increase in the values of the coagulation system. However, no effect of naproxen on platelet aggregation was observed against such a combination, associated with impaired arachidonic acid metabolism, and clinically significant prolongation of bleeding time.
No dose adjustment of apixaban when combined with moderate CYP3A4 isoenzyme inhibitors and / or P-glycoprotein is required.
CYP3A4 and P-glycoprotein isoenzyme inducers
Combination of apixaban with rifampicin (a potent inducer of CYP3A4 and P-glycoprotein isoenzyme) resulted in a decrease in the mean AUC and Cmax of apixaban by approximately 54% and 42%, respectively. The combination of apixaban with other potent inducers of the CYP3A4 isoenzyme and P-glycoprotein (in particular, phenytoin, carbamazepine, phenobarbital, or perforated periwort drugs) may also appear to reduce the concentration of apixababan in plasma. The dose adjustment of apixaban when combined with the agents of this group is not required, however, they should be combined with caution.
Anticoagulants, platelet aggregation inhibitors and NSAIDs
Following the co-administration of enoxaparin (40 mg once) and apixaban (5 mg once), the additive effect of these agents on FXa activity was observed.
There were no signs of pharmacokinetic or pharmacodynamic interaction of apixaban with acetylsalicylic acid (325 mg, once daily).
Combining apixaban with clopidogrel (75 mg, once daily) or a combination of clopidogrel (75 mg) and acetylsalicylic acid (162 mg, once daily) in phase I of the clinical study did not lead to an increase in bleeding time, further inhibition of platelet aggregation or increase in blood coagulation (prothrombin time, MHO, and APTV) compared with the use of these antiplatelet agents in monotherapy.
However, caution should be exercised when co-administering apixaban with NSAIDs (including acetylsalicylic acid), since these drugs increase the risk of bleeding.
It is not recommended to use concurrently drugs that may be associated with the development of serious bleeding, such as unfractionated heparin or heparin derivatives (including low molecular weight heparins), oligosaccharides, FXa inhibitors (eg fondaparinux), direct II inhibitors, eg , thrombolytic drugs, IIb / IIIa glycoprotein receptor antagonists, thienopyridines (eg, clopidogrel), dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists, and other anticoagulants for oral administration. It should be noted that unfractionated heparin can be used at the doses required to support the patency of a venous or arterial catheter.
Combination with other drugs
No clinically relevant pharmacokinetic or pharmacodynamic interaction of apixaban with atenolol or famotidine has been identified. The combination of apixaban (10 mg dose) with atenolol (100 mg dose) did not lead to the development of clinically relevant changes in the pharmacokinetics of apixaban, but was accompanied by a 15% and 18% decrease in the mean AUC and Cmax of apixaban, respectively, compared with the regimen. monotherapy. The administration of apixaban (10 mg dose) with famotidine (40 mg dose) did not affect the AUC or Cmax of apixaban.
Effect of apixaban on the pharmacokinetics of other drugs
In vitro studies, apixaban did not inhibit the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 / isoenzymes. activity of CYP2C19 isoenzyme (IC50> 20 μmol / l) by apixaban at a concentration significantly exceeding the maximum concentration of the drug in blood plasma when used clinically. Apixaban is not an inducer of CYP1A2, CYP2B6, CYP3A4 / 5 isoenzymes at concentrations up to 20 μmol / 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 P-glycoprotein activity.
In studies in healthy volunteers, apixaban did not significantly alter the pharmacokinetics of digoxin, naproxen, or atenolol.
Overdose
Symptoms: Increased risk of bleeding. In controlled clinical trials, apixaban was taken orally by healthy volunteers at doses up to 50 mg / day for 3 7 days (25 mg, 2 times daily for 7 days or 50 mg, 1 time for 3 days) for clinically relevant patients. there were no undesirable effects.
Treatment: Activated carbon can be considered. The antidote of the drug is unknown.
Storage conditions
At a temperature not exceeding 30 ° C.
The Expiration of
is 3 years.
Deystvuyuschee substances
Apyksaban
Dosage form
dosage form
tablets
