Instruction for use: Apixaban

Trade name of the drug – Eliquis

The Latin name of the substance Apixaban

Apixabanum (genus. Apixabani)

Chemical name

1- (4-Methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl] -4,5-dihydropyrazolo [5,4-c] pyridine-3-carboxamide

Gross formula

C25H25N5O4

Pharmacological group of substance Apixaban

Anticoagulants

The nosological classification (ICD-10)

I82.9 Embolism and thrombosis of unspecified vein: Venous embolism; Venous thrombosis; Diseases caused by blood clots in the vessels; Acute vascular occlusion; Acute venous thrombosis; Acute thrombosis of veins; Thrombosis; Thromboembolism; Phlebothrombosis; Embolism

Z100 * CLASS XXII Surgical practice: Abdominal surgery; adenomectomy; Amputation; Coronary angioplasty; Angioplasty of the carotid arteries; Antiseptic skin treatment for wounds; Antiseptic Hand; Appendectomy; atherectomy; Balloon coronary angioplasty; Vaginal hysterectomy; The coronary bypass; Interventions in the vagina and cervix; Interventions on the bladder; Intervention in the mouth; Restoration and reconstructive surgery; Hand hygiene of medical personnel; Gynecologic surgery; Gynecological intervention; Gynecological surgery; Hypovolemic shock during operations; Disinfection of purulent wounds; Disinfection of wounds edges; Diagnostic intervention; Diagnostic procedures; Cervical Diathermocoagulation; Long-surgery; Replacing the fistula catheters; Infection in orthopedic surgery; Artificial heart valve; cystectomy; Short-term outpatient surgery; Short-term operation; Short surgical procedures; Krikotireotomiya; Blood loss during surgery; Bleeding during surgery and in the postoperative period; Kuldotsentez; laser photocoagulation; laser coagulation; retinal laser coagulation; Laparoscopy; Laparoscopy in Gynecology; CSF fistula; Small gynecological operations; Small surgical procedures; Mastectomy and subsequent plastic; mediastinotomy; Microsurgical operations on the ear; Mukogingivalnye operation; suturing; Minor surgery; neurosurgical operation; Immobilization of the eyeball in ophthalmic surgery; testectomy; pancreatectomy; Perikardektomiya; The period of rehabilitation after surgery; The period of convalescence after surgery; Percutaneous transluminal coronary angioplasty; Pleural thoracentesis; Pneumonia postoperative and posttraumatic; Preparation for surgical procedures; Preparation for surgery; Preparation of the surgeon's hands before surgery; Preparation of the colon for surgical procedures; Postoperative aspiration pneumonia in neurosurgical and thoracic surgery; Postoperative nausea; Postoperative bleeding; postoperative granuloma; postoperative shock; The early postoperative period; myocardial revascularization; Radiectomy; gastric Resection; bowel resection; uterine Resection; liver Resection; enterectomy; Resection of part of the stomach; Reocclusion of the operated vessel; Bonding tissues during surgical procedures; Removal of sutures; Condition after eye surgery; Condition after surgery; Condition after surgery in the nasal cavity; Condition after gastrectomy; Status after resection of the small intestine; Condition after tonsillectomy; Condition after removal of the duodenum; Condition after phlebectomy; Vascular surgery; Splenectomy; Sterilization of surgical instruments; Sterilization of surgical instruments; sternotomy; Dental surgery; Dental intervention in periodontal tissues; strumectomy; Tonsillectomy; Thoracic surgery; Thoracic surgery; total gastrectomy; Transdermal intravascular coronary angioplasty; Transurethral resection; Turbinektomiya; Removal of a tooth; cataract surgery; Removal of cysts; tonsillectomy; Removal of fibroids; Removing the mobile primary teeth; Removing polyps; Removing broken tooth; Removal of the uterus body; Removal of sutures; Fistula likvoroprovodyaschih ways; Frontoetmoidogaymorotomiya; Surgical infection; Surgical treatment of chronic limb ulcers; Surgery; The surgery in the anal area; The surgery on the colon; Surgical practice; The surgical procedure; Surgical interventions; Surgery on the gastrointestinal tract; Surgical procedures on the urinary tract; Surgical procedures on the urinary system; Surgical intervention of the genitourinary system; Surgical procedures on the heart; Surgical manipulation; surgery; Surgery on the veins; Surgical intervention; Vascular surgery; Surgical treatment of thrombosis; Surgery; cholecystectomy; Partial gastric resection; hysterectomy; Percutaneous transluminal coronary angioplasty; Percutaneous transluminal angioplasty; Coronary artery bypass; tooth Extirpation; Extirpation of milk teeth; pulpectomy; pulsative cardiopulmonary bypass; tooth Extraction; teeth Extraction; cataract extraction; Electrocoagulation; endourological intervention; episiotomy; Etmoidotomiya; Complications after tooth extraction

CAS code

503612-47-3

Characteristics of the substance Apixaban

Anticoagulant direct action is a selective inhibitor of the coagulation factor Xa (FXa). Intended for oral administration.

Pharmacology

Mode action - anticoagulant.

Apixaban is a powerful direct inhibitor of FXa, reversibly and selectively blocking the active center of the enzyme. To realize 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 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.

Pharmacodynamics

The mechanism of action of apixaban is the inhibition of FXa activity. As a result, apixaban changes the values of indicators of the blood coagulation system: it extends the PV, MHO and APTTV. Changes in these parameters when the drug is used in a therapeutic dose are insignificant and individual. Therefore, their use to assess the pharmacodynamic activity of apixaban is not recommended. Inhibition of the activity of FXa by apixaban has been demonstrated using a chromogenic 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 expected maximum and minimum anti-FXa activity of apixaban in the equilibrium state when administered at a dose of 2.5 mg twice 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 index in the interval between taking the 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, but the performance of the anti-FXa test of Rotachrom activity may be useful for deciding whether to continue therapy.

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. Food intake does not affect the values of AUC or Cmax. 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. Metabolic indicators 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. Binding to human blood 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, most - through the intestine. Renal excretion of apixaban is approximately 27% of its total clearance. The total clearance of apixaban is approximately 3.3 liters per hour, and 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 metabolized predominantly with the participation of the isoenzyme CYP3A4 / 5, to a lesser extent - 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 protein resistance of breast cancer.

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 persons with impaired renal function of light (Cl creatinine - from 51 ml / min to 80 ml / min), medium (Cl creatinine - from 30 ml / min to 50 ml / min) and severe degree (Cl creatinine - from 15 ml / Min to 29 ml / min), the AUC values of apixaban in the blood plasma increased by 16%, 29% and 44%, respectively, compared with those with normal Cl creatinine values. 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 Cl creatinine <15 ml / min or those on dialysis were not 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. In the study of pharmacokinetics and pharmacodynamics of apixaban in its single dose of 5 mg in patients with hepatic insufficiency of the lung and middle steppes (Child-Pugh classes A and B, respectively) and healthy volunteers have been shown that liver failure does not affect these indicators. Changes in anti-FXa activity and MHO in patients with moderate hepatic impairment 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. Correction of the dose of the drug in elderly patients is not required.

Floor. The exposure of apixaban in women was 18% higher than that of men. Correction of the dose of the drug depending on the sex of the patient is not required.

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 in studies involving patients receiving apixaban after planned hip or knee replacement are consistent with Phase I studies. Correction of the dose of the drug depending on the race or ethnic origin of the patient is not required.

Body mass. In patients with a body weight of more than 120 kg, the concentration of apicaban in blood plasma 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 figure was approximately 30% higher. Correction of the dose depending on the patient's body weight is not required.

Dependence of pharmacokinetics and pharmacodynamics. The dependence between the parameters of pharmacokinetics and pharmacodynamics (including anti-FXa activity, MHO, 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. Dependence of pharmacokinetics and pharmacodynamics of apixaban, assessed in patients who underwent planned endoprosthetics of the hip or knee joint, was consistent with the observed in healthy volunteers.

Application of the substance Apixaban

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

Contraindications

Hypersensitivity, clinically significant bleeding, liver disease, accompanied by disorders in the blood clotting system and clinically significant risk of bleeding, severe violations of the liver, impaired renal function with Cl creatinine less than 15 ml / min, as well as use in patients on dialysis, the age Up to 18 years, pregnancy, breast-feeding.

It is not recommended to simultaneously use apixaban with drugs, the effect of which may be associated with the development of serious bleeding (see "Interaction").

Restrictions

Apixaban should be used with caution in performing spinal, epidural or puncture (see "Precautions"), 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). Care should also be taken 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).

Risk of bleeding

The drug is recommended to be used with caution in 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; Recent surgery on the brain or spinal cord, as well as on the organs of vision; With severe uncontrolled arterial hypertension (see "Precautions").

In addition, caution should be exercised with the simultaneous use of apixaban with NSAIDs (including acetylsalicylic acid), because these drugs increase the risk of bleeding.

Operative interventions related to hip fracture

In clinical trials, apixaban has not been used in patients who underwent emergency surgery for a hip fracture, so its efficacy and safety in this category of patients has not been studied.

Pregnancy and breast-feeding

There is only limited information on the use of apixaban during pregnancy. The use of apixaban in pregnancy is not recommended.

There is no information on excretion of apixaban or its metabolites with human breast milk. If it is necessary to use apixaban during lactation, breastfeeding should be discontinued.

Side effects of the substance Apixaban

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 damage associated with 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.

Further under the frequency of adverse reactions is understood: often - ≥1 / 100, <1/10; Infrequently - ≥1 / 1000; <1/100, rarely - ≥1 / 10000, <1/1000.

On the part of the blood and lymphatic system: often - anemia (including postoperative and posthemorrhagic, accompanied by appropriate changes in the results of laboratory studies); 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: often - bleeding (including hematoma, vaginal and urethral bleeding); 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.

On the part of the liver and bile ducts: infrequently, an increase in the activity of transaminases (including ALT, AST), an increase in GGTP activity, pathological changes in functional liver samples, increased activity of the alkaline phosphatase in the blood, an increase in the concentration of bilirubin 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.

Interaction

The effect of other drugs on the pharmacokinetics of apixaban

Inhibitors of the isoenzyme 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 C max. Correction of the dose of apixaban with its combination with ketoconazole is not required, but apixaban should be used with caution in patients receiving systemic therapy with azole antifungals, in particular ketoconazole, or other potent inhibitors of the isoenzyme CYP3A4 and P-glycoprotein.

Drugs that moderately reduce the rate of excretion of apixaban or the inhibiting isoenzyme CYP3A4 and / or P-glycoprotein are expected to lead to an increased concentration of apicaban in the blood plasma to a lesser extent. For example, diltiazem (a moderate inhibitor of the isoenzyme CYP3A4 and a weak inhibitor of the 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 the average values of Cmax by a factor of 1.3. Naproxen (P-glycoprotein inhibitor) when applied at a dose of 500 mg in healthy volunteers caused an increase in the mean 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 coagulation system. However, against the background of such a combination, there was no effect of naproxen on platelet aggregation associated with a violation of the metabolism of arachidonic acid, and a clinically significant lengthening 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. Apparently, 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 apixaban in the blood plasma. Correction of the dose of apixaban when it is combined with the agents of this group is not required, however, combine these agents with caution.

Anticoagulants, inhibitors of platelet aggregation and NSAIDs. After the combined administration of enoxaparin (once in a dose of 40 mg) and apixaban (once in a dose of 5 mg), the additive effect of these agents 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 once a 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 a day) in phase I of the clinical study did not lead to an increase in bleeding time, further inhibition of platelet aggregation, or an increase Of the parameters of the blood clotting system (MF, MHO and APTTV) in comparison with the use of these antiaggregants in monotherapy.

However, caution should be exercised with the simultaneous use of apixaban with NSAIDs (including acetylsalicylic acid), because these drugs increase the risk of bleeding.

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 sodium fondaparinux), direct thrombin II inhibitors (eg, desandin), thrombolytic drugs , Glycoprotein IIb / IIIa 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 in doses necessary to support the patency of the venous or arterial catheter.

Combination with other drugs. There was no clinically significant pharmacokinetic or pharmacodynamic interaction of apixaban with atenolol or famotidine. 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 mean values of AUC and Cmax apixaban by 15 and 18%, respectively, compared with the monotherapy regimen. The appointment of apixaban (10 mg dose) with famotidine (40 mg dose) 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 the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 (inhibitory concentration (IC50)> 45 μmol / L), but a slight suppression of the activity of the isoenzyme CYP2C19 (IC50> 20 μmol / L ) Apixaban in a concentration significantly higher than Cmax 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 P-glycoprotein activity.

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

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), which in 10 times higher than MPDH; Clinically significant adverse effects were not observed.

Treatment: in case of an overdose, the use of activated carbon can be considered. The antidote is unknown.

Routes of administration

Inside.

Dosing and Administration. Inside, 1 tab. (2.5 mg) 2 times a day, regardless of food intake (first reception 12-24 hours after surgery).

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

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

Use in patients with impaired renal function. In patients with impaired renal function of mild, moderate or severe degree with a decrease in Cl creatinine to 15 ml / min, dose adjustment is not required.

Data on the use of the drug in patients with Cl creatinine <15 ml / min, as well as in patients on dialysis, are absent. The use of apixaban in this category of patients is not recommended.

Use in patients with impaired liver function. Care should be taken when taking apixaban in patients with mild to moderate hepatic insufficiency (Child-Pugh class A or B), with no dose adjustment required. The use of the drug in patients with severe hepatic insufficiency is not recommended.

Use in elderly patients. Correction of the dose of the drug in elderly patients is not required.

Body mass. Correction of the dose depending on the patient's body weight is not required.

Floor. 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.

Precautions for the substance Apixaban

As with the use of other anticoagulants, careful monitoring of patients taking apixaban should be considered for bleeding. With the development of severe bleeding, apixaban 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 freshly frozen plasma.

Performing spinal, epidural, or puncture in patients receiving apixaban

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 subarachnoid catheters should be removed at least 5 hours before the first dose of apixaban is administered. 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, impaired bowel or bladder function) 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.

Influence on the ability to drive a car or perform work that requires an increased speed of physical and mental reactions

Apixaban does not significantly affect the ability to drive and operate machinery.