Эликвис®

General characteristics. Structure:

Active ingredient: 2,5 mg of an apiksaban.

Excipients: lactose, cellulose microcrystallic, croscarmellose sodium, sodium lauryl sulfate, magnesium stearate.

Film cover of Opadray the II Yellow (gipromelloza of 15 cps, lactoses monohydrate, titanium dioxide, triacetin, dye ferrous oxide yellow.

Pharmacological properties:

Pharmacodynamics. The mechanism of action of an apiksaban consists in inhibition of activity of FXa. As a result of it апиксабан changes values of indicators of system of a blood coagulation: extends a prothrombin time, MHO and the activated partial tromboplastinovy time (APTT). Changes of these indicators at use of drug in a therapeutic dose of a .neznachitelna are also individual. Therefore their use for the purpose of assessment of pharmakodinamichesky activity of an apiksaban is not recommended. The inhibition apiksabany is proved to activity of FXa by chromogenic test with use of Rotachrom heparin.

Change of anti-FXa of activity in direct ratio to increase in concentration of an apiksaban in plasma, blood, at the same time the maximum values of activity are observed at achievement maximum, concentration of an apiksaban in a blood plasma. Linear dependence between concentration and anti-FXa activity of an apiksaban is registered with the broad range of therapeutic doses of drug! Changes of anti-FXa of activity at change of a dose and concentration, an apiksaban are more expressed and less variable, than blood coagulation indicators. The expected maximum and minimum anti-FXa activity of an apiksaban in an equilibrium state, at its use in a dose 2,5 mg-2-times a day, makes 1,3 ME/ml (5/95 percentiles - 0,67 ME/ml - 2,4 ME/ml) and 0,84 ME/ml (5/95 percentiles - 0,37ME/ml-1,8ME/ml), respectively, that correlates with fluctuations of this indicator in an interval between reception of doses of drug (less than by 1,6 times). Against the background of therapy apiksabany carrying out routine monitoring of its concentration in a blood plasma is not required, however execution of the test of anti-FXa of activity of Rotachrom can be useful to making decision on therapy continuation.

Action mechanism. Apiksaban represents powerful direct FXa inhibitor, reversibly and selectively the blocking active center of enzyme intended for oral administration. Implementation of antitrombotichesky effect of an apiksaban does not require availability of antithrombin III. Apiksaban inhibits free and related FXa, and also activity of prothrombinase. Apiksaban does not exert a direct direct impact on, aggregation of thrombocytes, but indirectly inhibits the aggregation of thrombocytes induced by thrombin. At the expense of inhibition of activity of FXa апиксабан prevents formation of thrombin and blood clots.

Pharmacokinetics. Absorption. Absolute bioavailability of an apiksaban reaches 50% at its use in doses to 10 mg. Apiksaban is quickly soaked up from digestive tract, its maximum concentration (Cmax) is reached during 3-4 h after oral administration. Meal "concentration time" (AUC) or Cmax of an apiksaban does not exert impact on values of indicators of the area under a curve. The pharmacokinetics of an apiksaban for doses to 10 mg has linear character. At reception of an apiksaban in doses higher than 25 mg are noted drug absorption restriction that is followed by decrease in its bioavailability. Indicators of metabolism of an apiksaban are characterized low or moderate boundaries - and intra individual variability (the corresponding values of coefficient of variation make ∼20% and ∼30%, respectively).

Distribution. Communication of an apiksaban with proteins of a blood plasma of the person makes about 87%, the volume of distribution (V85) - about 21 l.

Metabolism and removal. About 25% of the accepted dose are removed in the form of metabolites, the most part - through intestines. Renal excretion of an apiksaban makes about 27% of its general clearance.

The general clearance of an apiksaban makes about 3,3 l/hour, an elimination half-life (T1/2) - about 12 hours. O-demethylation and a hydroxylation on the 3-oxopiperidinsilt rest are the main ways of biotransformation of an apiksaban. Apiksaban is preferential metabolized with participation of an isoenzyme of CYP3A4/5, in smaller degree - isoenzymes of CYP1A2, 2S8, 2S9, 2S19 and 2J2. Not changed апиксабан is the main substance circulating in a blood plasma of the person, the active metabolites circulating in a blood-groove are absent. Besides, апиксабан also the squirrel of resistance of a breast cancer (BCRP) is substrate of transport proteins, the R-glycoprotein 70.

Renal failure. The renal failure does not exert impact on the maximum concentration of an apiksaban. However the increase in concentration of an apiksaban correlating with the degree of depression of function of kidneys estimated on values of clearance of creatinine was noted. At persons with a renal failure easy (clearance of creatinine - from 51 ml/min. to 80 ml/min.), average (clearance of creatinine - from 30 ml/min. to 50 ml/min.) and heavy degree (clearance of creatinine - from 15 ml/min. to 29 ml/min.), AUC values of an apiksaban increased in a blood plasma for 16%, 29% and 44%, respectively, in comparison with the persons which had normal values of clearance of creatinine. At the same time the renal failure did not exert visible effect on interrelation between concentration of an apiksaban in a blood plasma and its anti-FXa activity. Researches of an apiksaban at patients with clearance of creatinine <15 ml/min. or being on dialysis were not conducted.

Abnormal liver function. Researches of an apiksaban at a heavy liver failure and active pathology of gepatobiliarny system were not conducted.

In a research of pharmacokinetics and a pharmacodynamics of an apiksaban at its single dose in a dose of 5 mg at patients with a liver failure of easy and average degree of manifestation (classes A and B on Chayld-Pyyu, respectively) and healthy volunteers it was shown that the liver failure does not exert impact on these indicators. Changes of anti-FXa of activity and MHO at patients to a liver failure of moderate severity and healthy volunteers were comparable.

Use for patients of advanced age. At patients of advanced age (65 years are more senior) higher values of concentration of drug in a blood plasma, than at younger patients were noted: average AUC value was about 32% higher. Dose adjustment of drug is not required from patients of advanced age.

Floor. Exposure of an apiksaban at women was 18% higher, than at men. Dose adjustment of drug depending on a sex of the patient is not required.

Race and ethnic origin. The results received within the phase researches I testify to lack of significant distinctions of pharmacokinetics of an apiksaban between representatives of Caucasian, Mongoloid and negroid races. Results of the analyses of pharmacokinetics in various populations made within the researches including the patients receiving апиксабан after planned endoprosthesis replacement of a hip or knee joint correspond to results of researches of a phase. Dose adjustment of drug depending on race or an ethnic origin of the patient is not required.

Body weight. At patients with body weight more than 120 kg concentration of an apiksaban in a blood plasma was about 30% lower, than at patients with a body weight from 65 kg to 85 kg; at patients with body weight less than 50 kg this indicator was about 30% higher. Dose adjustment depending on the body weight of the patient is not required.

Dependence of parameters of pharmacokinetics and pharmacodynamics. Dependence between parameters of pharmacokinetics and a pharmacodynamics (including anti-FXa of activity, MHO, a prothrombin time, AChTV) an apiksabana and an egokontsentration in a blood plasma was studied for the broad range of doses of drug (from 0,5 mg to 50 mg). It was shown that dependence between concentration of an apiksaban and activity of FXa is in the best way described with use of linear model. The dependence of parameters of pharmacokinetics and a pharmacodynamics of an apiksaban estimated at the patients who transferred planned endoprosthesis replacement of a hip or knee joint corresponded to that, observed at healthy volunteers.

Indications to use:

Prevention of a venous thromboembolism at patients after planned endoprosthesis replacement of a hip or knee joint.

Route of administration and doses:

Inside on 1 tablet (2,5 mg) 2 times a day irrespective of meal (the first reception in 12-24 h after an operative measure).

At the patients who transferred endoprosthesis replacement of a hip joint, the recommended duration of therapy makes from 32 to 38 days, a knee joint - from 10 to 14 days. In case of the admission of reception drug should be accepted as soon as possible, and further to continue reception 2 times a day according to the initial scheme. Use for patients with a renal failure. With a renal failure of easy, average or heavy degree with decrease in clearance of creatinine to 15 ml/min. of dose adjustment of drug it is not required from patients.

Data on use of drug for the patients having clearance of creatinine <15 ml/min., and also at patients which are on dialysis no. Use of the drug Elikvis® for this category of patients is not recommended.

Use for patients with an abnormal liver function. It is necessary to be careful at administration of drug of Elikvis® by patients with a liver failure easy and moderate severity (a class A or B on Chayld-Pyyu), at the same time is not required to dose adjustment. Use of drug for patients with a heavy liver failure is not recommended.

Use for elderly patients. Dose adjustment of drug is not required from patients of advanced age.

Body weight. Dose adjustment depending on the body weight of the patient is not required.

Dose adjustment of drug depending on a sex of the patient is not required.

Race and ethnic origin. Dose adjustment of drug depending on race or an ethnic origin of the patient is not required.

Features of use:

Use at pregnancy and during breastfeeding. Use at pregnancy. There are only limited data on use of the drug Elikvis® during pregnancy. Use of an apiksaban at pregnancy is not recommended.

Use during breastfeeding. There are no introductions about removal of an apiksaban or its metabolites with breast milk at the person. In need of use of the drug Elikvis® in the period of a lactation breastfeeding should be stopped.

As well as at use of other anticoagulants, careful observation of the patients accepting Elikvis® regarding development of bleedings is necessary. At development of heavy bleedings administration of drug of Elikvis® should be cancelled.

At development of hemorrhagic complications it is necessary to cancel treatment by drug and to execute inspection regarding identification of a bleeding point. If necessary appoint the corresponding treatment, in particular, a surgical stop of bleeding or a transfusion of a freshly frozen blood plasma.

Performance спиналыюй, epidural anesthesia or punctures at the patients receiving Elikvis®. When performing spinal or epidural anesthesia or a diagnostic puncture of these areas the patients receiving antitrombotichesky means for the purpose of prevention of a thromboembolism have a risk of development of epidural or spinal hematomas which, in turn, can be the reason of persistent or irreversible paralyzes. This risk can increase even more when using of the established epidural catheter in the postoperative period or at parallel use of other medicines influencing a hemostasis. The established epidural or subarachnoidal catheters have to be removed at least in 5 hours prior to a vvedeniyapervy dose of the drug Elikvis®. Similar increase in risk can be noted when performing traumatic or repeated punctures of epidural or subarachnoidal spaces. Frequent monitoring of patients regarding development of manifestations of dysfunctions of a nervous system is necessary (in particulars/numbness or weaknesses of the lower extremities, dysfunctions of intestines or a bladder). At development of such disturbances performance of the emergency inspection and treatment is necessary. Before performance of interventions on epidural or subarachnoid spaces at the patients receiving anticoagulants including for the purpose of prevention of thromboses, assessment of a ratio of potential advantage and risks is necessary.

Influence on ability to driving of motor transport and control of mechanisms. Эликвис® has no significant effect on ability to driving and work with mechanisms.

Side effects:

Undesirable reactions were noted at 11% of the patients receiving апиксабан in a dose of-2,5 mg 2 times a day. As well as at use of other anticoagulants, bleeding can arise at patients with risk factors, such as, the organic lesion connected with bleeding. Anemia, bleeding, hematomas, nausea were the most frequent side effects. The undesirable reactions which developed at the patients who transferred an orthopedic operative measure against the background of therapy apiksabany are given below.

Further as the frequency of side reactions it is understood: often - ≥1/100, <1/10, infrequently - ≥1/1000, <1/100, it is rare-> 1/10000, <1/1000.

From blood and lymphatic system: often - anemia (including postoperative and posthemorrhagic, followed by corresponding changes of results of laboratory researches); infrequently - thrombocytopenia (including decrease in quantity of thrombocytes).

From immune system: seldom - hypersensitivity.

From an organ of sight: seldom - hemorrhages in eyeglobe fabric (including hemorrhage in a conjunctiva).

From cardiovascular system: often - bleeding (including a hematoma, vaginal and urethral bleedings); infrequently - arterial hypotension (including hypotension during the procedure).

From respiratory system: infrequently - nasal bleeding; seldom - a pneumorrhagia.

From digestive tract: often - nausea; infrequently - gastrointestinal bleeding (including vomiting with impurity of blood and a melena), availability of not changed blood in Calais; seldom - rectal bleeding, an odontorrhagia.

From a liver and biliary tract: infrequently - increase in activity of transaminases (including increase in activity of alaninaminotranspherase), increase in activity of aspartate aminotransferase, gamma глутамилтранспептидазы, pathological changes of functional trials of a liver, increase in activity of an alkaline phosphatase in blood, increase in concentration of bilirubin in blood.

From a musculoskeletal system: seldom - muscular hemorrhage.

From an urinary system: infrequently - a hamaturia (including corresponding changes of results of laboratory researches).

Others: often - the closed injury; infrequently - hemorrhages and bleeding after implementation of invasive procedures (including a hematoma after the procedure, bleeding from a postoperative wound, a hematoma in the field of a puncture of a vessel and in a catheter installation site), existence separated from a wound, hemorrhage in the field of a section (including a hematoma in the field of a section), bleeding during an operative measure.

Interaction with other medicines:

Influence of other drugs on pharmacokinetics of an apiksaban Inhibitors of an isoenzyme CYP3A4 and R-glycoprotein. The combination of an apiksaban with ketokonazoly (in a dose of 400 mg, 1 times a day), the being powerful inhibitor of both CYP3A4 isoenzyme, and the R-glycoprotein, led to increase in average AUC value of an apiksaban twice and average Cmax value - by 1,6 times. Dose adjustment of an apiksaban at its combination with ketokonazoly is not required, however апиксабан it has to be applied with care at the patients receiving system therapy by azolovy antifungal means, in particular ketokonazoly or other powerful inhibitors of an isoenzyme CYP3A4 and R-glycoprotein.

The drugs in moderate degree reducing the speed of removal of an apiksaban or inhibiting an isoenzyme CYP3A4 and/or the R-glycoprotein, as expected, will lead to increase in concentration of an apiksaban in a blood plasma to a lesser extent. For example, diltiazem (moderate inhibitor of an isoenzyme CYP3A4 and weak inhibitor of the R-glycoprotein) in a dose of 360 mg of 1 times a day, led to increase in average AUC values of an apiksaban by 1,4 times and average Cmax values - by 1,3 times. Naproxenum (R-glycoprotein inhibitor) at use in a dose of 500 mg caused increase in average AUC and Cmax values of an apiksaban in 1,5 and 1,6 times in healthy volunteers, respectively. At the same time increase in values of indicators of coagulant system of blood was noted. However against the background of such combination influence of Naproxenum on the aggregation of thrombocytes connected with disturbance of metabolism of arachidonic acid, and clinically significant lengthening of a bleeding time was not observed.

Dose adjustment of an apiksaban at a combination with moderate inhibitors of an isoenzyme CYP3A4 and/or R-glycoprotein is not required.

Inductors of an isoenzyme CYP3A4 and R-glycoprotein. The combination of an apiksaban to rifampicin (the powerful inductor of an isoenzyme CYP3A4 and R-glycoprotein) led to decrease in average AUC and Cmax values of an apiksaban approximately by 54% and 42%, respectively. Apparently, the combination of an apiksaban to other powerful inductors of an isoenzyme CYP3A4 and the R-glycoprotein (in particular, Phenytoinum, carbamazepine, phenobarbital or drugs of the St. John's Wort which is made a hole) can also lead to decrease in concentration of an apiksaban in a blood plasma. Dose adjustment of an apiksaban at its combination with means of this group is not required, however it is necessary to combine these means with care.

Anticoagulants, inhibitors of aggregation of thrombocytes and NPVP. After joint introduction of an enoksaparin (once, in a dose of 40 mg) and an apiksabana (once, in a dose of 5 mg) the additive effect of these funds for activity of FXa was noted.

Signs of pharmacokinetic or pharmakodinamichesky interaction of an apiksaban with acetylsalicylic acid (in a dose of 325 mg, 1 times a day) at healthy people were not noted.

The combination of an apiksaban with klopidogrely (in a dose of 75 mg, 1 times a day) or a combination of a klopidogrel (75 mg) and acetylsalicylic acid (162 mg, 1 time a day) in the I phase of clinical trial did not lead to increase in a bleeding time, further oppression of aggregation of thrombocytes or increase in indicators of system of a blood coagulation (a prothrombin time, MHO and AChTV) in comparison with use of these antiagregant in monotherapy.

However it is necessary to be careful at simultaneous use of an apiksaban with NPVP (including, with acetylsalicylic acid) because these drugs increase risk of development of bleedings.

It is not recommended to use at the same time drugs which effect can be connected with development of serious bleedings, such as: unfractionated heparin or derivatives of heparin (including low-molecular heparins), the oligosaccharides inhibiting FXa (for example, фондапаринукс), direct inhibitors of thrombin II (for example, дезирудин), thrombolytic medicines, antagonists of receptors to IIb/IIIa glycoproteins, thienopyridines (for example, klopidogret), Dipiridamolum, a dextran, Sulfinpyrazonum, antagonists of vitamin K and other anticoagulants for intake. It should be noted that it is possible to apply unfractionated heparin in the doses necessary for support of passability of a venous or arterial catheter.

Combination with other medicines. Clinically significant pharmacokinetic or pharmakodinamichesky interaction of an apiksaban with atenololy or famotidine was not revealed. The combination of an apiksaban (in a dose of 10 mg) with atenololy (in a dose of 100 mg) did not lead to development of clinically significant changes of parameters of pharmacokinetics of an apiksaban, however it was followed by decrease in average AUC and Cmax values of an apiksaban by 15% and 18%, respectively, in comparison with the monotherapy mode. Purpose of an apiksaban (in a dose of 10 mg) with famotidine (in a dose of 40 mg) did not exert impact on, AUC or Cmax values of an apiksaban.

Influence of an apiksaban on pharmacokinetics of other medicines. In the researches in vitro апиксабан did not inhibit activity of isoenzymes of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4/(the inhibiting concentration (IC50)> of 45 µmol/l), however weak suppression of activity of an isoenzyme of CYP2C19 (IC50> of 20 µmol/l) apiksabany in the concentration considerably exceeding the maximum concentration of drug in a blood plasma at its clinical use was revealed. Apiksaban is not the inductor of isoenzymes CYP1A2, CYP2B6, CYP3A4/5 in concentration to 20 µmol/l. In this regard it is expected that at combined use it will not exert impact on clearance of the drugs which are metabolized these isoenzymes. Besides, апиксабан does not inhibit activity of the R-glycoprotein in significant degree.

In researches at healthy volunteers, апиксабан did not change pharmacokinetics of digoxin, Naproxenum or atenolol in significant degree.

Contraindications:

Hypersensitivity to any component of drug, clinically significant bleeding, the liver disease which is followed by disturbances in system of a blood coagulation and clinically significant risk of development of bleedings, heavy abnormal liver functions, a renal failure with clearance of creatinine less than 15 ml/min., and also use for the patients who are on dialysis, age up to 18 years, pregnancy, breastfeeding. It is not recommended to apply at the same time апиксабан with drugs which effect can be connected with development of serious bleedings (see the section "Interaction with Other Medicines").

With care. Apiksaban has to be applied with care when performing spinal, epidural anesthesia or punctures (see the section "Special Instructions"), and also at the patients receiving system therapy by powerful inhibitors of an isoenzyme CYP3A4 and R-glycoprotein, such as azolovy antifungal means (in particular кетоконазол, итраконазол, вориконазол and позаконазол), HIV protease inhibitors (for example, ритонавир). Also, it is necessary to be careful at use of an apiksaban with powerful inductors of an isoenzyme CYP3A4 and R-glycoprotein (in particular, rifampicin, Phenytoinum, carbamazepine, phenobarbital or drugs of the St. John's Wort which is made a hole).

Risk of development of bleedings. Drug is recommended to be used with care at the states which are characterized by the increased risk of bleedings: the inborn or acquired disturbances of coagulability of blood; aggravations of a peptic ulcer of digestive tract; bacterial endocarditis; thrombocytopenia; trombotsitopatiya; a hemorrhagic stroke, in the anamnesis; recently postponed operative measure on a head or spinal cord, and also on organs of sight; at heavy uncontrollable arterial hypertension (see the section "Special Instructions").

Besides, it is necessary to be careful at simultaneous use of an apiksaban with non-steroidal anti-inflammatory drugs (NPVP), (including, with acetylsalicylic acid) because these drugs increase risk of development of bleedings.

The operative measures tied with perepomy hip necks. Within clinical trials of Elikvis® it was not used at the patients who transferred urgent operative measures concerning a hip neck fracture therefore its efficiency and safety at this category of patients was not studied.

Overdose:

The antidote is not known. At overdose the risk of bleedings increases. Within controlled clinical trials апиксабан was accepted пероралыю by healthy volunteers in doses to 50 mg/days within from 3 to 7 days (25 mg, 2 times a day, within 7 days or 50 mg, 1 time a day, within 3 days) that is 10 times higher than the maximum recommended dose for the person; clinically significant undesirable effects at the same time were not noted.

In case of overdose of this drug it is possible to consider a question of use of absorbent carbon.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children! A period of validity - 3 years. Not to use upon termination of a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets are film coated, 2,5 mg. On 10 tablets in the blister from film PVH/PVDH. On 1,2 or 6 blisters together with the application instruction in a cardboard pack. On 10 tablets in the perforated blister from film PVH/PVDH. On 6 or 10 blisters together with the application instruction in a cardboard pack.