Elikvis - instructions for use, reviews, analogs and formulations (2.5 mg and 5 mg tablets) anticoagulant drugs for the treatment and prevention of thrombosis, embolism, thromboembolism in adults, children and pregnancy. Composition

In this article, you can read the instructions for using the drug Eliwis. There are reviews of visitors to the site - consumers of this medication, as well as opinions of doctors of specialists on the use of Elikvis in their practice. A big request is to actively add their feedback on the drug: the medicine helped or did not help get rid of the disease, which were observed complications and side effects, possibly not declared by the manufacturer in the annotation. Analogues of Elikvis in the presence of existing structural analogs. Use to treat thrombosis, embolism, thromboembolism in adults, children, as well as during pregnancy and lactation. Composition of the preparation.

Eliwis - direct anticoagulant, selective inhibitor of the coagulation factor 10a (F10a). Apixaban (the active substance of the drug Eliquis) is a powerful direct inhibitor of F10a, reversibly and selectively blocking the active center of the enzyme. The drug is intended for oral administration. To realize the antithrombotic activity of apixaban, no antithrombin 3 is required. Apixaban inhibits free and bound F10a, 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 F10a, apixaban prevents the formation of thrombin and thrombi. As a result of the suppression of F10a, the values ​​of the indices of the blood clotting system change: prothrombin time elapses, APTT and the INR increases. Changes in these parameters when the drug is used in a therapeutic dose are insignificant and highly variable. Therefore, their use to assess the pharmacodynamic activity of apixaban is not recommended.

The inhibition by apixaban of the activity of F10a has been demonstrated by a chromogenic test using Rotachrom heparin. The change in anti-F10a 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 the maximum concentration of apixaban in the blood plasma is reached. The linear relationship between the concentration and anti-F10a activity of apixaban is recorded in a wide range of therapeutic doses of the drug. Changes in anti-F10a activity with dose changes and apixaban concentrations are more pronounced and less variable than blood coagulation.

On the background of apixaban therapy, routine monitoring of its anticoagulant effect is not required, but the performance of a calibrated quantitative test of anti-F10a activity may be useful in situations where information about the presence of apixaban in the blood may be useful for making a decision about continuing therapy. In comparison with warfarin, amid the use of apixaban, there are fewer bleedings, including intracranial hemorrhage.

Composition

Apixaban + excipients.

Pharmacokinetics

With apixaban in doses up to 10 mg, its absolute bioavailability reaches 50%. 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 apixaban. The pharmacokinetics of apixaban for doses up to 10 mg is linear. When taking apixaban in doses above 25 mg, there is a restriction of absorption of the drug, which is accompanied by a decrease in its bioavailability. The metabolites of apixaban are characterized by low or moderate inter- and intra-individual variability (the corresponding values ​​of the coefficient of variation are approximately 20% and 30%, respectively). The binding of apixaban to human plasma proteins is approximately 87%, Vss is approximately 21 liters. Approximately 25% of the dose taken is excreted as metabolites. The main way of excretion is through the intestine. Renal excretion of apixaban is approximately 27% of its total clearance. O-demethylation and hydroxylation of the 3-oxo-piperidinyl residue are the main pathways of the biotransformation of apixaban. Apixaban is predominantly metabolized with the participation of the CYP3A4 / 5 isoenzyme, to a lesser extent - the isoenzymes CYP1A2, 2C8, 2C9, 2C19 and 2J2.Unchanged apixaban is the main substance circulating in human blood plasma, there are no active metabolites circulating in the bloodstream. In addition, apixaban is a substrate for transport proteins, P-glycoprotein and breast cancer resistance protein (BCRP).

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

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

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.

Indications

• prevention of venous thromboembolism in patients after planned endoprosthetics of the hip or knee joint;
• prevention of stroke and systemic thromboembolism in adult patients with non-valvular atrial fibrillation who have one or more risk factors (such as a stroke or transient ischemic attack in the anamnesis, age 75 years and older,arterial hypertension, diabetes mellitus, accompanied by symptoms of chronic heart failure (PK 2 and higher according to the NYHA classification)). Exceptions are patients with severe and moderately expressed mitral stenosis or with artificial heart valves;
• treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), as well as the prevention of recurrence of DVT and PE.

Forms of release

Tablets coated with 2.5 mg and 5 mg.

Instructions for use and dosage

Elixis is taken internally, regardless of food intake.

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

After planned endoprosthetics of the hip or knee joint: 2.5 mg 2 times a day (the 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 is 10 to 14 days.

Patients with atrial fibrillation: 5 mg twice a day. The dose of the drug is reduced to 2.5 mg twice a day in the presence of a combination of two or more of the following characteristics: age 80 years and older,body weight 60 kg or less, or creatinine concentration in the blood plasma more than 1.5 mg / dL (133 μmol / l).

Treatment of deep vein thrombosis, pulmonary embolism: 10 mg twice a day for 7 days, then 5 mg 2 times a day. Duration of treatment is determined individually, taking into account the ratio of expected benefits and the risk of clinically significant bleeding. The decision on the duration of therapy should be based on an assessment of the presence and reversibility of factors predisposing to recurrence (ie, previous surgical intervention, trauma, immobilization period, etc.), as well as manifestations of DVT and / or PE, 3 months.

Prevention of relapses of deep vein thrombosis, pulmonary embolism: 2.5 mg 2 times a day after at least 6 months of treatment of deep vein thrombosis or PE.

If the renal function is mild, moderate or severe with QC to 15 ml / min, dose adjustment of apixaban is not required. In patients with impaired renal function with a severity of QC less than 15 ml / min, as well as in patients on dialysis, the use of Elixies is not recommended.

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

Correction of the dose of the drug in elderly patients is not required (except for patients with atrial fibrillation with two of three criteria).

Dose adjustments are not required depending on the patient's body weight (the exception is patients with atrial fibrillation with two of three criteria).

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

Transition from or to therapy with parenteral anticoagulants

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

Transition from or to Warfarin or other antagonists of vitamin K

Transfer of patients with therapy with warfarin or other antagonists of vitamin K to therapy with Elixis should be performed with the INR value in the patient below 2.0.

When transferring patients with Elixies therapy to warfarin or other vitamin K antagonists, Eliksvis should continue therapy within 48 hours after taking the first dose of warfarin or other vitamin K antagonists. After 48 hours, the INR should be monitored before taking the next dose of Eliwis. Joint use of warfarin (or another vitamin K antagonist) and Eliwis preparation should be continued until the INR is more than 2.0. When the INR is more than 2.0, Elikvis should be discontinued.

Surgical and invasive procedures

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

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

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

Patients can continue taking Elikvis during cardioversion.

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

Side effect

• anemia (including postoperative and posthemorrhagic, accompanied by appropriate changes in the results of laboratory studies);
• bleeding (including vaginal and urethral bleeding);
• hematomas;
• thrombocytopenia (including a decrease in the number of platelets);
• hypersensitivity;
• hemorrhages in the tissue of the eyeball (including hemorrhage in the conjunctiva);
• arterial hypotension (incl.hypotension during the procedure);
• nose bleed;
• hemoptysis;
• nausea;
• gastrointestinal bleeding (including vomiting with an admixture of blood and melena);
• the presence of unchanged blood in the feces;
• positive reaction in the analysis of feces for occult blood;
• rectal bleeding;
• bleeding from the gums;
• increased transaminase activity, incl. increased activity of ALT, AST, GGT;
• pathological changes in functional liver samples;
• increased activity of alkaline phosphatase in the blood;
• increasing the concentration of bilirubin in the blood;
• hematomas of the abdominal wall;
• Malory-Weiss syndrome;
• muscle hemorrhage;
• hematuria (blood in the urine);
• closed trauma;
• hemorrhage 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 detachable wound;
• hemorrhage in the region of the incision (including hematoma in the region of the incision);
• bleeding during surgery.

Contraindications

• hypersensitivity to any component of the drug;
• clinically significant bleeding;
• conditions characterized by an increased risk of bleeding: congenital or acquired bleeding disorders; exacerbation 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 organ of vision; severe uncontrolled hypertension;
• severe violations of liver function, liver disease, accompanied by disorders in the blood coagulation system and clinically significant risk of bleeding;
• renal dysfunction with KK less than 15 ml / min, as well as use in patients on dialysis;
• simultaneous application of the preparations, the effect of which may be associated with the development of serious bleeding, such as any anticoagulant drugs, unfractionated heparin, low molecular weight heparins (enoxaparin, dalteparin), derivatives of heparin (fondaparinux), oral anticoagulants (warfarin, rivaroxaban, dabigatran), except those situations when the patient is transferred to therapy or with apixaban therapy or if unfractionated heparin is given in doses,necessary to maintain the patency of the central venous or arterial catheter;
• pregnancy (there are no data on the use of the drug);
• breastfeeding (no data on the use of the drug);
• children and adolescents under 18 years of age (no data on drug use);
• congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Application in pregnancy and lactation

During preclinical studies, the toxicity of the drug in relation to the reproductive function was not detected. There is limited information about the use of Elixis during pregnancy. The use of apixaban in pregnancy is not recommended.

In studies on rats, the concentration of the drug in breast milk was many times higher than that in blood plasma (Cmax is about 8 times higher, AUC is about 30 times higher), which may indicate an active transport of the drug into breast milk. The risk for infants who are breastfed can not be ruled out. There is no information on the excretion of apixaban or its metabolites with human breast milk.If you need to use Elixis during lactation, breastfeeding should be discontinued.

Impact on fertility

Apixaban did not affect fertility in animal studies.

Use in children

Contraindicated in children and adolescents under the age of 18 years.

Application in elderly patients

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

special instructions

Risk of bleeding

In patients with atrial fibrillation and conditions requiring monotherapy or therapy with a combination of two antiplatelet agents, a thorough assessment of the benefit / risk relationship should be conducted prior to the simultaneous use with the Eliksis drug.

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

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

As with the use of other anticoagulants, careful monitoring of patients taking Eliksis should be considered for the development of bleeding. With the development of severe bleeding, Elikvis should be withdrawn.

With the development of hemorrhagic complications, it is necessary to cancel the treatment with the drug and perform a check for the source of bleeding. If necessary, appropriate treatment is prescribed, in particular, surgical stopping of bleeding or transfusion of fresh-frozen blood plasma.

Cancellation of therapy with anticoagulants, incl. apixaban, with active bleeding, before routine surgery or an invasive procedure, may lead to an increased risk of thrombosis. Long-term cessation of therapy should be avoided, and if apyxaban therapy should be temporarily stopped, then it must be resumed as soon as possible.

Operative interventions related to hip fracture

In clinical trials, Eliksis was not used in patients who underwent emergency surgery for a hip fracture, thus, efficacy and safety in this category of patients were not studied.

Performing spinal, epidural anesthesia or puncture in patients receiving Eliwis

When performing spinal or epidural anesthesia or diagnostic puncture of these areas in patients receiving antithrombotic agents for the prevention of thromboembolism, there is a risk of developing epidural or spinal hematomas, which in turn can lead to persistent or irreversible paralysis. This risk can be further increased by using an established epidural catheter in the postoperative period or with the parallel application of other drugs that affect hemostasis. The established epidural or subarachnoidal catheters should be removed at least 5 hours before the first dose of Elikvis. Clinical experience of apixaban in patients with an established intrathecal or epidural catheter is absent. If this situation is necessary, based on the pharmacokinetic characteristics of apixaban, an interval of 20-30 h (ie 2 half-lives) between the last dose of apicaban taken and the removal of the catheter should be observed, so at least one dose of apixaban must be passed up to removal of the catheter.A similar increase in risk may be noted when performing traumatic or multiple punctures of the epidural or subarachnoid spaces. Frequent monitoring of patients for the development of manifestations of disorders of the nervous system (in particular, numbness or weakness of the lower limbs, bowel or bladder function disorder) is necessary. With the development of such violations, it is necessary to perform emergency screening and treatment. Before performing interventions on epidural or subarachnoid spaces in patients receiving anticoagulants, incl. with the purpose of prophylaxis of thromboses, it is necessary to estimate the ratio of potential benefit and risk.

Patients with artificial heart valves

The safety and efficacy of the drug in patients with artificial heart valves with and without atrial fibrillation have not been studied. Elixis is not recommended for this group of patients.

Treatment of deep vein thrombosis and PE

It is not recommended to replace unfractionated Heparin therapy with Eliwis during the initiation of therapy for patients with PE with unstable hemodynamics, possible thrombolysis or pulmonary thrombectomy.

Impact on the ability to drive vehicles and manage mechanisms

Elikvis does not have a significant impact on the ability to manage vehicles and work with mechanisms.

Drug Interactions

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), which is 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 1.6-fold in the mean Cmax. Correction of the dose of apixaban when combined with ketoconazole is not required, but apixaban should be used with caution in patients receiving systemic therapy with azole antifungal agents, in particular ketoconazole, or other potent inhibitors of the isoenzyme CYP3A4 and P-glycoprotein.

Preparations that do not relate to potent inhibitors of the isoenzyme CYP3A4 and P-glycoprotein (eg diltiazem, naproxen, amiodarone, verapamil, quinidine) appear to lead to an increase in the concentration of apicaban in blood plasma to a lesser extent.For example, diltiazem (moderate inhibitor of the isoenzyme CYP3A4 and a weak inhibitor of P-glycoprotein) at a dose of 360 mg 1 time per day, resulted in an increase in the mean values ​​of AUC apixaban by 1.4 times and the average values ​​of Cmax by 1.3 times. Naproxen (P-glycoprotein inhibitor) when applied at a dose of 500 mg in healthy volunteers caused an increase in the 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 parameters of the blood coagulation system (prothrombin time, MNO and APTT). However, there was no effect of naproxen on platelet aggregation induced by arachidonic acid and a clinically significant prolongation of bleeding time.

Dose correction 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) resulted in a decrease in the mean 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 perfumed) can also lead to a decrease in the concentration of apixaban in the blood plasma (by about 50%). Dose correction of apixaban when combined with this group is not required for prescribing: prevention of thromboembolism after arthroplasty, prevention of strokes and systemic thromboembolism in non-valvular atrial fibrillation and prevention of relapses of deep vein thrombosis, pulmonary embolism, but these agents should be combined with caution . During use in the treatment of deep vein thrombosis and pulmonary embolism combined use apixaban and powerful inducers isoenzyme CYP3A4 and P-glycoprotein is not recommended.

Anticoagulants, platelet aggregation inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs)

After the combined administration of enoxaparin (once, at a dose of 40 mg) and apixaban (once, at a dose of 5 mg), the additive effect of these agents on F10a activity was noted.

No evidence of pharmacokinetic or pharmacodynamic interaction apixaban with acetylsalicylic acid (325 mg 1 time per day) in healthy subjects was noted.

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

Combination of apixaban with clopidogrel (75 mg once daily) or a combination of clopidogrel (75 mg) and acetylsalicylic acid (162 mg once daily) or prasugrel (60 mg followed by a dose of 10 mg once a day) in 1 phase clinical study did not lead to an increase in bleeding time or more pronounced inhibition of platelet aggregation compared to the use of these antiplatelet agents as monotherapy. The increase in the parameters of the blood coagulation system (prothrombin time, MHO and APTT) corresponded to the effects of apixaban when applied in monotherapy.

It is not recommended 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 that inhibit F10a (eg fondaparinux), direct thrombin 2 inhibitors (eg, desandin), thrombolytic agents drugs, receptor antagonists to glycoproteins 2b / 3a,dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists and other oral anticoagulants. It should be noted that unfractionated heparin can be used in doses necessary to maintain the patency of the venous or arterial catheter. In patients after planned endoprosthetics of the hip or knee joint co-administration of apixaban with other antiplatelet agents or other antithrombotic drugs is not recommended.

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

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

The use of the drug together with powerful inducers of CYP3A4 and P-glycoprotein (such as rifampicin, phenytoin, carbamazepine, Phenobarbital and preparations of St. John's wort) can lead to a 50% reduction in plasma concentrations of the drug, so these combinations should be used with caution. It is not recommended to use apixaban together with powerful inducers of CYP3A4 and P-glycoprotein when using apixaban for the treatment of deep vein thrombosis and pulmonary embolism.

Combination with other drugs

There was no clinically significant pharmacokinetic or pharmacodynamic interaction of apixaban with Atenolol or famotidine. Combination of apixaban (10 mg dose) with atenolol (at a dose of 100 mg) did not lead to the development of clinically significant changes in the pharmacokinetics of apixaban, but it was accompanied by a decrease in the mean values ​​of AUC and Cmax apixaban by 15% and 18% respectively, compared with the monotherapy regimen. The administration of apixaban (10 mg) with Famotidine (at a dose of 40 mg) had no effect on the AUC or Cmax values ​​of apixaban.

Effect of apixaban on the pharmacokinetics of other drugs

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

Analogues of the drug Eliwis

Structural analogs for the active substance Eliksvis has no medicine.

Analogues for the pharmacological group (anticoagulants):

• Angioks;
• Angioflux;
• Antithrombin 3 human;
• Anfiber;
• Arikstra;
• Acenocoumarol;
• Warfarex;
• Warfarin;
• Venabos;
• Venolife;
• Viatrom;
• Hemapaksan;
• Gepalpan;
• Heparin;
• Heparin injection;
• Heparin ointment;
• Hetaroid Zentiva;
• Heparoid Lechiva;
• Hepatrombin;
• Dolobien;
• Yellon gel;
• Sigris;
• Calciparin;
• Clexan;
• Cleaver;
• Xarelto;
• Lavenum;
• Lyoton 1000;
• Marewan;
• Nadroparin calcium;
• Sodium citrate;
• Nigepan;
• Pelentan;
• Piyavit;
• Pradax;
• Seprotin;
• Cincumar;
• Skinlight;
• Troxevasin Neo;
• Trombleuss;
• Trombleuss Plus;
• Thrombogen 1000;
• Thrombophobia;
• Troparin;
• Phenylin;
• Fluxum;
• Fragmin;
• Fraksiparin;
• Fraksiparin Forte;
• Cibor;
• Emeran;
• Eniksum;
• Enoxaparin sodium;
• Essaven.

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