Eliquis, 5 mg 60 pcs

Pharmgroup:

A direct acting anticoagulant is a selective factor Xa inhibitor.

Pharmic action:

Eliquis is a direct acting anticoagulant – a selective inhibitor of factor Xa blood clotting.

The mechanism of action of apixaban is inhibition of FXa activity. As a result, apixaban changes values of indexes of blood coagulation system: prolongs prothrombin time, MHO and activated partial thromboplastin time (APTB). Changes of these parameters when using the drug in a therapeutic dose are insignificant and individual. Therefore, their use to assess pharmacodynamic activity of apixaban is not recommended.

The inhibition of FXa activity by apixaban has been proven by a chromogenic test using Rotachrom heparin. The change in anti-FXa activity is directly proportional to the increase in plasma apixaban concentration, with the maximum values of activity observed when the Cmax of apixaban in plasma is reached. A linear relationship between the concentration and anti-FXa activity of apixaban is registered in a wide range of therapeutic doses of the drug.

Changes in anti-FXa activity with changes in apixaban dose and concentration are more pronounced and less variable than blood clotting parameters. The expected maximal and minimal anti-FXa activity of apixaban at equilibrium, when administered at a dose of 2.5 mg 2 times/day, are 1.ZMe/ml (5/95 percentile – 0.67 ME/ml – 2.4 ME/ml) and 0.84 ME/ml (5/95 percentile -0.37 ME/ml – 1.8 ME/ml), respectively, which correlates with variation in this index between drug doses (less than 1.6 times). Routine monitoring of plasma concentrations is not required during therapy with apixaban, but performing an anti-FXaA activity Rotachrom test may be helpful in deciding whether to continue therapy.

Apixaban is a potent direct FXa inhibitor that reversibly and selectively blocks the active center of the enzyme for oral administration. Antithrombin III is not required for realization of the antithrombotic effect of apixaban. Apixaban inhibits free and bound FXa as well as prothrombinase activity. Apixaban has no direct direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting the activity of FXa apixaban prevents thrombin and thrombus formation.

Pharmacokinetics:

Intake

The absolute bioavailability of apixaban reaches 50% when used in doses up to 10 mg. Apixaban is rapidly absorbed from the gastrointestinal tract, Cmax is reached within 3-4 hours after oral administration. Food intake has no effect on the values of area under the curve “concentration-time” (AUC) or Cmax of apixaban. Apixaban pharmacokinetics for doses up to 10 mg has a linear character. When administering apixaban in doses above 25 mg, limitation of absorption of the drug is noted, which is accompanied by a decrease in its bioavailability. Metabolic parameters of apixaban are characterized by low to moderate inter- and intraindividual variability (the respective coefficient of variation values are 20% and 30%, respectively).

Distribution

The binding of apixaban to human plasma proteins is approximately 87% and the volume of distribution (Vss) is approximately 21 l.

Metabolism and excretion

About 25% of the dose taken is excreted as metabolites, most of it through the intestine. Renal excretion of apixaban is approximately 27% of its total clearance.

The total clearance of apixaban is approximately 3.3 L/hour, T1/2 is about 12 h. O-demethylation and hydroxylation at the 3-oxopiperidinyl residue are the main biotransformation pathways of apixaban. Apixaban is primarily metabolized with participation of CYP3A4/5 isoenzyme, to a lesser extent – CYP1A2, 2C8, 2C9, 2C19 and 2J2 isoenzymes. Unchanged apixaban is the main substance circulating in human plasma, there are no active metabolites circulating in the bloodstream. In addition, apixaban is a substrate of transport proteins, P-glycoprotein 70 and breast cancer resistance protein (BCRP).

Kidney dysfunction

Kidney dysfunction has no effect on the Cmax of apixaban. However, there was an increase in apixaban concentrations correlated with the degree of renal function impairment as assessed by creatinine clearance (CK) values. In patients with mild renal dysfunction (CK – from 51 ml/min to 80 ml/min), moderate (CK – from 30 ml/min to 50 ml/min) and severe (CK – from 15 ml/min to 29 ml/min) apixaban AUC values in plasma increased by 16%, 29% and 44%, respectively, compared to those with normal CK values. However, impaired renal function had no apparent effect on the relationship between plasma apixaban concentrations and its anti-FXa activity.

There have been no studies of apixaban in patients with creatinine clearance < 15 ml/min or on dialysis.

Hepatic impairment

There have been no studies of apixaban in severe hepatic insufficiency and active hepatobiliary pathology.
In investigation of pharmacokinetics and pharmacodynamics of apixaban at a single dose of 5 mg in patients with mild to moderate hepatic insufficiency (Child-Pugh grades A and B, respectively) and healthy volunteers it was shown that hepatic insufficiency has no effect on these parameters. Changes in anti-FXa activity and MHO in patients with moderate hepatic impairment and healthy volunteers were comparable.

The use in elderly patients

Elderly patients (over 65 years) showed higher plasma concentrations of the drug than younger patients: the average AUC was approximately 32% higher. No dose adjustment is required in elderly patients.

Per sex

The exposure of apixaban in women was 18% higher than in men. No adjustment of the drug dose depending on the patient’s sex is required.
Race and ethnicity

The results obtained within the framework of the phase I trials testify to the absence of significant differences of apixaban pharmacokinetics among representatives of Caucasoid, Mongoloid and Negroid races. The results of pharmacokinetic analyses in different populations performed in studies including patients receiving apixaban after elective hip or knee arthroplasty are consistent with the results of phase I studies. No dose adjustments are required based on the race or ethnicity of the patient.

Body weight

Patients with a body weight greater than 120 kg had a plasma apixaban concentration approximately 30% lower than that of patients with a body weight between 65 kg and 85 kg; patients with a body weight less than 50 kg had a plasma apixaban concentration approximately 30% higher. No dose adjustment is required depending on patient weight.

The relationship between pharmacokinetic and pharmacodynamic parameters

The relationship between pharmacokinetic and pharmacodynamic parameters (including anti-FXa activity, MHO, prothrombin time, ACTV) of apixaban and its plasma concentration has been studied for a wide range of drug doses (from 05 mg to 50 mg). It was shown that the relationship between apixaban concentration and FXa activity is best described using a linear model. The dependence of pharmacokinetic and pharmacodynamic parameters of apixaban evaluated in patients undergoing elective hip or knee arthroplasty was consistent with that observed in healthy volunteers.

Indications

– Prevention of venous thromboembolism in patients after planned hip or knee arthroplasty.

Active ingredient

Composition

1 tablet:
– apixaban 5 mg

Associates:

Lactose,

Microcrystalline cellulose,

p> croscarmellose sodium,

sodium lauryl sulfate,

magnesium stearate.

Composition of film coating:

Opadray II Yellow (hypromellose 15 cps, lactose monohydrate, titanium dioxide, triacetin, iron oxide yellow dye).

How to take, the dosage

Internal administration regardless of meals (first administration 12-24 hours after the surgery), 1 tablet 2 times a day.
The recommended therapy duration is from 32 to 38 days in patients who underwent hip arthroplasty and from 10 to 14 days in patients who underwent knee arthroplasty.

If the drug is missed, it should be taken as soon as possible and thereafter continued twice daily according to the original regimen.

Performance in patients with impaired renal function. No adjustment of the preparation dose is required in patients with renal dysfunction of mild, moderate or severe degree (creatinine Cl – from 15 to 29 ml/min). Since there are no data concerning the use of the preparation in patients with creatinine Cl Cl 15 ml/min or in patients on dialysis, the use of Eliquis® preparation is not recommended in this group of patients.

The use in patients with impaired liver function. Eliquis® may be used with caution in patients with mild to moderate hepatic insufficiency (class A or B according to Child-Pugh). No dose adjustment is required in patients with mild to moderate hepatic impairment. The use of the drug in patients with severe hepatic impairment is not recommended.

Interaction

The effect of other drugs on apixaban pharmacokinetics
CYP3A4 and P-glycoprotein inhibitors

. Combination of apixaban with ketoconazole (in dose 400 mg, once daily), which is potent inhibitor of both CYP3A4, and P-glycoprotein, led to increasing of mean AUC value of apixaban by 2 times and mean Cmax value – by 1.6 times. There is no dose adjustment of apixaban in combination with ketoconazole, however apixaban should be used with caution in patients receiving systemic therapy with azole antifungal agents, in particular ketoconazole, or other potent CYP3A4 and P-glycoprotein inhibitors.
Drugs that moderately inhibit apixaban elimination, CYP3A4 and/or P-glycoprotein are expected to increase plasma apixaban concentrations to a lesser degree. For example, diltiazem (in a dose of 360 mg, once daily), considered a moderate CYP3A4 inhibitor and a weak P-glycoprotein inhibitor, provided 1.4-fold increase in the mean AUC of apixaban and 1.3-fold increase in the mean Cmax.

Naproxen (500 mg dose), which is an inhibitor of P-glycoprotein, provided 1.5 and 1.6-fold increase of mean AUC and Cmax values of apixaban, respectively. At the same time, there was an increase in the values of blood coagulation indices. However, against the background of this combination there was no change in the effect of naproxen on platelet aggregation induced by arachidonic acid, and clinically significant prolongation of bleeding time.

Dose adjustment of apixaban when combining with less active CYP3A4 and/or P-glycoprotein inhibitors is not required.
CYP3A4 and P-glycoprotein inducers

Combining apixaban with rifampicin (a potent inducer of CYP3A4 and P-glycoprotein) resulted in reduction of average AUC and Cmax values of apixaban by approximately 54 and 42% respectively. Therefore, combining apixaban with other potent inducers of CYP3A4 and P-glycoprotein (particularly phenytoin, carbamazepine, phenobarbital or preparations of St. John’s wort) may also lead to a decrease in plasma concentrations of apixaban. Nevertheless, no dose adjustment of apixaban is required when combining it with agents of this group, but these agents should be combined with caution.

After coadministration of enoxaparin (singly, in a dose of 40 mg) and apixaban (singly, in a dose of 5 mg), an additive effect of these agents on factor Xa activity was observed.

Because of the increased risk of bleeding, apixaban should be combined with other anticoagulants with caution.
Platelet aggregation inhibitors and NSAIDs

There have been no signs of pharmacokinetic or pharmacodynamic interaction of apixaban with acetylsalicylic acid (in dose 325 mg, once daily).

The combination of apixaban with clopidogrel (in dose 75 mg, once daily) or combination of clopidogrel (75 mg) and acetylsalicylic acid (162 mg, once daily) did not lead to increase of bleeding time, platelet aggregation or clotting system parameters (PV, INR and ACTV) in comparison with use of these antiaggregants in monotherapy.

Despite these data, the pharmacodynamic response to therapy with antiplatelet agents may be enhanced when used in combination with apixaban. Therefore, caution should be exercised when combining it with NSAIDs (including acetylsalicylic acid) and/or platelet aggregation inhibitors, because these drugs usually increase the risk of bleeding.

Combination with other drugs

There have been no clinically significant pharmacokinetic or pharmacodynamic interactions of apixaban with atenolol or famotidine. Combination of apixaban (in dose 10 mg) with atenolol (in dose 100 mg) did not result in development of clinically significant changes of apixaban pharmacokinetic parameters, but it was accompanied by 15 and 18% lower mean AUC and Cmax values of apixaban than it was in monotherapy. Combination of apixaban (in a dose of 10 mg) with famotidine (in a dose of 40 mg) had no effect on the AUC or Cmax values of apixaban.

The effect of apixaban on pharmacokinetics of other drugs

. In in vitro studies, no inhibitory effect of apixaban on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6 or CYP3A4 activity (IC50 >45 μmol/L) and was found to have a weak inhibitory effect on CYP2C19 activity (IC50 >20 μmol/L) at a concentration significantly higher than the drug’s Cmax in plasma during its clinical use.

Apixaban was not an inducer of CYP1A2, CYP2B6, CYP3A4/5 at concentrations up to 20 μmol/L. Therefore, it is not expected to affect the metabolic clearance of drugs metabolized by these isoenzymes when used together. 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.
Digoxin. Combination of apixaban (20 mg, once daily) and digoxin (0.25 mg, once daily), a P-glycoprotein substrate, had no effect on digoxin AUC or Cmax values. Therefore, apixaban does not inhibit the transport of P-glycoprotein substrates.

Naproxen. The combination of apixaban (single dose of 10 mg) and naproxen (500 mg), a commonly used NSAID, had no effect on the AUC or Cmax values of naproxen.

Athenololol. Combination of apixaban (single dose of 10 mg) and atenolol (100 mg) – a frequently used beta-adrenoblocker – had no effect on pharmacokinetic parameters of the latter.

Special Instructions

As with other anticoagulants, patients taking Eliquis should be closely monitored for bleeding. If severe bleeding occurs, Eliquis should be discontinued. If hemorrhagic complications develop, it is necessary to cancel treatment with the drug and perform examination to identify the source of bleeding. If necessary, appropriate treatment, such as surgical stoppage of bleeding or transfusion of fresh frozen plasma, is indicated.

Performance of spinal, epidural anesthesia or punctures in patients receiving Eliquis

. When performing spinal or epidural anesthesia or diagnostic puncture of these areas in patients receiving antithrombotic agents to prevent thromboembolism, there is a risk of epidural or spinal hematomas which in turn can cause permanent or irreversible paralysis. This risk may be further increased if an epidural catheter is inserted in the postoperative period or if other medications affecting hemostasis are used in parallel. Installed epidural or subarachnoid catheters should be removed at least 5 h before the first dose of Eliquis.

A similar increased risk may be noted with traumatic or multiple epidural or subarachnoid punctures. Frequent monitoring of patients for signs of nervous system dysfunction (e.g., numbness or weakness in the lower extremities, bowel or bladder dysfunction) is necessary. If such abnormalities develop, an emergency examination and treatment should be performed. Prior to epidural or subarachnoid interventions in patients receiving anticoagulants, including for thrombosis prophylaxis, an assessment of the potential benefit-risk ratio should be performed.

Impact on driving and operating machinery

Eliquis has no significant effect on the ability to drive and operate machinery.

Contraindications

– Hypersensitivity to the active substance or excipients of the drug Eliquis;
– clinically significant active bleeding;
– liver disease accompanied by disorders in the blood clotting system and clinically significant risk of bleeding;
– severe liver function abnormalities;
– renal function abnormality with CKR less than 15 ml/min, as well as application in patients on dialysis;
– pregnancy;
– breastfeeding;
– age under 18 years.
It is not recommended to use apixaban simultaneously with the drugs, the effect of which may be associated with the development of serious bleeding.
With caution: Apixaban should be used with caution when performing spinal, epidural anesthesia or punctures, and in patients receiving systemic therapy with potent CYP3A4 and P-glycoprotein isoenzyme inhibitors such as azole antifungals (particularly ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (such as ritonavir). Caution should also be exercised when using apixaban with potent inducers of CYP3A4 isoenzyme and P-glycoprotein (in particular, rifampicin, phenytoin, carbamazepine, phenobarbital or preparations of St. John’s wort).

The risk of bleeding

The drug is recommended to be used with caution in conditions characterized by an increased risk of bleeding: congenital or acquired disorders of blood clotting; exacerbations of peptic ulcer disease; bacterial endocarditis; thrombocytopenia; thrombocytopathies; history of hemorrhagic stroke; recent surgical intervention on the brain or spinal cord, or on the visual organs; severe uncontrolled arterial hypertension.

In addition, caution should be exercised when concomitant use of apixaban with NSAIDs (including acetylsalicylic acid), due to the fact that these drugs increase the risk of bleeding.

The surgical interventions associated with femoral neck fracture

Eliquis has not been used in patients who have undergone emergency surgery for femoral neck fracture in clinical trials, so its effectiveness and safety in this category of patients has not been studied.

Side effects

Adverse reactions have been reported in 11% of patients receiving apixaban at a dose of 2.5 mg 2 times/day. As with other anticoagulants, bleeding may occur in patients with risk factors such as, organic lesions associated with bleeding. The most common side effects were anemia, bleeding, hematomas, and nausea. Unwanted reactions developed in patients who underwent orthopedic surgery against the background of apixaban therapy are presented below.
The following is the frequency of adverse reactions: frequently, > 1/100, < 1/10, infrequently, > 1/1000, < 1/100, rarely, > 1/10000, < 1/1000.

Blood and lymphatic system disorders: frequently – anemia (including postoperative and post-hemorrhagic anemia accompanied by corresponding changes in the results of laboratory tests); infrequent – thrombocytopenia (including decrease of thrombocyte number).

Immune system disorders: rarely – hypersensitivity.

An organ of vision: rarely – haemorrhage in the eyeball tissue (including conjunctival haemorrhage).

The cardiovascular system: frequently – bleeding (including hematoma, vaginal and urethral bleeding); infrequently – arterial hypotension (including hypotension during treatment).

Respiratory system: infrequent – nasal bleeding; rarely – hemoptysis.

Gastrointestinal system disorders: frequently – nausea; infrequently – gastrointestinal bleeding (including vomiting with blood and melena), unchanged blood in stools; rarely – rectal bleeding, gingival bleeding.

Hepatic and biliary tract disorders: infrequent – increased transaminase activity (including ALT), elevated AST activity, gamma-glutamyl transpeptidase, abnormal changes of liver function tests, increased ALP activity in blood, increased bilirubin concentration in blood.

Musculoskeletal system disorders: rare – muscle bleeding.

Urinary system disorders: infrequent – hematuria (including corresponding changes in the results of laboratory tests).

Others: often – closed trauma; infrequent – hemorrhage and bleeding after invasive procedures (including hematoma after the procedure, bleeding from the postoperative wound, hematoma in the area of vessel puncture and catheter placement), presence of discharge from the wound, bleeding around the incision (including hematoma around the incision), bleeding during surgical intervention.

Overdose

Symptoms: an overdose may increase the risk of bleeding. In controlled clinical trials apixaban was taken orally in healthy volunteers in doses up to 50 mg/day for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily, for 3 days), which is 10 times the maximum recommended dose for humans; no clinically significant adverse effects were observed.

Treatment: The antidote for apixaban is not known. In preclinical studies it was shown that oral administration of activated charcoal for 3 h after oral administration of apixaban reduced the values of apixaban exposure; therefore, in case of overdose of this drug, the use of activated charcoal may be considered.

Pregnancy use

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

There are no data on excretion of apixaban or its metabolites with breast milk in humans. If it is necessary to use the drug Eliquis during lactation, breastfeeding should be stopped.