Eliquis, 5 mg 20 pcs.

Pharmacotherapeutic group

Direct-acting anticoagulant – selective inhibitor of clotting factor Xa (FXa).

ATX code: B01AF02

Pharmacological properties

Pharmacodynamics

Apixaban is a potent direct FXa inhibitor that reversibly and selectively blocks the active center of the enzyme. The drug is intended for oral administration. Antithrombin III is not required for realization of antithrombotic activity 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 FXa activity, apixaban prevents thrombin and thrombus formation. As a result of FXa inhibition values of blood coagulation system are changed: prothrombin time, activated partial thromboplastin time (APTT) and international normalized ratio (INR) are prolonged. Changes in these parameters when using the drug in a therapeutic dose are insignificant and highly variable. Therefore, their use to assess the pharmacodynamic activity of apixaban is not recommended. In the thrombin generation test apixaban decreased endogenous thrombin potential – a measure of thrombin formation in human plasma.

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 an increase in plasma apixaban concentration, with maximum activity values observed when the maximum plasma apixaban concentration 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 the dose and concentration of apixaban are more pronounced and less variable than blood clotting parameters.

Table 1 shows the estimated equilibrium concentrations and anti-FXa activity with apixaban for each indication. In patients receiving apixaban after elective hip or knee arthroplasty, the ratio of maximum to minimum anti-FXa activity between doses does not exceed 1.6. In patients receiving apixaban for prevention of stroke and systemic thromboembolism in non-valvular atrial fibrillation, the ratio is less than 1.7, and in patients receiving apixaban for treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis it is less than 2.2.

Table 1.

Estimated equilibrium concentrations (ng/mL) and anti-FXa activity (IU/mL)

* Dose adjustment according to dose reduction criteria in the ARISTOTLE study.

Routine monitoring of apixaban’s anticoagulation effect is not required during therapy, but performing a calibrated quantitative test of anti-FXa activity may be useful in situations where information about the presence of apixaban in the blood may be useful in deciding whether to continue therapy. Compared with warfarin, fewer bleeding events, including intracranial hemorrhage, have been reported with apixaban.

Pharmacokinetics

Eabsorption

The absolute bioavailability of apixaban is up to 50% when administered in doses up to 10 mg. Apixaban is rapidly absorbed from the gastrointestinal tract, its maximum concentration (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 is linear. 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 corresponding values of coefficient of variation are -20% and -30%, respectively).

After oral administration of apixaban at a dose of 10 mg as 2 crushed 5 mg tablets diluted in 30 ml of water, exposure to the drug was comparable to that after oral administration of 2 whole 5 mg apixaban tablets. After oral administration of apixaban at a dose of 10 mg as 2 crushed 5 mg tablets with 30 g apple puree, Cmax and AUC values were 21% and 16% lower, respectively, than after administration of 2 whole 5 mg tablets.

After administration through the nasogastric tube of a crushed 5 mg apixaban tablet diluted in 60 mL of 5% aqueous dextrose solution (5DV), apixaban exposure was comparable to that observed in other clinical studies involving healthy volunteers who received a single oral dose of 5 mg apixaban as a tablet.

Distribution

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

Metabolism and excretion

About 25% of the dose taken is excreted as metabolites. The main route of excretion is through the intestine. Renal excretion of apixaban is approximately 27% of its total clearance.

The total clearance of apixaban is approximately 3.3 l/h, the half-life (T 1 /2) is about 12 h. O-demethylation and hydroxylation by 3-oxopiperidinyl residue are the main pathways of apixaban biotransformation. 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 and breast cancer resistance protein (BCRP).

Kidney dysfunction

Kidney dysfunction has no effect on the maximum concentration of apixaban. However, there was an increase in apixaban concentrations correlated with the degree of renal function impairment as assessed by creatinine clearance values. In patients with mild (creatinine clearance – 51 ml/min to 80 ml/min), moderate (creatinine clearance – 30 ml/min to 50 ml/min) and severe (creatinine clearance – 15 ml/min to 29 ml/min) renal function disorders the AUC values of apixaban in plasma increased by 16%, 29% and 44%, respectively, compared to those patients with normal creatinine clearance values. At the same time, 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 less than 15 ml/min or on dialysis.

Hepatic impairment
Studies of apixaban in severe hepatic insufficiency and active hepatobiliary pathology have not been performed.

There were no significant changes in pharmacokinetic and pharmacodynamic parameters with single administration of apixaban at a dose of 5 mg in patients with mild to moderate hepatic impairment (Child-Pugh grades A and B, respectively) compared to healthy volunteers. Changes in anti-FXa activity and INR in patients with mild to moderate hepatic impairment and healthy volunteers were comparable.

The use in elderly patients

The elderly patients (over 65 years) showed higher plasma concentrations of the drug than younger patients: the average AUC was approximately 32% higher.

Position of apixaban in women was 18% higher than in men.

Race and ethnicity

The results from the phase I studies suggest that there are no significant differences in apixaban pharmacokinetics between Caucasoid, Mongoloid, and Negroid races. The results of pharmacokinetic analyses in different populations performed as part of the apixaban clinical trial program, which included patients receiving apixaban after elective hip or knee arthroplasty, are generally consistent with the results of phase 1 studies.

Body weight

Patients with a body weight greater than 120 kg had plasma apixaban concentrations approximately 30% lower than patients with a body weight between 65 kg and 85 kg; patients with a body weight less than 50 kg had approximately 30% higher concentrations.

The relationship between pharmacokinetic and pharmacodynamic parameters

. The relationship between the pharmacokinetic and pharmacodynamic parameters (including anti-FXa activity, INR, prothrombin time, ACTV) of apixaban and its plasma concentration has been studied for a wide range of drug doses (from 0.5 mg to 50 mg). It was shown that the relationship between apixaban concentration and FXa activity is best described using a linear model. Dependence of parameters of pharmacokinetics and pharmacodynamics of apixaban. evaluated in patients receiving apixaban in phase II and phase III clinical trials was consistent with that in healthy volunteers.

Indications

Active ingredient

Composition

1 film-coated tablet contains:

The active ingredient: apixaban 5.0 mg.

Excipients: Lactose 100.50 mg, microcrystalline cellulose 82.00 mg, croscarmellose sodium 8.00 mg, sodium lauryl sulfate 2.00 mg, magnesium stearate 2.50 mg.

Film Coating: Opadray II Pink 8.0 mg (hypromellose 15 cps 2.96 mg, lactose monohydrate 2.48 mg, titanium dioxide 1.87 mg, triacetin 0.64 mg, iron oxide red dye 0.046 mg).

How to take, the dosage

Eliquis® is taken orally regardless of meals.
If missed, the drug should be taken as soon as possible and thereafter continued twice daily according to the original regimen.

For patients who cannot swallow the whole tablet, the Eliquis® tablet may be crushed and diluted in water or 5% dextrose (5DV) or apple juice or mixed with apple puree and immediately taken orally (see section “Pharmacological properties”). Alternatively, the tablet of Eliquis® may be crushed and diluted in 60 ml of water or 5DV and the resulting suspension administered immediately through a nasogastric tube (see section “Pharmacological properties”).

The drug substance in crushed tablets of Eliquis® is stable in water, 5DV, apple juice and apple puree for up to 4 hours.

1. In patients after elective hip or knee arthroplasty: 2.5 mg 2 times per day (first administration 12-24 h after surgical intervention).
When deciding on the time to start therapy, physicians should consider the potential beneficial effect of early anticoagulant therapy in the prevention of venous thromboembolism on par with the risk of postoperative bleeding.
In patients who have undergone hip arthroplasty, the recommended duration of therapy is 32 to 38 days, and 10 to 14 days in the knee.

2. in patients with atrial fibrillation: 5 mg twice daily.
In patients with atrial fibrillation the dose of the preparation is decreased to 2.5 mg twice daily: – If there is the combination of two or more of the following characteristics – age 80 years and older, body weight 60 kg or less or creatinine concentration in plasma ≥ 1.5 mg/dL (133 µmol/L).
The therapy should be continued for a long time.

3. Treatment of deep vein thrombosis, pulmonary embolism (TELA):
10 mg twice daily for 7 days, then 5 mg twice daily.
Duration of treatment is determined individually, taking into account the ratio of expected benefit to 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 (i.e., previous surgery, trauma, period of immobilization, etc.) and manifestations of DVT and/or TELA, making a minimum of 3 months.

4. Prevention of recurrence of deep vein thrombosis, pulmonary embolism (TELA):
At 2.5 mg twice daily after at least 6 months of treatment of deep vein thrombosis or TELA with apixaban at 5 mg twice daily or other anticoagulant as indicated in Table 2.

Table 2

Dosages

The maximum daily dose

Treatment of deep vein thrombosis, TELA

10 mg twice daily for the first 7 days

20 mg

Then 5 mg twice daily

10 mg

Prevention of recurrence of deep vein thrombosis, TELA after 6 months of treatment for deep vein thrombosis or TELA.

2.5 mg twice daily

5 mg

. Total duration of therapy should be chosen individually after careful assessment of the ratio of benefits from taking the drug and the risk of bleeding (see “Indications. See section “Special Precautions”).

The use in patients with impaired renal function
For patients with mild to moderate renal function impairment the following recommendations are applicable:
– no dose adjustment is required when using apixaban for prevention of deep vein thrombosis in patients after elective hip or knee arthroplasty, for treatment of deep vein thrombosis, for treatment of VTE and prevention of recurrence of deep vein thrombosis, VTE (see section “Pharmacological properties”).
– When using apixaban in patients with atrial fibrillation and creatinine concentration ≥ 1.5 mg/dL (133 μmol/L) in plasma, in combination with age ≥ 80 years or body weight ≤ 60 kg requires reduction of the drug dose as described above. If other criteria for dose reduction are not met (age, body weight), correction of therapy is not required (see section “Pharmacological properties”).

In patients with severe renal dysfunction (with creatinine clearance 15-29 ml/min), the following recommendations apply (see sect. Sections “Special Indications” and “Pharmacological properties”):
– apixaban should be used with caution to prevent deep vein thrombosis in patients after elective hip or knee arthroplasty, to treat deep vein thrombosis, to treat VTE and to prevent recurrence of deep vein thrombosis, VTE;
– In patients with atrial fibrillation, a 2.5 mg dose of apixaban twice daily should be used.

There are no data on the use of apixaban in patients with creatinine clearance < 15 ml/min, as well as in patients on dialysis. Therefore, the use of Eliquis® in such patients is contraindicated (see section “Special Precautions” and “Pharmacological properties”).

The use of the drug in patients with hepatic impairment
Eliquis® is contraindicated in patients with liver diseases accompanied by blood clotting disorders and clinically significant risk of bleeding (see section “Contraindications”). The use of the drug in patients with severe hepatic insufficiency is contraindicated (see section “Contraindications”).

Patients with mild to moderate hepatic impairment (Child-Pugh class A or B) should use Eliquis® with caution; no dose adjustment is required (see sections “Special Indications” and “Pharmacological properties”).

Patients with increased hepatic alanine aminotransferase (ALT)/aspartate aminotransferase (ACT) enzyme activity twice the upper limit of normal or total bilirubin 1.5 times or more above the upper limit of normal have been excluded from clinical trials. In this regard, apixaban should be used with caution in patients in this group (see sections “Special Precautions” and “Pharmacological properties”). Liver function should be evaluated prior to initiation of therapy with Eliquis®.

Use in elderly patients
No adjustment of the drug dose is required in elderly patients (the exception is patients in p. 2 – use in atrial fibrillation).

Body weight
There is no need to adjust the dose depending on the patient’s body weight (except for patients in p. 2 – use in atrial fibrillation).

Gender
There is no need to adjust the dose depending on the gender of the patient.

Race and ethnicity
There is no need to adjust the drug dose based on the race or ethnicity of the patient.

Transition from or to parenteral anticoagulant therapy
Conversion from parenteral anticoagulants to Eliquis® and vice versa can be done at the time of the next scheduled dose of the discontinued drug (and the next dose of the discontinued drug is not taken).

Interaction

CYP3A4 and P-glycoprotein isoenzyme inhibitors
Combination of apixaban with ketoconazole (400 mg, once daily), which is a potent inhibitor of both CYP3A4 and P-glycoprotein isoenzymes, resulted in 2-fold increase in average AUC of apixaban and 1.6-fold increase in average Cmax.

The use of Eliquis® is not recommended in patients receiving concomitant systemic treatment with potent CYP3A4 and P-glycoprotein isoenzyme inhibitors, such as azole antimycotics (e.g. ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g. ritonavir) (see section “Special Indications”).

Drugs other than potent CYP3A4 and P-glycoprotein isoenzyme inhibitors (e.g., diltiazem, naproxen, clarithromycin, amiodarone, verapamil, quinidine) are likely to result in lower plasma apixaban concentrations. Dose adjustment of apixaban in combination with other drugs that are not potent inhibitors of CYP3A4 isoenzyme and P-glycoprotein, is not required. For example, diltiazem (moderate CYP3A4 isoenzyme inhibitor and weak P-glycoprotein inhibitor) at a dose of 360 mg once daily resulted in 1.4-fold increase of average AUC values of apixaban and 1.3-fold increase of average Cmax values. Naproxen (it is inhibitor of P-glycoprotein, but not CYP3A4 isoenzyme) in 500 mg dose caused 1.5 and 1.6 times increase of averaged AUC and Cmax values of apixaban, respectively. Clarithromycin (P-glycoprotein inhibitor and potent inhibitor of CYP3A4 isoenzyme) at a dose of 500 mg twice daily caused 1.6 and 1.3-fold increase of aUC and Cmax values of apixaban, respectively.

CYP3A4 and P-glycoprotein isoenzyme inducers
Combination of apixaban with rifampicin (a potent inducer of CYP3A4 and P-glycoprotein isoenzyme) resulted in decreased mean AUC and Cmax values of apixaban by approximately 54 % and 42 %, respectively. Apparently, combination of apixaban with other potent inducers of CYP3A4 isoenzyme and P-glycoprotein (in particular, phenytoin, carbamazepine, phenobarbital or preparations of Saint John’s wort) may also lead to reduction of apixaban plasma concentration (by about 50%). Dose adjustment of apixaban when combining it with agents of this group is not required when prescribed for indications: prevention of thromboembolism after joint endoprosthesis, stroke prevention and systemic thromboembolism in non-valvular atrial fibrillation and prevention of recurrent deep vein thrombosis, pulmonary embolism, but these agents should be combined with caution. During the use for treatment of deep vein thrombosis and VTE, co-administration of apixaban and potent inducers of CYP3A4 isoenzyme and P-glycoprotein is not recommended, because this may decrease the effectiveness (see section “Special indications”).

Anticoagulants, platelet aggregation inhibitors and NSAIDs
Due to the high risk of bleeding, concomitant use with any other anticoagulants is contraindicated (see section “Contraindications”). After co-administration of enoxaparin (once, in a dose of 40 mg) and apixaban (once, in a dose of 5 mg) an additive effect of these drugs on FXa activity was observed.

There was no evidence of pharmacokinetic or pharmacodynamic interaction between apixaban and acetylsalicylic acid (325 mg, once daily dose) in healthy subjects.

. Combination of apixaban with clopidogrel (in dose 75 mg, once daily) or combination of clopidogrel (75 mg) and acetylsalicylic acid (162 mg, once daily) or prasugrel (60 mg followed by 10 mg once daily) in phase I clinical trial did not lead to increased bleeding time or more pronounced inhibition of platelet aggregation compared to use of these antiaggregants in monotherapy. Increase of coagulation system parameters (prothrombin time, INR and ACTV) was consistent with the effects of apixaban when used in monotherapy.

Naproxen (500 mg), which is a P-glycoprotein inhibitor, increases mean AUC and Cmax values of apixaban by 1.5 and 1.6 times, respectively. A corresponding increase in blood clotting was observed with apixaban administration. No changes were observed in the effect of naproxen on platelet aggregation induced by arachidonic acid, and there was no clinically significant increase in bleeding duration after combined use of apixaban and naproxen. Despite these data, individual patients may show a more pronounced pharmacodynamic response after coadministration of apixaban with other antiaggregants. The drug Eliquis® should be used with caution concomitantly with NSAIDs (including acetylsalicylic acid), since these drugs usually increase the risk of bleeding. There was a statistically significant increase in the risk of major bleeding according to the criteria of the International Society on Thrombosis and Haemostasis (ISTH) when using triple therapy of apixaban, acetylsalicylic acid (ASA) and clopidogrel in a clinical study in patients with acute coronary syndrome with high risk of thrombosis and several concomitant cardiac and non-cardiac diseases.

The concomitant use of drugs which may be associated with the development of serious bleeding, such as: thrombolytic drugs, glycoprotein IIb/IIIa receptor antagonists, thienopyridines (e.g., clopidogrel), dipyridamole, dextran and sulfinpyrazone is not recommended.

Combination with other medicinal products
No clinically significant pharmacokinetic or pharmacodynamic interaction of apixaban with atenolol or famotidine has been observed. Combination of apixaban (in dose 10 mg) with atenolol (in dose 100 mg) did not lead to development of clinically significant changes of apixaban pharmacokinetic parameters, but it was accompanied by 15% and 18% reduction of mean AUC and Cmax values of apixaban in comparison with monotherapy regimen, respectively. Administration of apixaban (10 mg) with famotidine (40 mg) had no effect on the AUC or Cmax values of apixaban.

. In in vitro studies, apixaban did not inhibit the activity of the CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, or CYP3A4 isoenzymes (inhibitory concentration (IC50) > 45 μmol/L) and, at the same time, weakly inhibited the activity of the CYP2C19 isoenzyme (IC50 > 20 μmol/L) at a concentration significantly higher than the maximum plasma concentration of the drug during its clinical use. Apixaban is not an inducer of CYP1A2, CYP2B6, CYP3A4/5 isoenzymes at concentrations up to 20 µmol/l. In this regard, it is expected that when used together it will not affect clearance of drugs metabolized by these isoenzymes. In addition, apixaban does not significantly inhibit the activity of P-glycoprotein.

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

Digoxin
The AUC or Cmax of digoxin (in a dose of 20 mg once daily) and digoxin (in a dose of 0.25 mg once daily), which is a P-gp substrate, did not change. Thus, apixaban does not inhibit transport of P-glycoprotein substrates.

Naproxen
Simultaneous use of single doses of apixaban (10 mg) and naproxen (500 mg), a commonly used NSAID, had no effect on the AUC and Cmax of naproxen.

Atenolol
Simultaneous use of a single dose of apixaban (10 mg) and atenolol (100 mg), a commonly used beta-adrenoblocker, did not alter the pharmacokinetics of atenolol.

Activated charcoal
Taking activated charcoal decreases the effects of apixaban (see section “Overdose”).

Special Instructions

Risk of bleeding
As with other anticoagulants, patients receiving Eliquis® should be closely monitored for signs of bleeding. In conditions with a high risk of bleeding, it is recommended to use the drug with caution. The use of Eliquis® should be stopped if severe bleeding occurs (see sections “Side effects” and “Overdose”).

While therapy with apixaban does not require continuous monitoring of blood concentrations, calibrated quantitative analysis of anti-Xa activity may sometimes be appropriate in exceptional cases where data on the effects of apixaban may contribute to clinical decision-making, such as in overdose and emergency surgery (see section “Pharmacological properties”).

Interaction with other drugs affecting hemostasis
Due to the high risk of bleeding, concomitant use with any other anticoagulants is contraindicated (see section “Contraindications”).

The concomitant use of Eliquis® with antiaggregants increases the risk of bleeding (see section “Interaction with other medicinal products”).

The therapy in patients concomitantly receiving NSAIDs, including ASA, should be used with caution.

After surgery, it is not recommended to use other platelet aggregation inhibitors concomitantly with Eliquis® (see section “Interaction with other medicinal products”).

In patients with atrial fibrillation and conditions requiring antiaggregant therapy with one or both drugs, a careful assessment of the potential benefit-risk ratio should be made before concomitant therapy with Eliquis®.

In a clinical trial involving patients with atrial fibrillation, concomitant use of ASA led to an increased risk of major bleeding with both apixaban and warfarin. In this clinical trial, combined therapy with two antiaggregants was rarely used.

The use of thrombolytics for the treatment of acute ischemic stroke
Experience with thrombolytics for the treatment of acute ischemic stroke in patients receiving apixaban is very limited.

Patients with artificial heart valves
Safety and efficacy of the drug in patients with artificial heart valves with and without atrial fibrillation have not been studied. The use of Eliquis® in this group of patients is not recommended.

Surgical and invasive procedures
The use of Eliquis® should be discontinued at least 48 hours before a planned surgery or invasive procedure with moderate or high risk of bleeding. This includes interventions for which the possibility of clinically significant bleeding has not been ruled out or for which the risk of bleeding is unacceptable.

The use of Eliquis® should be discontinued at least 24 hours before a planned surgery or invasive procedure with a low risk of bleeding. This includes interventions where minimal, non-critical in location, or easily controlled bleeding is expected.

If an operation or invasive procedure cannot be delayed, it must be performed with appropriate caution, given the increased risk of bleeding. The risk of bleeding must be weighed against the need for emergency intervention. In non-valvular atrial fibrillation, the use of “bridge therapy” for 24-48 h after withdrawal of apixaban before surgical interventions is usually unnecessary.

Eliquis® should be restarted as soon as possible after an invasive procedure or surgery, provided that the clinical situation permits and sufficient hemostasis has been established (see section “Administration and Dose” for information on cardioversion).

Temporary discontinuation of therapy
Discontinuation of anticoagulants, including Eliquis® , ® due to active bleeding, elective surgery or an invasive procedure increases the risk of thrombosis for the patient. Interruption of treatment should be avoided, and if temporary discontinuation of anticoagulant therapy with Eliquis® is necessary for any reason, it should be resumed as soon as possible.

The treatment of deep vein thrombosis and VTE
Substitution of unfractionated heparin therapy with Eliquis® is not recommended during initiation of therapy in patients with VTE with unstable hemodynamics, possible thrombolysis or pulmonary thrombectomy because the safety and efficacy of apixaban in these clinical situations have not been established.

Patients with cancer
The efficacy and safety of apixaban in the treatment of DVT, treatment of TELA, and prevention of recurrent DVT and TELA (lVTE) in patients with an actively progressive malignancy have not been established.

Patients with renal impairment
Limited clinical data indicate that patients with severe renal impairment (creatinine clearance 15-29 mL/min) have increased plasma concentrations of apixaban, which may increase the risk of bleeding. For treatment of DVT, treatment of VTE and prevention of recurrent DVT and VTE (LVTE) apixaban in patients with severe renal impairment (creatinine clearance 15-29 ml/min) (see sections “Dosage and administration” and “Pharmacological properties”) should be used with caution.

For the prevention of stroke and systemic embolism in patients with NSF, patients with severe renal impairment (creatinine clearance 15-29 mL/min), and patients with serum creatinine levels ≥1.5 mg/dL (133 µmol/L) in combination with age ≥80 years or body weight ≤60 kg, the dose of apixaban should be reduced to 2.5 mg twice daily (see section “Dosage and administration”).

Because of the lack of experience in clinical use of apixaban in patients with creatinine clearance < 15 ml/min or on dialysis, administration of apixaban in this group of patients is not recommended (see sections “Dosage and administration” and “Pharmacological properties”).

Elderly patients
The risk of bleeding may increase with age (see section “Pharmacological properties”).
Also, concomitant use of Eliquis® and ASA in elderly patients requires caution due to the potentially higher risk of bleeding.

Body weight
At low body weight (< 60 kg) the risk of bleeding may increase (see section “Pharmacological properties”).

Patients with hepatic impairment
Eliquis® is contraindicated in patients with liver disease associated with coagulopathy and clinically significant risk of bleeding (see section “Contraindications”).

The drug is not recommended for patients with severe hepatic impairment (see section “Pharmacological properties”).

The drug should be used with caution in patients with mild to moderate hepatic impairment (Child-Pugh stage A or B) (see sections “Dosage and administration” and “Pharmacological properties”).

Patients with elevated hepatic enzyme levels of ALT/AST > 2 x HGH or total bilirubin ≥1.5 x HGH were excluded from clinical trials. Therefore, Eliquis® should be used with caution in this population (see section “Pharmacological properties”). Biochemical parameters of liver function should be checked before starting the use of Eliquis® .

Interaction with cytochrome P450 inhibitors and P-gp inhibitors
It is not recommended to use Eliquis® in patients receiving concomitant systemic treatment with potent CYP3A4 isoenzyme and P-glycoprotein inhibitors, such as azole antimycotics (e.g., ketoconazole, itraconazole, voriconazole and posaconazole) and HIV protease inhibitors (e.g., ritonavir). These drugs may increase the exposure of apixaban twofold (see section “Interaction with other medicinal products”) or higher in the presence of additional factors that also increase the exposure of apixaban (e.g., severe renal impairment).

Interaction with CYP3A4 and P-gp isoenzyme inducers
Co-administration of Eliquis® with potent CYP3A4 isoenzyme inducers and P-gp inducers (e.g., rifampicin, phenytoin, carbamazepine, phenobarbital and preparations of Saint John’s wort) may also lead to decrease of apixaban concentration in blood plasma (by about 50%). In a clinical study involving patients with atrial fibrillation, a decrease in efficacy and increased risk of bleeding were noted when apixaban and potent CYP3A4 and P-gp isoenzyme inducers were used simultaneously compared to apixaban in monotherapy.

The following guidelines apply to patients receiving systemic therapy with potent CYP3A4 and P-gp isoenzyme inhibitors (see section “Interaction with other medicinal products”):

– For the prevention of venous thromboembolism in patients after elective hip or knee arthroplasty, the prevention of stroke and systemic thromboembolism in non-valvular atrial fibrillation, and for the prevention of recurrent DVT and TELA, apixaban should be used with caution:
– For treatment of DVT and TELA, apixaban should not be used because efficacy may be reduced.

Surgical interventions related to femoral neck fracture
The efficacy and safety of apixaban have not been evaluated in clinical trials in patients after surgical intervention for femoral neck fracture. Therefore, it is not recommended for these patients.

Laboratory parameters
The effect of the mechanism of action of apixaban on coagulation parameters (e.g., prothrombin time (PV), INR and activated partial thromboplastin time (APT)) was as expected. The observed changes in these clotting parameters at the expected therapeutic dose were small and had considerable variability (see section “Pharmacological properties”).

Information on excipients
Eliquis® contains lactose. Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Eliquis® .

Performance of spinal or 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 for the prevention of thromboembolism, there is a risk of epidural or spinal hematomas which, in turn, may 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 hours before the first dose of Eliquis®. The risk may also increase with traumatic or repeated epidural or spinal punctures. Patients should be frequently checked for manifestations and symptoms of neurological deficit (e.g., numbness or weakness in the legs, bowel or bladder dysfunction). If a neurological abnormality is detected, immediate diagnosis and treatment is necessary. Prior to neuroaxial intervention, the physician should analyze the potential benefit-risk ratio for patients who are receiving anticoagulant therapy or will receive it to prevent thrombosis.

There is no clinical experience with the use of apixaban in patients with an intrathecal or epidural catheter. If this situation is necessary, based on pharmacokinetic features of apixaban, an interval of 20-30 h (i.e. 2 half-lives) should be observed between the last dose of apixaban taken and catheter removal, so that at least one dose of apixaban should be skipped before catheter removal. The next dose of apixaban may be administered not earlier than 5 hours after catheter removal. As with all new anticoagulant drugs, experience with apixaban in neuroaxial blockade is limited, and therefore extreme caution should be exercised in this situation.

The drug Eliquis® has no or negligible effect on the ability to drive vehicles and operate mechanisms.

Contraindications

Cautions
Risk of bleeding
The drug is not recommended in cases of liver disease accompanied by bleeding disorders and clinically significant risk of bleeding. The drug should be discontinued in case of severe bleeding.

In case of complications in the form of bleeding, therapy with the drug should be stopped; the source of bleeding should also be determined. Surgical hemostasis or transfusion of fresh frozen plasma may be considered among the options for stopping bleeding; in life-threatening conditions that cannot be controlled by the above methods, administration of prothrombin complex concentrate (PPC) or recombinant clotting factor VIIa may be considered. In healthy volunteers, reversibility of pharmacodynamic effects of Eliquis® according to the results of thrombin generation test was observed after infusion of CRP containing 4 clotting factors. However, there is no experience of clinical use of CPK containing 4 clotting factors to stop bleeding in patients treated with Eliquis®. There is currently no experience with recombinant factor VIIa in patients receiving apixaban therapy.

Caution should be exercised when concomitant use of apixaban with nonsteroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid) due to the fact that these drugs increase the risk of bleeding.

The concomitant use of Eliquis® and acetylsalicylic acid (ASA) in elderly patients requires caution due to a potentially higher risk of bleeding. In patients with atrial fibrillation and conditions requiring mono- or dual antiaggregant therapy, a careful risk-benefit assessment should be performed before prescribing apixaban.

Side effects

Frequent adverse reactions were bleeding, bruising, nasal bleeding, and hematoma (see adverse reaction profile and frequency by indication below). The frequency of adverse reactions is defined as: frequently ≥ 1/100, < 1/10, infrequently ≥ 1/1000, < 1/100, rarely ≥ 1/10000, < 1/1000.

The use of Eliquis® may be associated with an increased risk of bleeding (including occult bleeding) from any organ or tissue, which in turn may lead to the development of post-hemorrhagic anemia. Symptoms, signs, and severity will vary depending on the source of the bleeding and the extent or spread of the bleeding.

Overdose

An antidote is not known. In case of overdose, the risk of bleeding increases. Hemodialysis for apixaban overdose is not expected to be effective.

In controlled clinical trials, apixaban was taken orally in healthy volunteers at 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); no clinically significant adverse effects were observed.

The use of activated charcoal may be considered if there is an overdose of this drug.

When activated charcoal was administered to healthy volunteers 2 and 6 hours after administration of apixaban at a dose of 20 mg, the area under the concentration-time curve (AUC) for apixaban decreased by 50% and 27%, respectively (Cmax was not changed). The half-life of apixaban decreased from 13.4 to 5.3 and 4.9 hours, respectively.

Pregnancy use

Pregnancy use
There are no data on the use of apixaban in pregnant women. During preclinical studies no direct or indirect negative effects on reproductive function were found. The use of apixaban in pregnancy is contraindicated.

Pregnant use
There are no data on excretion of apixaban or its metabolites with breast milk in humans. According to the available data from animal studies, apixaban is excreted into breast milk. In studies on rats, the drug concentration in breast milk was many times higher than that in blood plasma (Cmax is approximately 8 times higher, AUC approximately 30 times higher), which may indicate active transport of the drug into breast milk. The risk to breastfed infants cannot be excluded. A decision should be made to discontinue the drug or to stop breastfeeding if the use of Eliquis® is necessary.

Impact on fertility
Apixaban did not affect fertility in animal studies.