Elikvis - instructions for use, doses, side effects, contraindications

Active substanceApixabanApixaban

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Elikvis®

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Bristol-Myers Squibb Company USA

Elikvis®

pills inwards

Bristol-Myers Squibb Company USA

Dosage form: & nbspFilm-coated tablets.

Composition:

1 tablet, film-coated, contains:

Active substance: apixaban 5.0 mg.

Excipients:

For tablets 5.0 mg:

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 Sheath:

For tablets 5.0 mg: Opadrai 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, ferric oxide red oxide 0.046 mg).

Description:

Tablets 5.0 mg: oval, biconvex tablets, film-coated, pink with engraved "894" on one side and "5" on the other side.

Pharmacotherapeutic group:Anticoagulant direct action is a selective inhibitor of the coagulation factor Ha (FXa).

ATX: & nbsp

B.01.A.F.02 Apixaban

Pharmacodynamics:

Apixaban is a powerful direct inhibitor of FXa, reversibly and selectively blocking the active site of the enzyme. The drug is intended for oral administration. To realize the antithrombotic activity of apixaban, the presence of antithrombin III is not required. Apixaban inhibits free and bound FXa, as well as prothrombinase activity. Apixaban has no direct direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by thrombin. By inhibiting FXa activity apixaban prevents the formation of thrombin and thrombi. As a result of FXa suppression, the values of the parameters of the blood clotting system change: the prothrombin time, activated partial thromboplastin time (APTT) is prolonged and the international normalized ratio (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 ns is recommended.

Inhibition of apixaban activity FXa proven using a chromogenic test using heparin Rotachrom. Change in anti-FXa-activity is directly proportional to the increase in the concentration of apixaban in the blood plasma, while the maximum values of activity are observed when the maximum concentration of apixaban in the blood plasma is reached. The linear relationship between concentration and anti-FXa-the activity of apixaban is recorded in a wide range of therapeutic doses of the drug. Changes in anti-FXa-activity with a change in dose and concentration of apixaban are more pronounced and less variable than blood coagulation.

Table 1 shows the expected equilibrium concentrations and anti-FXa-activity with drug application apixaban for each of the readings. In patients receiving apixaban after a planned endoprosthesis of the hip or knee joint, the ratio of the maximum and minimum levels of anti-FXa-activity in the interval between taking doses of the drug does not exceed 1.6. In patients receiving apixaban for the prevention of stroke and systemic thromboembolism in non-valvular atrial fibrillation, this ratio is less than 1.7, and in patients receiving apixaban about the treatment of deep vein thrombosis and the prevention of relapses of deep vein thrombosis, less than 2.2.

Table 1. Estimated equilibrium concentrations (ng / ml) and anti-FXa-Activity (IU/ ml)

	Apixaban	Apixaban	Anti-Xa-	Anti-Xa-
	FROMmOh	Cmin	activity apixaban	activity apixaban
			Mach	Min
		Median 15 th, 95 th Percertile]
Prevention	venous thromboembolism in		patients after a planned
arthroplasty of the hip or knee joint
2.5 mg 2 times in	77 [41, 146]	51 [23, 109]	1,3 [0,67, 2,4]	0,84 [0,37, 1,8]
day
Prevention	stroke and systemic thromboembolism in patients			with fibrillation
atria
2.5 mg 2 times a day *	12,3 [69, 221]	79 [34, 162]	1,8 [1,0, 3,3]	1,2 [0,51, 2,4]
5 mg 2 times in	171 [91, 321]	103 [41, 230]	2,6 [1,4, 4,8]	1,5 [0,61, 3,4]
day
Treatment of thromboembolism
2.5 mg 2 times in	67 [30, 153]	32 [11, 90]	1,1 [0,47, 2,4]	0,51 [0,17, 1,4]
day
5 mg 2 times in	132 [59, 302]	63 [22, 177]	2,1 [0,93, 4,8]	1,0 [0,35, 2,8]
day
10 mg twice daily	251 [111, 572]	120 [41, 335]	4,0 [1,8, 9,1]	1,9 [0,65, 5,3]
day

* Correction of dose according to the criteria for dose reduction in the study ARISTOTLE.

Against the background of therapy with apixaban, routine monitoring of its anticoagulant effect is not required, but the performance of a calibrated quantitative anti-FHa-activity can be useful in situations where information about the presence of apixaban in the blood can be useful for deciding whether to continue therapy. In comparison with warfarin, amid the use of apixaban, there are fewer bleedings, including intracranial hemorrhage.

Pharmacokinetics:

Suction

Absolute bioavailability of apixaban reaches 50% when administered in doses up to 10 mg. Apixaban quickly absorbed from the gastrointestinal tract, its maximum concentration (Cmah) is achieved within 3-4 hours after oral administration.The intake of food does not affect the values of the area under the "concentration-time" curve (AUC) or withmah 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 drug, which is accompanied by a decrease in its bioavailability. Metabolic indexes of apixaban are characterized by low or moderate inter- and intra-individual variability (the corresponding values of the coefficient of variation are ~ 20% and ~ 30%, respectively).

Distribution

The association of apixaban with human plasma proteins is approximately 87%, the volume of distribution (Vss) - approximately 21 liters.

Metabolism and excretion

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.

The total clearance of apixaban is approximately 3.3 liters / h, the half-life (T1 / 2) is about 12 hours. O-demethylation and hydroxylation of the 3-oxopiperidinyl residue are the main ways of biotransformation of apixaban. Apixaban mainly metabolized with the participation of isoenzyme CYP3A4/5, to a lesser extent - isoenzymes CYP1A2, 2С8, 2С9, 2С19 and 2J2. Unchanged apixaban is the main substance circulating in the human blood plasma, active metabolites circulating in the blood stream are absent. Besides, apixaban is a substrate of transport proteins, P-glycoprotein and breast cancer resistance protein (BCRP).

Impaired renal function

Impaired renal function does not affect the maximum concentration of apixaban. However, there was an increase in the concentration of apixaban, correlated with the degree of decrease in renal function, estimated from the values of creatinine clearance. In persons with impaired renal function, mild (creatinine clearance from 51 ml / min to 80 ml / min), medium (creatinine clearance from 30 ml / min to 50 ml / min) and severe (creatinine clearance from 15 ml / min to 29 ml / min), the values AUC apixaban in blood plasma increased by 16%, 29% and 44%, respectively, compared with those who had normal values of creatinine clearance. At the same time, renal dysfunction did not have an obvious effect on the relationship between the concentration of apixaban in the blood plasma and its anti--FXa-activity.Studies of apixaban in patients with creatinine clearance less than 15 ml / min or those on dialysis have not been performed.

Impaired liver function

Studies of apixaban in severe hepatic insufficiency and active pathology of the hepatobiliary system were not carried out.

There were no significant changes in the parameters of pharmacokinetics and pharmacodynamics with a single dose of apicaban 5 mg in patients with mild to moderate hepatic insufficiency (Child-Pugh classes A and B, respectively) compared with healthy volunteers. Changes in anti-FXa activity and INR in patients with mild and moderate hepatic insufficiency and healthy volunteers were comparable.

Use in elderly patients

In elderly patients (over 65 years of age), the plasma concentrations of the drug were higher than in younger patients: mean AUC was approximately 32% higher.

Floor

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

Race and ethnic origin

The results obtained in the framework of Phase I studies,testify to the absence of significant differences in the pharmacokinetics of apixaban between representatives of the Caucasoid, Mongoloid and Negroid races. Results of analyzes of pharmacokinetics in various populations carried out within the program of clinical studies of apixaban, including patients who received apixaban after a planned endoprosthesis of the hip or knee joint, are generally consistent with the results of Phase I studies.

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.

Dependence of parameters of pharmacokinetics and pharmacodynamics

The relationship between the parameters of pharmacokinetics and pharmacodynamics (including anti--FXa-activity, INR, prothrombin time, APTT) of apixaban and its concentration in plasma was studied for a wide range of doses (from 0.5 mg to 50 mg). It was shown that the relationship between apixaban concentration and activity FXa is best described using a linearmodel. Dependence of the parameters of pharmacokinetics and pharmacodynamics of apixaban, evaluated in patients who received apixaban in clinical studies of II and III phases, corresponded to that of healthy volunteers.

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 with one or more risk factors (such as a stroke or transient ischemic attack in history, age 75 years and older, hypertension, diabetes mellitus, symptomatic chronic heart failure (functional class II and higher by classification NYHA)). 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.

Contraindications:

- Hypersensitivity to any component of the drug.

- Clinically significant bleeding.

- In conditions characterized by an increased risk of bleeding: congenital or acquired bleeding disorders; exacerbations of peptic ulcer of the gastrointestinal tract; 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; with severe uncontrolled arterial hypertension.

- Severe violations of liver function, liver disease, accompanied by disorders in the blood coagulation system and clinically significant risk of bleeding.

- Impaired renal function with creatinine clearance less than 15 ml / min, as well as use in patients on dialysis.

- Age under 18 years (no data on the use of the drug).

- Pregnancy (there are no data on the use of the drug).

- Breastfeeding period (there are no data on the use of the drug).

- Simultaneous use with drugs, the effect of which may be associated with the development of serious bleeding, such as any anticoagulant drugs, unfractionated heparins, low molecular weight heparins (enoxaparin,dalteparin), heparin derivatives (fondaparinux), oral anticoagulants (warfarin, rivaroxaban, dabigatran), except for situations in which the patient is switched to therapy or with apixaban therapy, or if unfractionated heparin is given at the doses necessary to maintain the permeability of the central venous or arterial catheter (see "Interactions with Other Drugs"),

- Congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption.

Carefully:

The experience of using the drug with thrombolytic agents for the relief of acute ischemic stroke is limited.

Apixaban should be used with caution in patients with moderate or mild liver function disorder (Child-Pugh class A or B).

Apixaban should be used with caution in performing spinal / epidural anesthesia or spinal / epidural puncture (see "Special instructions"), as well as in patients receiving systemic therapy with potent inhibitors of isoenzyme CYP3A4 and P-glycoprotein, such as azole antifungal agents (in particular, ketoconazole, itraconazole, voriconazole and posaconazole), HIV protease inhibitors (e.g., ritonavir). Care should also be taken when using apixaban with powerful isoenzyme inducers CYP3A4 and P-glycoprotein (in particular, rifampicin, phenytoin, carbamazepine, phenobarbital or preparations of St. John's wort perfumed).

Risk of bleeding

It is not recommended to use the drug for liver diseases accompanied by disorders in the blood coagulation system and clinically significant risk of bleeding. It is necessary to stop using the drug when heavy bleeding occurs.

If complications occur in the form of bleeding, therapy with the drug should be stopped; also need to establish a source of bleeding. Among the possible options for stopping bleeding, surgical hemostasis or transfusion of freshly frozen plasma can be considered, in life-threatening conditions that can not be controlled by the above methods, one may consider the possibility of introducing a recombinant coagulation factor VIII, although there is currently no experience with the use of this clotting factor in patients receiving apixaban therapy.

Caution should be exercised while using apixaban with non-steroidal anti-inflammatory drugs (NSAIDs) (including acetylsalicylic acid) because these drugs increase the risk of bleeding.

Operative interventions related to hip fracture

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

Pregnancy and lactation:

Application in pregnancy

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

Application in the period of breastfeeding

In studies on rats, the concentration of the drug in breast milk was many times higher than that in blood plasma (Cmah about 8 times higher, AUC approximately 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 Eliksvis ® during lactation, breastfeeding should be discontinued.

Impact on fertility

Apixaban did not affect fertility in animal studies.

Dosing and Administration:

Elikvis ® is taken orally, 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.

1. In patients after planned endoprosthetics of the hip or knee joint:

2.5 mg 2 times a day (first reception 12-24 hours after surgery).

The recommended duration of therapy is 32 to 38 days, the knee joint is 10 to 14 days.

2. In patients with atrial fibrillation:

One tablet 5 mg 2 times a day.

Dosage 2.5 mg (tablet 2.5 mg) is used when there is 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 blood plasma> 1.5 mg / dL (133 μmol / l).

3. Treatment of deep vein thrombosis, pulmonary thromboembolism (PE):

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.

4. Prevention of relapses of deep vein thrombosis, pulmonary thromboembolism (PE):

2.5 mg 2 times a day after at least 6 months of treatment of deep vein thrombosis or PE.

Appliedue the naof patients with impaired renal function

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

Use in patients with impaired liver function

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.

Application v elderly patients

Correction of the dose of the drug in elderly patients is not required (except for patients referred to in paragraph 2 - use in atrial fibrillation).

Body mass

Correction of the dose, depending on the patient's body weight, is not required (the exception is the patients mentioned in paragraph 2 - application in atrial fibrillation).

Floor

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

Race and ethnic origin

Correction of the dose of the drug depending on the race or ethnic origin of the patient is not required.

Transition from or to therapy with parenteral anticoagulants

The translation from parenteral anticoagulants to Elikvis® and vice versa can be performed at the time of the next scheduled use of the withdrawn drug (with the nextdose of the drug is not taken).

Transition from or to warfarin or other antagonists of vitamin K

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

When transferring patients from Elikvis® to warfarin or other vitamin K antagonists, continue therapy with Eliksis® for 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 Elikvis®. The combined administration of warfarin (or another vitamin K antagonist) and Eliksis® should be continued until MBUT > 2.0. When the INR> 2.0 is reached, Elicvis® should be discontinued.

Surgical and invasive procedures

Eliwis® should be discontinued at least 48 hours before the scheduled operation or an invasive procedure with an estimated average or high risk of life-threatening or clinically significant bleeding. Eliksis® should be discontinued at least 24 hours before the planned operation or invasive procedure,if 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 may continue to receive Eliksis® 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 effects:

The frequency of adverse reactions is understood: often -> 1/100, <1/10, infrequently -> 1/1000, <1/100, rarely -> 1/10000, <1/1000.

Prophylaxis of venous thromboembolism the patients after planned endoprosthetics of the hip or knee joint

Undesirable reactions were noted in 11% of patients who received apixaban in a dose of 2.5 mg 2 times a day. As with other anticoagulants, bleeding may occur in patients with risk factors, such as organic lesions, which may be accompanied by bleeding. The most common side effects were anemia, bleeding, bruising, nausea. The undesirable reactions that have developed in patients who underwent orthopedic surgery, against apyxaban therapy are presented below.

From the side of the blood and lymphatic system: often - Anemia (including postoperative and posthemorrhagic, accompanied by appropriate changes in the results of laboratory tests), bleeding (including hematoma, vaginal and urethral bleeding); infrequently - Thrombocytopenia (including a decrease in the number of platelets).

From the immune system: rarely - hypersensitivity.

Co side of the organ of vision: rarely - hemorrhages in the tissue of the eyeball (including hemorrhage in the conjunctiva).

From the cardiovascular system: infrequently - arterial hypotension (including hypotension during the procedure).

Co the respiratory system: infrequently - nose bleed; rarely - hemoptysis.

Co side of the gastrointestinal tract: often - nausea; infrequently - gastrointestinal bleeding (including vomiting with an admixture of blood and melena), the presence of unchanged blood in the stool; rarely - rectal bleeding, bleeding from the gums.

Co side of the liver and bile ducts: infrequently - increased transaminase activity, including increased activity of alanine aminotransferase, aspartate aminotransferase, increased activity of gamma-glutamyltranspeptidase, pathological changes in functional liver samples, increased activity of alkaline phosphatase in the blood, increased bilirubin concentration in the blood.

From the musculoskeletal system: rarely - Muscular hemorrhage.

Co side of the urinary system: infrequently - hematuria (including corresponding changes in the results of laboratory studies).

Other reactions: often - closed trauma; infrequently - hemorrhages and bleeding after performing invasive procedures (including hematoma after the procedure, bleeding from the postoperative wound, hematoma in the area of the vascular puncture and at the site of the catheter installation), the presence of a discharge from the wound, hemorrhage in the incision area (including hematoma in the region of the incision ), bleeding during surgery.

Prevention of strokes and systemic embolism the patients with atrial fibrillation

Co side of the immune system: infrequently - hypersensitivity (including drug hypersensitivity reactions, such as skin rashes and anaphylactic reactions, such as allergic edema).

Co side of the nervous system: infrequently - intracranial hemorrhages, Subarachnoid hemorrhages, subdural hematomas, cerebral hemorrhages, spinal hematoma.

From the side of the eye: often - hemorrhages in the tissue of the eyeball (including hemorrhage in the conjunctiva).

From the cardiovascular system: often - other types of bleeding, bruising; infrequently - bleeding into the abdominal cavity.

From the respiratory system: often - nose bleed; infrequently - hemoptysis; rarely - bleeding into the respiratory system (including pulmonary alveolar bleeding, guttural and pharyngeal bleeding).

From the gastrointestinal tract: often - gastrointestinal bleeding (including vomiting with an admixture of blood and melena), rectal bleeding, bleeding from the gums; infrequently - hemorrhoidal bleeding, the presence of unchanged blood in the stool, bleeding into the mouth; rarely - retroperitoneal hemorrhage.

From the urinary system: often - Hematuria.

Co side of the reproductive system: infrequently - intermenstrual vaginal bleeding, urogenital bleeding.

Reactions at the site of administration: infrequently - bleeding at the injection site.

Laboratory indicators: infrequently - a positive reaction in the analysis of feces for latent blood.

Other reactions: often - closed trauma; infrequently - traumatic bleeding, bleeding after the procedure, hemorrhage in the region of the incision.

Treatment of deep vein thrombosis, pulmonary embolism

From the side of the blood and lymphatic system: rarely - hemorrhagic anemia, hemorrhagic diathesis, spontaneous occurrence of hematomas.

From the nervous system: rarely - craniocerebral hemorrhages, hemorrhagic stroke.

From the side of the organ of vision: infrequently - hemorrhage in the conjunctiva; rarely - haemorrhage in the eyeball tissue, hemorrhage to the retina, sclera, vitreous.

From the organs of hearing: rarely - Ear bleeding.

From the cardiovascular system: often - hematomas; rarely - pericardial bleeding, other types of bleeding, bleeding into the abdominal cavity, hemorrhagic shock.

From the respiratory system: often - nose bleed; infrequently - hemoptysis; rarely - pulmonary alveolar bleeding.

From the gastrointestinal tract: often bleeding from the gums, infrequently - rectal bleeding, the presence of unchanged blood in the stool, hemorrhoidal bleeding, gastrointestinal bleeding, bloody vomiting; rarely - melena, anal bleeding, bleeding from stomach and duodenal ulcers, bleeding into the oral cavity, abdominal wall bruising, Malory-Weiss syndrome, gastric bleeding,bleeding in the small intestine.

From the skin: infrequently - bruising, bleeding from the skin, rarely - Petechia, purpura, increased tendency to bleeding, a corn, a bleeding from skin ulcers.

From the musculoskeletal system: rarely - hemorrhage in the muscles.

From the urinary system: often - hematuria, rarely - bleeding of the urinary system.

On the part of the reproductive system: often - Hypermenorrhea, infrequently - vaginal bleeding, metrorrhagia, rarely - menometrorrhagia, uterine bleeding, genital bleeding, hemorrhages in the mammary gland, hematospermia, uterine bleeding after the onset of menopause.

Reactions at place of administration and other reactions: infrequently - hematoma at the site of injection, hematoma at the site of the vascular puncture, bleeding from the wound, traumatic hematoma, rarely - bleeding at the injection site, hematoma at the infusion site, periorbital hematoma, vascular pseudoaneurysm, subcutaneous hematoma, hematoma during and after the procedure, hematuria after the procedure, extradural hematoma, subdural bleeding, hematoma of the kidney.

Laboratory indicators: infrequently - the presence of blood in the urine, a positive reaction in the analysis of feces for latent blood, rarely - latent blood, the presence of erythrocytes in the urine.

Overdose:

The antidote is not known. Overdose increases the risk of bleeding. It is not expected that the use of hemodialysis in case of an overdose of apixaban will be an effective measure.

Within the framework of controlled clinical trials apixaban was taken orally by healthy volunteers in doses up to 50 mg / day for 3 to 7 days (25 mg, 2 times a day, for 7 days or 50 mg, once a day, for 3 days); clinically significant adverse effects were not observed.

In case of an overdose of this drug, one can consider the use of activated carbon.

With the introduction of healthy volunteers activated carbon at 2 and 6 hours after taking apixaban at a dose of 20 mg, the area under the concentration-time curve (AUC) for apixaban decreased by 50% and 27%, respectively (Cmah did not change). The half-life of apixaban decreased from 13.4 to 5.3 and 4.9 hours, respectively.

Interaction:

The effect of other drugs on the pharmacokinetics of apixaban

Inhibitor inhibitors CYP3A4 and P-glycoprotein

The combination of apixaban with ketoconazole (400 mg once a day), which is a potent inhibitor of both isoenzyme CYP3A4, and P-glycoprotein, led to an increase in the mean value AUC apixaban by 2 times and the average value of Cmah in 1,6 times. Correction of the dose of apixaban when combined with ketoconazole is not required, however apixaban Caution 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 not related to potent inhibitors of isoenzyme CYP3A4 and P-glycoprotein (e.g., diltiazem, naproxen, amiodarone, verapamil, quinidine), apparently, will lead to an increase in the concentration of apixaban in the blood plasma to a lesser extent. For example, diltiazem (moderate isoenzyme inhibitor CYP3A4 and a weak inhibitor of P-glycoprotein) at a dose of 360 mg once a day led to an increase in the mean values AUC apixaban by a factor of 1.4 and the average values of Cmah 1,3 times. Naproxen (inhibitor of P-glycoprotein) when administered at a dose of 500 mg in healthy volunteers caused an increase in the mean values AUC and Cmah apixaban in 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, MPO and APTT). However, there was no effect of naproxen on arachidonic acid-induced platelet aggregation, as well as clinically significant lengthening of bleeding time.

Correction of dose of apixaban when combined with moderate isoenzyme inhibitors CYP3A4 and / or P-glycoprotein is not required.

Inductors of isoenzyme CYP3A4 and P-glycoprotein

The combination of apixaban with rifampicin (a powerful isoenzyme inducer CYP3A4 and P-glycoprotein) led to a decrease in the mean values AUC and Cmah apixabana approximately 54% and 42%, respectively. It seems that the combination of apixaban with other potent inducers of the isoenzyme CYP3A4 and P-glycoprotein (in particular, phenytoin, carbamazepine, phenobarbital or preparations of St. John's wort) can also lead to a decrease in the concentration of apixaban in the blood plasma (by approximately 50%). Correction of the dose of apixaban when it is combined with the funds of this group is not required for prescription according to indications: prevention of thromboembolism after arthroplasty,prevention of strokes and systemic thromboembolism in patients with non-valvular atrial fibrillation and prevention of relapses of deep vein thrombosis, pulmonary embolism, but these agents should be combined with caution. During the application for the treatment of deep vein thrombosis and PE, the joint application of apixaban and powerful inducers of the isoenzyme CYP3A4 and P-glycoprotein is not recommended.

Anticoagulants, inhibitors of platelet aggregation and NSAIDs

After the joint administration of enoxaparin (once, at a dose of 40 mg) and apixaban (once, at a dose of 5 mg), the additive effect of these drugs on the activity FXa.

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 (at a dose of 75 mg once a day) or a combination of clopidogrel (75 mg) and acetylsalicylicacid (162 mg once daily) or prasugrel (60 mg followed by a dose of 10 mg once daily) did not lead to an increase in bleeding time or more severe inhibition of platelet aggregation in the phase I clinical study compared with the use of these antiplatelet agents in monotherapy. The increase in the parameters of the blood clotting system (prothrombin time, MNO and APTT) corresponded to the effects of apixaban when used 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 inhibiting FXa (eg fondaparinux), direct thrombin inhibitors II (eg, desandin), thrombolytic drugs, glycoprotein receptor antagonists IIb/IIIa, dipyridamole, dextran, sulfinpyrazone, vitamin K antagonists and other oral anticoagulants. It should be noted that unfractionated heparin can be used in doses necessary to support the permeability of the central 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 in conjunction with powerful inducers CYP3A4 and P-glycoprotein (such as rifampicin, phenytoin, carbamazepine, phenobarbital and preparations of St. John's wort perfumed) can lead to a 50% reduction in the concentration of the drug in the blood plasma, so these combinations should be used with caution.The combined use of apixaban with powerful inducers is not recommended CYP3A4 and P-glycoprotein in the use of 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 (at a dose of 10 mg) with atenolol (at a dose of 100 mg) did not lead to the development of clinically significant changes in the pharmacokinetics of apixaban, but it was accompanied by a decrease in mean values AUC and Cmah apixaban by 15% and 18% respectively, compared with the regimen of monotherapy. The appointment of apixaban (at a dose of 10 mg) with famotidine (at a dose of 40 mg) had no effect on the values AUC or withmah apixaban.

Effect of apixaban on the pharmacokinetics of other drugs

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

Special instructions:

Risk of bleeding

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

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 the presence of multiple as cardiac,and non-cardiac 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 compared with placebo.

As with the use of other anticoagulants, careful monitoring of patients taking Eliwis®, for the development of bleeding. With the development of severe bleeding, the drug Elikvis® should be canceled.

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.

The abolition of therapy with anticoagulants, including apixaban, with active bleeding, before routine surgery or an invasive procedure can 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 the framework of clinical studies Eliwis® It was not used in patients who underwent urgent surgical interventions 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 subarachnoid 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 hours (ie, 2 half-lives) between the last dose of apixaban 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 patients receiving anticoagulants, including for the prevention of thrombosis, it is necessary to assess the ratio of potential benefits and risks.

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. Application of Elikvis® for this group of patients is not recommended.

Treatment of deep vein thrombosis and PE

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

Effect on the ability to drive transp. cf. and fur:

Eliwis® does not have a significant impact on the ability to drive vehicles and work with mechanisms.

Form release / dosage:Tablets, film-coated, 5 mg.

Packaging:

(Information is indicated only for packaging at the company Bristol-Myers Squibb Sr.L .. Italy):

Tablets, film-coated, 5 mg.

For 10 or 14 tablets in a blister of PVC / PVDC film and aluminum foil.

For 2, 6 or 10 blisters of 10 tablets together with instructions for use in a cardboard pack.

For 4 blisters of 14 tablets together with instructions for use in a cardboard bundle.

But 10 tablets in a perforated blister from PBX/PVDH film and aluminum foil.

For 2, 6 or 10 perforated blisters, together with instructions for use in a cardboard bundle.

Or (the information is indicated only when packing at the enterprise JSC "AKRIKHIN", Russia):

Tablets, film-coated, 5 mg.

For 10 tablets in a perforated blister of PVC / PVDC film and aluminum foil.

For 2 or 6 perforated blisters together with instructions for use in a cardboard bundle.

Storage conditions:

Store at a temperature not exceeding 30 ° C.

Keep out of the reach of children!

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002007

Date of registration:19.02.2013

The owner of the registration certificate:Bristol-Myers Squibb CompanyBristol-Myers Squibb Company USA

Manufacturer: & nbsp

BRISTOL-MYERS SQUIBB Manufacturing Company Puerto Rico

Representation: & nbspBRISTOL-Majers SKVIBB, LLCBRISTOL-Majers SKVIBB, LLCRussia

Information update date: & nbsp21.04.2015

Illustrated instructions

Instructions

Elikvis® (Eliquis®)