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Eliquis 5 mg No. 60 tablet p.p.o.

Instructions for medical use of the drug Eliquis Trade name Eliquis International nonproprietary name Apixaban Dosage form Film-coated tablets, 2.5 mg and 5 mg Composition One tablet contains the active substance - apixaban 2.5 mg or 5 mg, excipients: anhydrous lactose , microcrystalline cellulose, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate. Composition of the shell for a dosage of 2.5 mg - Opadry® II yellow (hypromellose, lactose monohydrate, titanium dioxide (E171), triacetin -, iron oxide dye yellow (E 172)) for a dosage of 5 mg - Opadry® II pink (hypromellose, lactose monohydrate, titanium dioxide (E171), triacetin, red iron oxide dye (E172)) Description Round, biconvex, yellow film-coated tablets, embossed “893” on one side and “2 ½” on the other side (dosage 2.5 mg) . Oval, biconvex, pink film-coated tablets, embossed with “894” on one side and “5” on the other side (dosage 5 mg). Pharmacotherapeutic group Blood and hematopoietic organs. Antithrombotic drugs. Direct factor Xa inhibitors. Apixaban. ATC code B01AF02 Pharmacological properties Pharmacokinetics Absorption When taken orally in doses up to 10 mg, the absolute bioavailability of apixaban is approximately 50%. Apixaban is rapidly absorbed and reaches maximum concentration (Cmax) 3-4 hours after taking the tablet. Taking the drug at a dose of 10 mg with food does not affect the values of AUC (drug exposure in the blood plasma or area under the concentration-time curve) or Cmax. Therefore, apixaban can be taken with or without food. Apixaban in the dose range up to 10 mg demonstrates linear pharmacokinetics, i.e. the increase in exposure is proportional to the dose taken. When taking doses of ³ 25 mg, apixaban is characterized by limited absorption and decreased bioavailability. Apixaban exposure parameters show low to moderate interindividual variability, with coefficients of variation of approximately 20% and 30%, respectively. Following oral administration of apixaban 10 mg as 2 crushed 5 mg tablets suspended in 30 mL of water, drug exposure levels were comparable to those following oral administration of 2 whole 5 mg apixaban tablets. Following oral administration of apixaban 10 mg as 2 crushed 5 mg tablets with 30 g applesauce, Cmax and AUC were 21% and 16% lower, respectively, than after administration of 2 whole 5 mg tablets. This change in exposure level is not considered clinically significant. Following administration of a crushed 5 mg apixaban tablet suspended in 60 mL of 5% dextrose aqueous solution via nasogastric tube, exposure levels of apixaban were comparable to those observed in other clinical studies in healthy subjects receiving a single oral dose of apixaban 5 mg tablet. Given the predictable and dose-proportional pharmacokinetic profile of apixaban, the bioavailability results of apixaban obtained in these studies are applicable to lower doses of apixaban. Distribution Protein binding in humans is approximately 87%. The volume of distribution (Vss) is approximately 21 liters. Metabolism The total clearance of apixaban is about 3.3 l/h, the half-life is approximately 12 hours. O-demethylation and hydroxylation at the 3-oxopiperidinyl residue are the main pathways of biotransformation of apixaban. Apixaban is metabolized predominantly by the CYP3A4/5 isoenzyme, and to a lesser extent by the CYP1A2, 2C8, 2C9, 2C19 and 2J2 isoenzymes. Unchanged apixaban is the main substance circulating in human plasma, while there are no active metabolites circulating in the bloodstream. Apixaban is a substrate of the transport proteins P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Elimination There are several routes for elimination of apixaban. Approximately 25% of the dose taken is found as metabolites, most of which are found in the feces. Renal excretion of apixaban accounts for approximately 27% of total clearance. Additional excretion through the biliary tract and directly through the intestines is also possible. Renal failure The presence of renal failure in a patient does not affect the maximum plasma concentration of apixaban. There was an increase in apixaban concentrations, which correlated with the degree of renal impairment, assessed by creatinine clearance values. In subjects with mild (creatinine clearance 51–80 ml/min), moderate (creatinine clearance 30–50 ml/min) and severe renal impairment (creatinine clearance 15–29 ml/min), apixaban plasma concentrations (AUC) increased by 16, 29 and 44%, respectively, compared with those in individuals who had normal creatinine clearance values. Impaired renal function had no obvious effect on the relationship between plasma concentrations of apixaban and its anti-factor Xa activity. In patients with end-stage renal disease (ESRD), the AUC value of apixaban after a single dose of 5 mg immediately after the end of hemodialysis was 36% higher than the AUC value in patients with normal renal function. Hemodialysis initiated two hours after a single 5 mg dose of apixaban resulted in a 14% decrease in AUC in patients with ESRD, corresponding to an apixaban dialysis clearance of 18 mL/min. Therefore, it is unlikely that hemodialysis is an effective treatment option for apixaban overdose. Hepatic impairment: After administration of a single 5 mg dose of apixaban to patients with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment and healthy patients, no changes in pharmacokinetic and pharmacodynamic parameters were detected in patients with hepatic impairment. Changes in anti-Xa factor activity and INR (International Normalized Time) were comparable in healthy patients and patients with mild to moderate hepatic impairment. Elderly Patients Elderly patients (over 65 years of age) had higher plasma apixaban concentrations than younger patients, with an approximately 32% higher mean AUC and no difference in Cmax. Gender Exposure to apixaban in women was approximately 18% greater than in men. Race and Ethnicity There are no significant differences in the pharmacokinetics of apixaban between representatives of the Caucasian, Mongoloid and Negroid races and in different ethnic populations of patients receiving apixaban. Body weight In patients weighing more than 120 kg, the plasma concentration of apixaban was approximately 30% lower than in patients weighing from 65 kg to 85 kg, and in patients weighing less than 50 kg this figure was approximately 30% lower. % higher. Relationship between pharmacokinetic and pharmacodynamic parameters The relationship between apixaban concentration and its anti-factor Xa activity is best described using a linear model. The dependence of the pharmacokinetics and pharmacodynamics parameters of apixaban in patients corresponds to those in healthy volunteers. Pharmacodynamics Mechanism of Action Apixaban is a potent oral direct inhibitor that reversibly and highly selectively blocks the active site of factor Xa (FXa). The antithrombotic activity of the drug does not require the presence of antithrombin III. Apixaban inhibits both free and clot-bound factor Xa as well as prothrombinase activity. Apixaban has no direct effect on platelet aggregation, but indirectly inhibits thrombin-induced aggregation. By inhibiting factor Xa, apixaban prevents thrombin generation and blood clot formation. Pharmacodynamic effects The mechanism of action of apixaban (inhibition of factor Xa) is reflected in its pharmacodynamic effects. As a result of the inhibition of factor Xa by apixaban, the values of blood clotting parameters such as prothrombin time (PT), INR and activated partial thromboplastin time (APTT) increase. The observed changes in these coagulation assays at expected therapeutic doses of apixaban are small and highly variable. It is not recommended to evaluate the pharmacodynamic effects of apixaban using these indicators. In the thrombin generation test, apixaban decreased the endogenous thrombin potential, an indicator of thrombin generation in human plasma. The anti-Xa factor activity of apixaban is also confirmed by a decrease in factor Xa enzymatic activity, determined using a number of commercial anti-Xa factor activity kits, but the results obtained from different kits vary. Anti-Xa factor activity shows a direct linear relationship with plasma concentrations of apixaban, reaching maximum values during peak concentrations. The relationship between apixaban plasma concentrations and anti-factor Xa activity remains linear over a wide dose range. The table below shows expected systemic exposure and anti-Xa activity at steady state for each indication. In patients taking apixaban for the prevention of HTO after hip or knee replacement, the maximum and minimum concentrations of apixaban differed by less than 1.6 times. In patients with non-valvular atrial fibrillation who took apixaban for the prevention of stroke and systemic embolism, the maximum and minimum concentrations of apixaban differed by less than 1.7 times. In patients taking apixaban for the treatment of VTO and PE or the prevention of recurrent DVT and PE, the maximum and minimum concentrations of apixaban differed by less than 2.2 times. Expected level of systemic exposure to apixaban and its expected anti-Xa factor activity at steady state Apixaban Cmax, ng/ml Apixaban Cmin (ng/ml) Apixaban Maximum anti-Xa factor activity (IU/ml) Apixaban Minimum anti-Xa factor activity activity (IU/ml) Median (5th percentile, 95th percentile) Prevention of HTO: elective hip or knee replacement 2.5 mg 2 times/day. 77 (41, 146) 51 (23, 109) 1.3 (0.67, 2.4) 0.84 (0.37, 1.8) Prevention of stroke and systemic embolism: NKPP 2.5 mg 2 r. /day* 123 (69, 221) 79 (34, 162) 1.8 (1.0, 3.3) 1.2 (0.51, 2.4) 5 mg 2 times / day. 171 (91, 321) 103 (41, 230) 2.6 (1.4, 4.8) 1.5 (0.61, 3.4) DVT therapy, PE therapy, and prevention of recurrent DVT and PE (tPTE) 2.5 mg 2 times/day. 67 (30, 153) 32 (11, 90) 1.0 (0.46, 2.5) 0.49 (0.17, 1.4) 5 mg 2 times a day. 132 (59, 302) 63 (22, 177) 2.1 (0.91, 5.2) 1.0 (0.33, 2.9) 10 mg 2 times/day. 251 (111, 572) 120 (41, 335) 4.2 (1.8, 10.8) 1.9 (0.64, 5.8) *Dose-adjusted population based on 2 of 3 dose reduction criteria in ARISTOTLE study. Although apixaban therapy does not require continuous monitoring of blood concentrations, it may sometimes be appropriate to perform an anti-factor Xa activity assay using a calibration assay in exceptional cases where data on apixaban exposure can help guide clinical decisions, such as in overdose and emergency situations. surgical intervention. Indications for use of Eliquis 2.5 mg and 5 mg are the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation (NVAF) who have one or more risk factors, such as chronic heart failure NYHA class II-IV (according to the New York classification). York Heart Association), hypertension, age 75 years or older, diabetes mellitus, previous stroke or transient ischemic attack (TIA) - treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults Eliquis 2.5 mg - prevention of venous thromboembolic complications (VTE) in adult patients after planned hip or knee replacement. Method of administration and dosage: Orally, regardless of food intake. Eliquis tablets must be swallowed with water. For patients who are unable to swallow tablets whole, Eliquis tablets can be crushed and suspended in water or 5% dextrose aqueous (5% Aqueous) solution or apple juice or mixed with applesauce and taken immediately by mouth. Alternatively, Eliquis tablets can be crushed and suspended in 60 ml of water or 5DV and the resulting suspension administered immediately through a nasogastric tube. The active ingredient in crushed Eliquis tablets is stable in water, 5DV, apple juice and applesauce for up to 4 hours. Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) The recommended dose of apixaban is 5 mg twice daily. Dose reduction The recommended dose of apixaban for patients with NCAF and at least two of the following risk factors—age 80 years or older, body weight ≤60 kg, or serum creatinine concentration ≥1.5 mg/dL (133 μmol/L)—is 2.5 mg twice daily. Therapy should be long-term. Treatment of DVT, Treatment of PE, and Prevention of Recurrent DVT and PE (Treatment of VTE) The recommended dose of apixaban for the treatment of acute DVT and treatment of PE is 10 mg orally twice daily for the first 7 days, followed by 5 mg orally twice daily. According to current medical recommendations, a short duration of treatment (at least 3 months) should be based on temporary risk factors (eg, recent surgery, trauma, or immobilization). The recommended dose of apixaban for the prevention of recurrent DVT and PE is 2.5 mg orally twice daily. When prophylaxis of recurrent DVT and PE is indicated, dosing at a dose of 2.5 mg orally twice daily should be initiated after completion of 6 months of treatment with apixaban 5 mg twice daily or another anticoagulant, as listed in Table 1 below. Table 1. Dosage regimen Maximum daily dose Treatment of DVT and PE 10 mg twice daily for the first 7 days 20 mg Then 5 mg twice daily 10 mg Prevention of recurrent DVT and (or) PE after completion of a 6-month course of treatment for DVT or PE 2.5 mg twice daily 5 mg Duration of therapy should generally be individualized after careful assessment of the benefit of treatment versus the risk of bleeding. Prevention of HTO: elective hip or knee replacement. The recommended dose of apixaban is 2.5 mg twice daily. The first dose should be taken within 12 to 24 hours after surgery. When choosing when to take the drug within this interval, clinicians may be guided by considerations of the potential benefit of earlier initiation of anticoagulant therapy for the prevention of HTO and the risk of bleeding after the procedure. For patients after hip replacement, the recommended duration of therapy is 32 to 38 days. For patients after knee replacement, the recommended duration of therapy is 10 to 14 days. Missing a dose If a dose of a drug is missed, the patient should take Eliquis immediately and then continue taking it twice daily. Drug change Switching from parenteral anticoagulant therapy to Eliquis (and vice versa) can be done at the time the next dose is scheduled. These drugs should not be used at the same time. Switching from vitamin K antagonist (VKA) therapy to Eliquis When switching patients from vitamin K antagonist (VKA) therapy to Eliquis, discontinue warfarin or other VKAs and initiate Eliquis when the international normalized ratio (INR) is less than 2.0. Switching from Eliquis to VKA When switching patients from Eliquis to VKA, Eliquis should be continued for at least two days after starting VKA therapy. After 2 days of simultaneous use of Eliquis and VKA, the INR value should be determined before taking the next scheduled dose of Eliquis. Concomitant use of Eliquis and VKA should be continued until an INR value of ≥ 2.0 is achieved. Renal Impairment - For patients with mild to moderate renal impairment, the following recommendations apply: for the prevention of VTE after elective hip or knee arthroplasty (pHTE) (2.5 mg dosage only), treatment of DVT, treatment of PE, and prevention of recurrent DVT and PE. (lVTE) no dose adjustment required; - for the prevention of stroke and system embolism in patients with NKFP and the level of serum creatinine ≥ 1.5 mg/DL (133 μmol/l) in combination with an age of ≥ 80 years or body weight ≤ 60 kg, a dose of 2.5 mg twice is required twice per day. In the absence of other criteria for reducing the dose (age, body weight), the dose correction is not required against patients with severe renal failure (creatinine clearance of 15–29 ml/min) the following recommendations are in force: - for the prevention of the WTO after planned endoprosthetics of the hip or knee joint (PVTO ), therapy of TGV, therapy for the heating and the prevention of recurrent TGV and FEL (TVTO) Apixaban should be taken with caution; - For the prevention of stroke and system embolism in patients with NKFP, patients should receive a reduced dose of Apixaban 2.5 mg twice a day. Due to the lack of experience in the clinical use of Apixaban in patients with creatinine clearance <15 ml/min or on dialysis, taking the drug is not recommended for this group of patients. Hepatic insufficiency of the intake of an eclovis is contraindicated in patients with liver disease in combination with coagulopathy and a clinically significant risk of bleeding. The drug is not recommended for patients with severe liver failure. The drug should be used with caution in patients with mild and moderate degree of liver failure (class A or B on the Child-Pew scale). In patients with mild and moderate degree of liver failure of the dose of the drug, the drug is not required. Patients with increased activity of liver enzymes (ALT/AST are more than 2 times higher than the upper boundary of the norm) or a total bilirubin by 1.5 times or higher than the upper boundary of the norm were not included in clinical studies. In this regard, in this group of patients, Elikvis should be used with caution. Before the intake of Elikvis, it is necessary to study the function of the liver. NKFP body weight - dose correction is not required, except when the patient's condition meets the criteria for the need to reduce the dose. WTO prevention and WTO treatment - dose correction is not required. The floor correction gender is not required. The elderly patients of the NKFP - dose correction is not required, except when the patient's condition meets the criteria for the need to reduce the dose. WTO prevention and WTO treatment - dose correction is not required. Patients undergoing cardiovence patients with NKFP who need cardioversion may begin or continue therapy with Apixaban. Patients who have not previously received anticoagulant should take at least 5 doses of apixaban in a dosage of 5 mg twice a day (2.5 mg twice a day for patients who are recommended to reduce dose) before the start of the cardiovence procedure to provide sufficient anticoagulant effect. If a cardioversion is necessary earlier than 5 doses of apixaban can be accepted, an initial load dose of 10 mg should be used, then 5 mg twice a day. The load dose should be reduced to 5 mg, with the subsequent dosage mode 2.5 mg twice a day, if the patient meets the criteria for reducing the dose. The initial load dose should be accepted at least 2 hours before the start of cardioversion. Before conducting a cardioversion, it is necessary to obtain confirmation that the patient accepted the Apixban according to the order. When making decisions on initiation and the duration of treatment, the recommendations of recognized guidelines for anticoagulant therapy of patients undergoing cardiovence should be taken into account. Patients of childhood safety and the effectiveness of the use of ekvis in children and adolescents under 18 years of age have not been established. No data available. Side effects The frequency of undesirable reactions is classified as follows: often (≥ 1/100 and <1/10); infrequently (≥ 1/1 000 and <1/100); rarely (≥ 1/10 000 and <1/1000); It is unknown (it is impossible to set the frequency on the basis of the available data). Side effects in the prevention of stroke and system embolism in adult patients with NKFP with one or more risk factors (NKFP) often - anemia - intraocular hemorrhage (including conjunctival hemorrhage) - bleeding, hematoma - hypotension (including hypotension after the procedure) - nasal bleeding - тошнота — кровотечение в ЖКТ — ректальное кровотечение, кровотечение из десен — повышение уровня гаммаглутамилтрансферазы в крови — гематурия — синяк Нечасто — тромбоцитопения — гиперчувствительность, аллергический отек и анафилаксия — кожный зуд — кровоизлияние в головной мозг† — внутрибрюшное кровотечение — кровохарканье — геморроидальное кровотечение — Bleeding in the oral cavity - the presence of unchanged blood in the feces - a deviation from the norm of biochemical indicators of the liver function, increased activity of aspartateaminotransferase, an increase in the level of alkaline phosphatase in the blood, increasing the level of bilirubin in the blood - an increase in the level of alanineine -console in the blood - skin rash - pathological vaginal bleeding, urogenital bleeding. bleeding - bleeding at the place of administration - a positive test for hidden bleeding - hemorrhage after the procedure (including hematoma after performing the procedure, bleeding from the wound, hematoma at the site of the vessel puncture and bleeding at the site of the installation of the catheter), discharge from the wound, bleeding at the site of the cut (including hematoma at the site of the section), intraoperative bleeding - traumatic bleeding is rare - bleeding from the respiratory tract - retroperitoneal bleeding - muscle bleeding Side effects during the treatment of TGV and fat and prevention of recurrent TGV and TEL (TVTO) often - anemia - thrombicitopenia - bleeding, hematoma - nasal - nasal bleeding - nausea - bleeding in the oral cavity - bleeding in the gastrointestinal tract - rectal bleeding, gum bleeding - increasing the level of gammaglutamiltransferase in the blood - an increase in the level of alanineine -spheres in the blood - skin rash - hematological - pathological vaginal bleeding, urogenital bleeding - bruise - hypersensitivity, allergic edema and anaphylaxia - skin itching - intraocular hemorrhage (including conjunctival hemorrhage) - hypotension (including hypotension after the procedure) - hemorrhage - hemorrhoids bleeding - the presence of unchanged blood in the feces - deviation from the norm of biochemical indicators of the liver function, an increase in aspartaminotransa function, and an increase Blood phosphatase, increasing blood bilirubin level - muscle bleeding - bleeding at the place of administration - a positive test for hidden bleeding - hemorrhage after the procedure (including hematoma after the procedure, bleeding from the wound, hematoma at the site of the vessel and bleeding at the place of installation of the catheter) , bleeding at the section of the section (including hematoma at the site of the section), intraoperative bleeding - traumatic bleeding is rare - hemorrhage in the brain † - bleeding from the respiratory tract is unknown - intra -abdominal bleeding - retirement bleeding Side effects in the prevention of the WTO after adult patients planned endoprosthetics of the hip or knee joint (PVTO) often - anemia - bleeding, hematoma - nausea - bruise infrequently - thrombocytopenia - skin itching - hypotension (including hypotension during the procedure) - nasal bleeding - the presence of unchanged blood in the feces - Deviation from the norm of biochemical indicators of the liver function, increasing the activity of aspartateaminotransferase, increasing the level of alkaline phosphatase in the blood, increasing the level of bilirubin in the blood - an increase in the level of gammaglutamiltransferase - an increase in the level of alanineine -veransferase in the blood - hematological vaginal bleeding, urogenital bleeding - hemorrhages after the procedure (inclusion Hematom tea After performing the procedure, bleeding from the wound, hematomas at the site of the vessel puncture and bleeding at the place of installation of the catheter), discharge from the wound, bleeding at the site of the incision (including hematoma at the site of the incision), intraoperative bleeding - hypersensitivity reaction, allergic edema and anaphylaxis - intraocular - intraocular Hemorrhage (including conjunctival hemorrhage) - hemoptysis - rectal bleeding, gum bleeding - muscle bleeding is unknown - hemorrhage in the brain † - intra -heart -free bleeding - bleeding from the respiratory tract - hemorrhoidal bleeding - bleeding bleeding - skin rash - bleeding - bleeding in The place of introduction is a positive trial for hidden bleeding - traumatic bleeding † The term “hemorrhage in the brain” combines all types of intracranial and intraspinal bleeding (for example, hemorrhagic stroke in the basal core, hemorrhage into a core, subdural and intraventure bleeding. The use of an eclovis may be associated with an increased risk of hidden or obvious bleeding from any tissue or organ that can cause post -hemorrhagic anemia. Its symptoms and severity will depend on localization and the degree of bleeding. The message of information about the alleged undesirable reactions is the message of information about the alleged undesirable reactions identified after the registration of the drug is of great importance. This allows you to continue monitoring the ratio of the benefits and risk of the drug. Medical workers and patients are asked to report any undesirable reactions at the address indicated at the end of this instructions for medical use. Contraindications - hypersensitivity to the active substance or any of the excipients of the drug - clinically expressed active bleeding - liver disease in combination with coagulopathy and a clinically significant risk of bleeding - the presence of a lesion or condition associated with a pronounced risk of massive bleeding, for example, the gastrointestinal ulcer in the present or The recent past, the presence of malignant neoplasms with a high risk of bleeding, a recent injury to the brain or spinal cord, the recently undergone surgery on the brain, spinal cord or eyes, recent intracranial bleeding, detected or suspected varicose veins of the esophagus, blood vessel development, vascular aneurysm or pathological The states of large intra -election or brain vessels are simultaneous use with any other anticoagulant, for example, Nefracted by heparin (NFG), low molecular weight heparins (Enoxaparin, Dalteparin, etc.), derivatives of heparin (Fontaparinux, etc.), oral anticoagulants (varfarin, varfarin, varfarin. Rivaroxaban, Dabigatran, etc.), except for the transition to therapy with Apixban or from the Apixaban (see. Section “Method of application”) or when the NFG is administered in the doses necessary to ensure patency of the central venous or arterial catheter - hereditary intolerance of galactose, LACP lactase deficiency or glucose malabsorption syndrome - pregnancy - children's and adolescence up to 18 years of age of medicinal interaction CYP3A4 And P-GP simultaneously taking an apixaban with ketoconazole (400 mg once a day), a strong CYP3A4 and P-GP inhibitor, led to a 2-fold increase in the average AUC Apixaban and a 1.6-fold increase in the average CMAX apixaban. It is not recommended to use an eclovice in patients who simultaneously use the systemic use of strong CYP3A4 and P-GP inhibitors, such as antimycotics of the Azole group (for example, ketoconazole, itraconazole, toriconazole and jigsaw) and HIV proteases (for example, ritonavir). It is assumed that active substances that are not considered strong inhibitors of CYP3A4 and P-GP (for example, diltiazem, steady, clarithromycin, amiodarone, verapamil, quinidine) will be less increased in plasma. Apixaban’s dose is not required when it is jointly used with other drugs that are not strong CYP3A4 and P-GP inhibitors. For example, diltiazem (at a dose of 360 mg once a day), which is considered a moderate CYP3A4 inhibitor and a weak P-GP inhibitor, causes an increase in AUC Apixaban by 1.4 times and an increase in the average CMAX value by 1.3 times. Narpoxen (a single dose of 500 mg), which is an P-GP inhibitor, but does not inhibit CYP3A4, increases the average AUC and CMAX values by 1.5 and 1.6 times, respectively. Clarithromycin (at a dose of 500 mg 2 times a day), P-GP inhibitor and strong