EDARBI instructions for use, description of the medicinal product EDARBI: contraindications, side effects, dosages, composition

Description of the drug EDARBI

When taken orally, Cmax of azilsartan in blood plasma is achieved on average within 1.5-3 hours. The absolute bioavailability of azilsartan medoxomil is approximately 60%. Food intake does not affect the bioavailability of azilsartan.

After single or multiple oral administration in a dose range from 20 mg to 320 mg, the pharmacokinetics of azilsartan medoxomil are dose proportional.

Vd of azilsartan is about 16 l. Plasma protein binding is more than 99%, mainly with albumin. Plasma protein binding remains constant when azilsartan plasma concentrations are significantly higher than the range achieved when taken at recommended doses. Css of azilsartan is achieved within 5 days; its accumulation in the blood plasma does not occur with daily use once a day.

Animal studies with radioactive tracers have shown that the amount of azilsartan that penetrates the BBB is minimal.

After oral administration during absorption from the gastrointestinal tract, azilsartan medoxomil is converted into the pharmacologically active metabolite azilsartan under the action of the enzyme carboxymethylenebutenolidase in the intestines and liver. Azilsartan is metabolized to two primary metabolites primarily in the liver. The main metabolite in blood plasma is formed by O-dealkylation, the minor metabolite by decarboxylation. The AUC values for these metabolites in humans are respectively 50% and less than 1% compared to azilsartan. These metabolites do not affect pharmacological activity. Metabolism of azilsartan occurs mainly with the participation of the CYP2C9 isoenzyme.

In patients with mild, moderate and severe renal impairment, AUC was increased by 30%, 25% and 95%, respectively. No increase in AUC (5%) was observed in patients with end-stage renal disease on hemodialysis. Clinical data on pharmacokinetics in patients with severe or end-stage renal failure are not available. Azilsartan is not removed from the systemic circulation by hemodialysis.

Use of azilsartan medoxomil for more than 5 days in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment leads to a slight increase in AUC (1.3-1.6 times, respectively). Pharmacokinetics in patients with severe (Child-Pugh class C) hepatic impairment has not been studied.

Edarbi Clo tablets 40 mg+12.5 mg 28 pcs.

Edarbi Clo is a combination drug that contains an angiotensin II receptor antagonist (azilsartan medoxomil) and a thiazide-like diuretic (chlorthalidone). The simultaneous use of two active substances leads to a more pronounced decrease in blood pressure (BP) compared to taking each of them in monotherapy. When taking the drug once a day, an effective reduction in blood pressure is achieved within 24 hours. Azilsartan medoxomil, one of the active ingredients of the drug Edarbi® Clo, is a specific antagonist of angiotensin II type 1 receptors (AT1). Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the main vasoconstrictor factor of the RAAS (renin-angiotensin-aldosterone system), its actions include vasoconstriction, stimulation of aldosterone synthesis and secretion, increased heart rate (HR) and sodium reabsorption by the kidneys. Azilsartan medoxomil is an oral prodrug. Azilsartan medoxomil is rapidly converted to the active azilsartan molecule, which selectively inhibits the effects of angiotensin II by blocking its binding to AT1 receptors in various tissues, such as vascular smooth muscle and the adrenal glands. Therefore, its action is not related to the angiotensin II biosynthetic pathway. The AT2 receptor is also found in many tissues, but it is not involved in the regulation of the cardiovascular system. The affinity of azilsartan for the AT1 receptor is 10,000 times higher than for the AT2 receptor. Inhibition of RAAS activity through ACE inhibitors, which suppress the formation of angiotensin II from angiotensin I, is widely used in the treatment of arterial hypertension. ACE inhibitors also suppress the breakdown of bradykinin, which is catalyzed by ACE. Since azilsartan does not inhibit ACE (kininase II), it should not affect bradykinin activity. Azilsartan does not bind to or block other receptors or ion channels that play an important role in the regulation of the cardiovascular system. Azilsartan dose-dependently suppresses the vasoconstrictor effects of angiotensin II infusion. A single dose of azilsartan at a dose equivalent to 32 mg of azilsartan medoxomil suppressed the maximum vasoconstrictor effect of angiotensin II by approximately 90% at the time of highest concentration, and by approximately 60% 24 hours after administration. In healthy volunteers, plasma concentrations of angiotensin I and angiotensin II and renin activity increased, and aldosterone concentrations decreased after a single oral dose and after repeated doses of azilsartan medoxomil; No clinically significant effect on serum potassium or sodium levels was detected. In general, the pharmacodynamic properties of azilsartan medoxomil are consistent with blocking the AT1 receptor. The antihypertensive effect of azilsartan medoxomil develops during the first 2 weeks of use with the maximum therapeutic effect achieved after 4 weeks. A reduction in blood pressure after oral administration of a single dose is usually achieved within a few hours and persists for 24 hours. Chlorthalidone, a thiazide-like diuretic, inhibits the active reabsorption of sodium ions in the renal tubules (the initial part of the distal convoluted tubule of the nephron), increasing the excretion of sodium and chloride ions and increasing diuresis. In addition, chlorthalidone increases the excretion of potassium, magnesium and bicarbonate ions, and retains calcium ions and uric acid. The antihypertensive effect of chlorthalidone is associated with the removal of fluid and sodium from the body. The diuretic effect develops 2-3 hours after taking chlorthalidone orally and persists for 2-3 days. The antihypertensive effect of chlorthalidone develops gradually with the maximum therapeutic effect achieved 2-4 weeks after the start of therapy. In clinical trials, the combination of azilsartan medoxomil/chlorthalidone was more effective than the combination of azilsartan medoxomil with hydrochlorothiazide or the combination of olmesartan medoxomil/hydrochlorothiazide, although a higher proportion of study participants in the comparison group required a dose increase due to insufficient blood pressure (BP) control. In a double-blind, 12-week dose-escalation study, azilsartan medoxomil/chlorthalidone 40 mg/25 mg was statistically significantly superior to olmesartan medoxomil/hydrochlorothiazide 40 mg/25 mg in reducing systolic blood pressure in moderate to severe hypertension. Similar results were obtained in all patient subgroups, regardless of age, gender or race. The combination of azilsartan medoxomil/chlorthalidone lowered blood pressure more effectively than the combination of olmesartan medoxomil/hydrochlorothiazide in each hour of the 24-hour interval between doses of drugs, according to ABPM (24-hour blood pressure monitoring).

EDARBI TAB. 20MG No. 28

Suction

Azilsartan medoxomil is a prodrug. After oral administration, it is converted to the pharmacologically active metabolite azilsartan during absorption from the gastrointestinal tract under the action of the enzyme carboxymethylenebutenolidase in the intestine and liver.

The estimated absolute bioavailability of azilsartan medoxomil when taken orally is approximately 60 %

according to the profile of concentrations in blood plasma. The maximum concentration (Cmax) of azilsartan in blood plasma is on average reached within 1.5 - 3 hours after taking the drug orally. Food intake does not affect the bioavailability of azilsartan.

Distribution

The volume of distribution of azilsartan is about 16 liters. Azilsartan binds to blood plasma proteins (more than 99%), mainly to blood plasma albumin. The binding to plasma proteins remains constant when the concentration of azilsartan in the blood plasma significantly exceeds the range achieved when taking recommended doses.

There are no data on the use of the drug during pregnancy and breastfeeding. Azilsartan crosses the placenta of pregnant rats and is excreted into the milk of lactating rats (see section Use during pregnancy and breastfeeding).

Radiolabeled animal studies have shown that the amount of azilsartan that crosses the blood-brain barrier is minimal.

Metabolism

Azilsartan is metabolized to two primary metabolites primarily in the liver. The main metabolite in blood plasma is formed by O-dealkylation and is designated as metabolite M-II, the minor metabolite is formed by decarboxylation and is designated as metabolite M-I. The AUC (area under the concentration-time pharmacokinetic curve) values for these metabolites in humans are respectively 50% and less than 1% compared to azilsartan. M-I and M-II do not affect the pharmacological activity of Edarbi. The main enzyme responsible for the metabolism of azilsartan is the CYP2C9 isoenzyme.

Removal

Azilsartan and its metabolites are excreted from the body, both through the intestines and the kidneys. Studies have shown that after oral administration of azilsartan medoxomil, about 55% (mainly in the form of metabolite M-I) is found in the feces and about 42% (15% in the form of azilsartan, 19% in the form of metabolite M-II) in urine . The half-life of azilsartan is about 11 hours and the renal clearance is about 2.3 ml/min. The equilibrium concentration of azilsartan is achieved within 5 days and its accumulation in the blood plasma does not occur with a single daily use.

Linearity/Nonlinearity

The pharmacokinetics of azilsartan in azilsartan medoxomil are dose proportional over a dose range of 20 mg to 320 mg following single or multiple oral doses.

Pharmacokinetics in special groups

Children

The pharmacokinetics of azilsartan in children under 18 years of age has not been studied.

Elderly patients

The pharmacokinetics of azilsartan in young (18-45 years) and elderly (65-85 years) patients does not differ significantly.

Kidney failure

In patients with mild, moderate and severe renal impairment, AUC was increased by +30%, +25% and +95%, respectively. Increases (+5 %)

AUC was not observed in patients with end-stage renal disease on hemodialysis. Clinical data on pharmacokinetics in patients with severe or end-stage renal failure are not available.

Azilsartan is not removed from the systemic circulation by hemodialysis.

Liver failure

Use of Edarbi for more than 5 days in patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) severity of liver failure leads to a slight increase in AUC (1.3 - 1.6 times, respectively) ). The pharmacokinetics of Edarbi in patients with severe (class C on the Child-Pugh scale) degree of liver failure have not been studied.

Gender

The pharmacokinetics of azilsartan in men and women is not significantly different. No dose adjustment is required depending on gender.

Race

The pharmacokinetics of azilsartan do not differ significantly depending on the race of patients. No dose adjustment is required based on race.

Introduction

Arterial hypertension (AH) is the most common chronic disease of the circulatory system, the prevalence of which is about 40% among the adult population of the Russian Federation, i.e.
more than 42 million people. Currently, according to the recommendations of the All-Russian Scientific Society of Cardiologists, in the classification of hypertension it is customary to distinguish stages of the process, gradation of hypertension according to the level of blood pressure (BP), as well as stratification of the risk of cardiovascular complications, including identification of risk factors, target organ damage and associated clinical states. Risk factors include male gender, age, smoking, family history of early cardiovascular disease, dyslipidemia, abdominal obesity, impaired glucose tolerance, physical inactivity, and elevated levels of fibrinogen and C-reactive protein. Signs of target organ damage include left ventricular hypertrophy according to ECG (electrocardiographic) criteria and echocardiography (EchoCG), ultrasound signs of arterial wall thickening or atherosclerotic plaques of the great vessels, increased serum creatinine levels, microalbuminuria. Associated clinical conditions include:

Cerebrovascular diseases: ischemic cerebral stroke, hemorrhagic cerebral stroke, transient ischemic attack.
Heart diseases: myocardial infarction, angina pectoris, coronary revascularization, chronic heart failure.
Kidney damage: diabetic nephropathy, renal failure: serum creatinine > 133 µmol/l (1.5 mg/dl) for men or > 124 µmol/l (1.4 mg/dl) for women, proteinuria > 300 mg/day.
Peripheral artery disease: dissecting aortic aneurysm, symptomatic peripheral arterial disease.
Hypertensive retinopathy: hemorrhages or exudates, swelling of the optic nerve nipple.

Diabetes mellitus is included in a separate category of factors influencing prognosis. Currently, in terms of the risk of developing cardiovascular complications, it is equal to coronary heart disease and therefore ranks in importance along with associated clinical conditions. Depending on the degree of increase in blood pressure, the presence of risk factors, target organ damage and associated clinical conditions, all patients can be classified into one of four risk levels: low, moderate, high and very high. The risk level is assessed using the SCORE (Systematic COronary Risk Evaluation) system, which estimates the risk of death from diseases associated with atherosclerosis within 10 years. According to this model, a low risk corresponds to a value of less than 4%, a moderate risk – 4–5%, a high risk – 5–8% and a very high risk – more than 8%. Such differentiation into risk groups is important for choosing tactics for managing patients with hypertension. The main goal of treatment of patients with hypertension is to minimize the risk of developing cardiovascular complications and death from them. The target level for the treatment of hypertension is taken to be a blood pressure of less than 140/90 mmHg. Currently, seven classes of antihypertensive drugs are recommended for the treatment of hypertension: diuretics; β-blockers; calcium channel blockers; angiotensin-converting enzyme inhibitors; angiotensin receptor blockers (AT1); imidazoline receptor antagonists; α-blockers. Currently, it is possible to use two strategies for initial treatment of hypertension: monotherapy and low-dose combination therapy. The most commonly used drugs in the treatment of patients with hypertension are angiotensin-converting enzyme and AT1 inhibitors. Numerous multicenter studies have proven their high effectiveness and good tolerability by patients of any age, gender, and with any type of hemodynamics. Drugs in this group combine well with other antihypertensive drugs, as well as with lipid-lowering drugs. AT1 blocks the action of angiotensin II, thereby eliminating pathological vasoconstriction, weakening sympathetic activation, inhibiting interstitial growth in the myocardium and proliferation of smooth muscle cells. In addition, sartans reduce sodium and water retention.

One of the representatives of the new generation of AT1 is azilsartan medoxomil, a specific antagonist of angiotensin II type 1 receptors (AT1). Azilsartan medoxomil is an oral prodrug. It is rapidly converted to the active molecule azilsartan, which selectively interferes with the effects of angiotensin II by blocking its binding to AT1 receptors in various tissues. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system with effects including vasoconstriction, cardiac stimulation, stimulation of aldosterone synthesis, release and subsequent renal sodium reabsorption.

AT1 receptor blockade inhibits the negative regulatory response of angiotensin II to renin secretion, but the resulting increase in plasma renin activity and circulating angiotensin II levels does not suppress the hypotensive effect of azilsartan.

The hypotensive effect of azilsartan medoxomil develops during the first 2 weeks of use, achieving the maximum therapeutic effect after 4 weeks. A reduction in blood pressure after oral administration of a single dose is usually achieved within a few hours and persists for 24 hours.

The purpose of this study was to study the clinical efficacy and tolerability of azilsartan medoxomil monotherapy in patients with hypertension. The objectives of the study were to conduct an open clinical study of the use of azilsartan medoxomil in patients meeting the criteria for the diagnosis of hypertension of I–II degrees, to evaluate the dynamics of morphofunctional, biochemical and hemodynamic parameters during monotherapy with azilsartan medoxomil, to evaluate the effect of azilsartan medoxomil on the quality of life of patients and the level of anxiety on the scale Hamilton.

Material and methods

The study, which was conducted at the Diagnostic Center No. 5 in Moscow, included 120 patients with grades I–II hypertension. Among them there were 56 (46.6%) men and 64 (53.4%) women. The average age of the group was 49.7±10.04 years. The average duration of hypertension was 7.47±5.65 years. 34 (28.3%) patients suffered from coronary heart disease, and 11 (9.2%) patients suffered from diabetes mellitus.

The duration of the study was 12 weeks.

Inclusion criteria: patient age from 30 to 65 years, blood pressure level at the time of inclusion more than 140/90 and less than 180/110 mmHg, duration of hypertension disease - at least 12 months, signed informed consent of the patients.

Exclusion criteria: symptomatic hypertension, cerebrovascular accident or acute coronary syndrome within the next year, the presence of chronic heart failure of functional classes III–IV according to NYHA (New York Heart Association), decompensated diabetes mellitus type 2 or 1, atrioventricular blockade of II–III degrees , impaired renal and liver function, chronic obstructive pulmonary diseases, pregnancy and lactation, hypersensitivity to the drug or its components.

Patients took azilsartan medoxomil for 12 weeks once a day at an initial dose of 40 mg, followed by a possible increase in case of failure to achieve the target blood pressure level (less than 140/90 mmHg) to 80 mg/day in one dose.

The safety assessment of the use of azilsartan medoxomil was carried out on the basis of data on the side effects of the drug identified during use, taking into account the study of subjective and objective criteria. Depending on the presence and severity of side effects, a conclusion was made about the tolerability of the drug.

During the study (12 weeks), four visits were planned: visit 1 – inclusion (the patient did not receive antihypertensive therapy for 5 days before the inclusion visit). During follow-up visits (2, 3, 4), a physical examination was performed, including determination of body mass index (BMI), waist/hip index (W/H), measurement of blood pressure in sitting and standing positions, and determination of heart rate (HR). ). In addition, laboratory tests were carried out at visits 1 and 4: complete blood count, general urine test, lipid profile, levels of blood glucose, blood potassium, blood creatinine, microalbuminuria were determined, according to a rapid test. Functional studies included ECG (heart rate, voltage criteria for left ventricular myocardial hypertrophy - LV), precise blood pressure monitoring - ABPM (average daily, day and night blood pressure figures, load indices, daily index, blood pressure variability), echocardiography (sizes of heart chambers, hypertrophy LV myocardium). Volumetric sphygmography was performed using a VaSera-1000 device, Japan, with the help of which the brachial-ankle (L-PWV m/s, R-PWV m/s) and cardiobrachial pulse wave velocity (B-PWV m/s) were assessed; pulse wave velocity in the aorta (PWV m/s); mixed arterial (CAVI-1) and aortic (CAVI-2) stiffness indices. During the visits, the level of anxiety on the Hamilton Anxiety Rating Scale (HARS) and the quality of life indicator on the visual analogue scale (VAS) were also determined, and adherence to therapy was assessed.

Statistical processing of the results was performed using the statistical computer program Statistica 6.0. To evaluate the characteristics, average values and standard deviations were calculated; To compare two groups according to one characteristic characterized by a normal distribution, Student's t-test was used. To compare two groups based on a characteristic whose distribution differed from normal, the Mann–Whitney test was used.

Research results

As can be seen from table. 1, the values of BMI, WC/BV, heart rate, lipid metabolism indicators, blood potassium and creatinine levels did not have statistically significant dynamics, however, there was a persistent tendency for these parameters to improve. The dynamics of blood pressure parameters during manual measurement, as well as blood glucose levels, on the contrary, were reliable.

From the table Figure 2 shows that after 3 months of monotherapy with azilsartan medoxomil, changes in ECG and EchoCG parameters were not statistically significant, which should be explained by the short duration of the study. The positive dynamics of all volumetric sphygmography indicators (L-PWV, R-PWV, B-PWV, PWV, CAVI-1, CAVI-2) was significant, which indicates a positive structural and functional restructuring of the vascular wall of elastic and mixed type arteries. The positive dynamics of the following indicators of daily blood pressure monitoring were statistically significant: average daily, day and night blood pressure figures, SBP and DBP load indices, SBP variability.

In table Figure 3 demonstrates statistically significant dynamics in microalbuminuria (MAU) indicators, as well as the level of anxiety and quality of life.

During the study, 21 (17.5%) patients experienced side effects characteristic of taking sartans: increased fatigue, general weakness. All phenomena were short-term and did not require discontinuation of the drug.

Conclusion

According to the results of the study, it was shown that azilsartan medoxomil, used as monotherapy for 3 months in doses of 40 and 80 mg in patients with stage I and II hypertension, is an effective antihypertensive agent that statistically significantly improves blood pressure and ABPM levels. It significantly improves the stiffness of elastic and mixed arteries, according to volumetric sphygmography (VaSera), which helps reduce the rigidity of the vascular wall, prevents vascular remodeling and the development of atherosclerotic changes. The drug is well tolerated by patients. Azilsartan medoxomil is a metabolically neutral drug, and the study revealed a statistically significant decrease in blood glucose levels. Azilsartan medoxomil has been shown to have nephroprotective properties, significantly reducing microalbuminuria. As a result, azilsartan medoxomil significantly improves the quality of life of patients and reduces the level of anxiety on the Hamilton scale.