Pharmacological properties

Pharmacodynamics. medoksomit an azilsartan is the active precursor of medicinal substance intended for oral administration. the predecessor quickly turns into an active molecule of an azilsartan which due to blocking of processes of linking of ii angiotensin with receptors at1 in many fabrics acts as the selection antagonist of effects of ii angiotensin. ii angiotensin — the main blocking agent system renin-angiotenzinovoy; vasoconstriction, stimulation of synthesis and release of Aldosteronum, stimulation of cardiac performance and a reabsorption of sodium in kidneys belong to effects of ii angiotensin.

Blocking of receptors of AT ₁ leads

to oppression of negative return impact of angiotensin II on renin secretion, but increase in activity of renin in plasma of blood and level of angiotensin II in a system blood-groove which arise owing to blocking of receptors and do not interfere with development of hypotensive action of an azilsartan.

Pharmacokinetics. After oral administration of an azilsartan medoksomit quickly it is hydrolyzed in a GIT and/or during absorption to active agent (azilsartan).

Research in vitro is shown that enzyme of a karboksimetilenbutenolidaz participates in processes of hydrolysis in an intestinal path and a liver. Also plasmatic esterases participate in hydrolysis of an azilsartan of a medoksomil to an azilsartan.

Absorption. Proceeding from concentration of an azilsartan in blood plasma, the estimated absolute oral bioavailability of an azilsartan of a medoksomil is about 60%. After oral administration of an azilsartan of a medoksomil of the C _max azilsartana in blood plasma is reached in 1.5-3 h. Food does not affect bioavailability of an azilsartan.

Distribution. The volume of distribution of an azilsartan is about 16 l. Azilsartan intensively (99%) contacts proteins of blood plasma, mainly albumine. Linking with proteins of blood plasma does not change in the range of the concentration considerably exceeding reached at use in the recommended doses.

Biotransformation. Metabolic splitting of an azilsartan leads to formation of two main metabolites. The main metabolite in blood plasma is formed by O-dealkylation, it is designated as a metabolite of M-II. The minor metabolite which is formed as a result of decarboxylation is designated as a metabolite of M-I. Levels of system exposure of the main and minor metabolites at the person were ≈50 and 1% of level of exposure of an azilsartan respectively. M-I and M-II do not make additional impact on pharmacological action of an azilsartan of a medoksomil. Metabolism of an azilsartan generally happens at the expense of CYP enzyme 2C9.

Removal. After oral administration of 5 mg of an azilsartan of a medoksomil, marked radioactive ^{14 isotope} With, about 55% of radioactivity were brought out of an organism with a stake and about 42% — with urine. About 15% of medicament were removed with urine in the form of not changed azilsartan. T _½ azilsartana makes of blood plasma about 11 h, and renal clearance — about 2.3 ml/min. Equilibrium concentration of an azilsartan is reached within 5 days, and during multiple dose of medicament in the mode of 1 times in day of cumulation in blood plasma it is noted.

Linearity/nonlinearity. In the range of doses of an azilsartan of a medoksomil from 20 to 320 mg after reception of single or repeated doses the dependence of exposure of an azilsartan on the accepted dose is established.

Characteristic in special subgroups of patients

Children. The pharmacokinetics of an azilsartan at children (aged up to 18 years) was not investigated.

Patients of advanced age. Significant differences in pharmacokinetics of an azilsartan at young faces (at the age of 18–45 years) and elderly people (65–85 years) are not revealed.

Renal failure. At patients with slight, moderate and heavy renal failures the general exposure of an azilsartan (AUC) increased by 30; 25 and 95% respectively. At patients with a terminal renal failure on dialysis growth of exposure is noted (+5%). At the same time clinical experience of use of medicament for patients with heavy renal failures or an end-stage of a renal failure is absent. Azilsartan is not brought from system blood circulation at a hemodialysis.

Disturbance of functions of a liver. Treatment of Edarbi of patients with a lung (class A on Chaylda — I Drink) or moderated (class B on Chaylda — I Drink) an abnormal liver function within no more than 5 days led to insignificant increase in exposure of an azilsartan (increase in AUC by 1.3-1.6 times). Use of the medicament Edarbi for treatment of patients with heavy disturbances of functions of a liver was not investigated.

Floor. Significant differences in pharmacokinetics of an azilsartan at men and women are not revealed. Need for dose adjustment depending on a sex of the patient is absent.

Race. Significant differences in pharmacokinetics of an azilsartan at patients of Caucasian and negroid race are not revealed. Need for dose adjustment depending on race of the patient is absent.

Indication

Treatment of essential hypertensia at adults.

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Use

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Edarbi it is intended for oral administration, a pill can be taken irrespective of meal.

Recommended initial dose makes 40 mg of 1 times a day.

For patients at whom this dose adequately does not control the ABP a dose can increase to the maximum recommended dose 80 mg of 1 times a day.

Steady antihypertensive effect is reached by

during 2 weeks of treatment. The maximum effect is reached in 4 weeks of administration of drug.

If during monotherapy by the medicament Edarbi does not manage to reach adequate control of the ABP level, additional decrease in the ABP can be reached at the expense of the combined treatment with other antihypertensives, including diuretics (for example Chlortalidonum and Hydrochlorthiazidum) and blockers of calcium channels.

to Patients of advanced age (of 65 years) correction of an initial dose of Edarbi is not required to

. However for patients 75 years with risk of developing of arterial hypotension are aged more senior it is necessary to consider the possibility of use of medicament in a dose of 20 mg (see Pharmacokinetics).

Renal failure. It is necessary to apply with care Edarbi at patients with AG and heavy renal failures or an end-stage of a renal failure as experience of use of medicament for such patients is absent. Azilsartan is not brought from system blood circulation at a hemodialysis. Patients with a slight or moderate renal failure do not need dose adjustment.

Abnormal liver function. The research on use of Edarbi for patients with heavy abnormal liver functions was not conducted therefore medicament is not recommended to be used at patients of this group.

As experience of use of Edarbi for patients with slight and moderate abnormal liver functions is limited to

, it is recommended to control carefully a condition of such patients and to consider the possibility of use of medicament in an initial dose of 20 mg.

Deficit of intravascular volume. To patients with possible deficit of intravascular volume or salt exhaustion (for example to patients with vomiting, diarrhea or to patients who receive high doses of diuretics) the medicament Edarbi is appointed under observation of the doctor, it is also necessary to consider the possibility of use in an initial dose of 20 mg.

Patients of negroid race. There is no need for dose adjustment though at these patients note less significant decrease in the ABP in comparison with patients of other race. Usually it concerns other blockers of receptors of angiotensin II and APF inhibitors. For this population more frequent increase in a dose of Edarbi and medicaments of the accompanying therapy can be required.

Contraindication

Hypersensitivity to active agent or other components of drug. pregnancy or to the women planning pregnancy (see use during pregnancy and feeding by a breast). not to apply an edarba with the medicaments containing aliskiren at patients with diabetes or a renal failure (glomerular filtration rate of 60 ml/min. / 1.73 sq.m).

Side effects

Undesirable effects on the frequency of emergence classify

by such categories: very often (≥1/10), it is frequent (≥1/100, 1/10), infrequently (≥1/1000, 1/100), is rare (≥1/10,000 and 1/1000), is very rare (1/10,000), including isolated cases.

side reactions are specified by

In each system and organ class in decreasing order of their clinical value.

from nervous system: often — dizziness.

from the vascular system: infrequently — hypotension.

from a digestive tract: often — diarrhea; infrequently — nausea.

from skin and hypodermic fabrics: infrequently — rash, an itching; seldom — a Quincke's disease.

from a musculoskeletal system and connective tissue: infrequently — spasms of muscles.

General disturbances: infrequently — fatigue, peripheral hypostases.

Laboratory researches: often — increase in the KFK level in blood; infrequently — increase in level of creatinine in blood, increase in level of uric acid in a blood/hyperuricemia.

Description of separate undesirable reactions. During the combined use of Edarbi and Chlortalidonum the frequency of increase in level of creatinine in blood and hypotension increased from infrequently to often.

during the combined use of Edarbi and an amlodipin the frequency of development of peripheral hypostases increased from infrequently to often, but was lower, than characteristic of an amlodipin in monotherapy.

Laboratory researches

creatinine Level in blood serum. In randomized placebos - controlled researches of monotherapy the frequency of increase in level of creatinine in blood serum after treatment of Edarbi did not differ in medicament from that in group of placebo. Simultaneous use of Edarbi and diuretic drugs, for example Chlortalidonum, led to higher frequency of increase in level of creatinine. This observation will be coordinated with the known facts for other blockers of receptors of angiotensin II and APF inhibitors. Increase in level of creatinine during the combined use of Edarbi and diuretic medicaments is connected with more significant decrease in the ABP in comparison with use of one of these drugs. The majority of episodes of increase in level of creatinine was temporary or did not progress at treatment continuation. After the treatment termination the level of creatinine is in most cases normalized independently.

Uric acid. At use of Edarbi the small average increase in level of uric acid in blood plasma in comparison with placebo is noted (10.8 µmol/l against 4.3 µmol/l).

Gemoglobin and hematocrit. In placebo - controlled researches of monotherapy medicament noted small decrease in level of hemoglobin and a hematocrit (about 3 g/l and 1 about. % respectively). This effect is also noted at use of other inhibitors the system renin-angiotensin-aldosteronovoy (SRAA).

Special instructions

Activation raas. at patients, the vascular tone and which function of kidneys depend mainly on activity raas (for example patients with stagnant heart failure, a heavy renal failure or a renal artery stenosis) treatment by medicaments which influence on raas (for example inhibitors apf and blockers of receptors of ii angiotensin) was connected with developing of acute arterial hypotension, an azotemia, oliguria or, in rare instances, opn. it is impossible to exclude emergence of the similar phenomena at use of an edarba.

Should apply with care Edarbi to treatment of patients with AG and heavy renal failures, stagnant heart failure or a renal artery stenosis as experience of use of medicament for treatment of such patients is absent.

Excessive decrease in the ABP at patients with an ischemic heart disease or disturbances of cerebral circulation of ischemic character can lead

to a myocardial infarction or a stroke.

Double blockade of RAAS. The combined use of APF inhibitors, blockers of receptors of angiotensin II or an aliskiren increases risk of developing arterial hypotension, a hyperpotassemia and deterioration in function of kidneys (including OPN). Therefore double blockade of RAAS owing to the combined use of APF inhibitors, blockers of receptors of angiotensin II or an aliskiren is not recommended (see INTERACTIONS). In case of need therapies by double blockade it should be carried out under observation of the doctor and control of function of kidneys, level of electrolytes and the ABP. Patients with a diabetic nephropathy should not accept APF inhibitors together with blockers of receptors of angiotensin II.

Transplantation of kidneys. For today experience of use of Edarbi for the patients who recently transferred transplantation of a kidney no.

Disturbance of functions of a liver. Use of Edarbi for treatment of patients with heavy disturbances of functions of a liver was not investigated therefore patients of this group are not recommended to appoint this drug.

Arterial hypotension at patients with deficit of OCK and/or salt exhaustion. Patients with the significant deficit of OCK and/or salt exhaustion (for example patients with diarrhea, vomiting or the patients accepting high doses of diuretic drugs) after an initiation of treatment of Edarbi can have a symptomatic hypotension. Prior to treatment it is necessary to take measures for compensation of a hypovolemia or to begin treatment under careful medical control. Also it is necessary to consider the possibility of purpose of an initial dose of 20 mg.

Primary hyper aldosteronism. Patients with primary aldosteronism usually have no response to treatment by hypotensive medicines which mechanism of action consists in suppression system renin-angiotensin-aldosteronovoy. Thus, use of Edarbi for such patients is not recommended.

Hyperpotassemia. As a matter of experience can lead uses of other medicines influencing RAAS, simultaneous use of Edarbi with kaliysberegayushchy diuretic drugs, kaliysoderzhashchy additives, salt substitutes with the content of potassium or other medicines which are capable to increase potassium level in blood (for example heparin) to increase in level of potassium in blood of patients with AG. At patients of advanced age, with a renal failure, with diabetes and/or with other associated diseases the risk of a hyperpotassemia (which can be lethal) increases. If necessary it is necessary to control potassium level.

Stenosis of aortal and mitral valves, subaortic hypertrophic stenosis. Treatment of patients with a stenosis of the aortal or mitral valve or with a hypertrophic subaortic stenosis demands extra care.

Lities. As well as for other blockers of receptors of angiotensin II, Edarbi it is not necessary to appoint along with lithium drugs.

Use during pregnancy and feeding by a breast

Pregnancy. Drug should not be used at pregnant women or women who plan pregnancy. If during treatment the pregnancy is confirmed, use of medicament it is necessary to stop and appoint immediately other medicine allowed for use for pregnant women.

Data on use of Edarbi for pregnant women are absent. Researches on animals revealed reproductive toxicity.

Epidemiological data do not confirm risk of teratogenecity as a result of exposure of APF inhibitors during the I trimester of pregnancy, however slight increase of risk cannot be excluded. Due to the lack of controlled epidemiological data on the risk connected with blockers of receptors of angiotensin II it is impossible to exclude this risk for medicaments of this class. The patients planning pregnancy should pass to alternative antihypertensive therapy which has more studied safety profile for use for pregnant women.

Therapy by blockers of receptors of angiotensin II at women in II and III trimester of pregnancy can lead

to a fetotoksichnost (depression of function of kidneys, oligogidramnion, a delay of ossification of bones of a skull) and neonatal toxicity (a renal failure, arterial hypotension, a hyperpotassemia).

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In need of use of blockers of receptors of angiotensin ІІ in the II trimester of pregnancy recommends performing ultrasonography for definition of function of kidneys and ossification of bones of a skull at a fruit.

Should be watched carefully babies whose mothers applied blockers of receptors of angiotensin II, regarding development of hypotension (see CONTRAINDICATIONS, SPECIAL INSTRUCTIONS).

Feeding by a breast. Drug is not recommended to be used during feeding by a breast due to the lack of the relevant data. During feeding it is desirable to begin with a breast alternative treatment with more studied safety profile, especially during feeding of the newborn or premature baby.

Fertility. Data on influence of an azilsartan of a medoksomil on reproductive function of the person are absent. By results of preclinical trials, azilsartan did not influence reproductive function of females and males of rats.

Children. There are no data on use of medicament for children (up to 18 years).

Ability to influence speed of response at control of vehicles or work with other mechanisms. Considering pharmakodinamichesky characteristics of drug, azilsartan medoksomit can have insignificant impact on speed of response at control of vehicles or work with other mechanisms. At the same time during intake of any hypotensive medicament it is necessary to know about possible developing of dizziness or fatigue.

Interaction

Combination which are not recommended

Lities. At simultaneous use of medicaments of lithium and APF inhibitors noted reversible increase in concentration of lithium in blood serum and reversible increase in expressiveness of manifestations of toxicity. With blockers of receptors of angiotensin II the similar effect is possible. Due to the lack of experience of simultaneous use of an azilsartan of a medoksomil and medicaments of lithium such combination of medicaments is not recommended. In need of co-administration of these medicaments it is necessary to control carefully lithium level in blood serum.

Combination which should be applied with care

NPVP, including selection TsOG-2 inhibitors, acetylsalicylic acid in a dose of 3 g/days and non-selective NPVP. At simultaneous use of NPVP (that is selection TsOG-2 inhibitors, for example acetylsalicylic acid in a dose of 3 g/days and non-selective NPVP) and blockers of receptors of angiotensin II easing of expressiveness of hypotensive action of the last is possible. Besides, simultaneous use of blockers of receptors of angiotensin II and NPVP can lead to increase in risk of deterioration in function of kidneys and level of potassium in blood. Thus, it is recommended to provide adequate hydration of the patient and control of functions of kidneys in an initiation of treatment.

Kaliysberegayushchy diuretic drugs, kaliysoderzhashchy additives, salt substitutes with the content of potassium and other substances which can increase potassium level in blood. Kaliysberegayushchy diuretic drugs, kaliysoderzhashchy additives, salt substitutes with the content of potassium and other medicaments (for example heparin) at simultaneous use can increase potassium level in blood. If necessary it is necessary to control potassium level in blood serum.

Additional information. Data of clinical trials showed that double blockade of RAAS at the combined use of APF inhibitors, blockers of receptors of angiotensin II or an aliskiren increases risk of developing arterial hypotension, a hyperpotassemia, deterioration in function of kidneys (including OPN) in comparison with monotherapy by the active agent of RAAS (see CONTRAINDICATIONS, SPECIAL INSTRUCTIONS).

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In researches of use of an azilsartan of a medoksomil or azilsartan in a combination with amlodipiny, antiacid drugs, Chlortalidonum, digoxin, flukonazoly, Glyburidum, ketokonazoly, metformin and warfarin did not register clinically significant interactions of medicines.

medoksomit Azilsartan's

quickly it is hydrolyzed by esterases of a digestive tract and/or during absorption to active agent of an azilsartan. The researches in vitro indicate the low probability of the interactions based on oppression of esterases.

Overdose

Symptoms. proceeding from pharmacological properties, it is possible to expect that symptomatic hypotension and dizziness will be the main manifestations of overdose. in controlled clinical trials with participation of healthy faces the participants received edarb in a dose to 320 mg of 1 times a day within 7 days. these doses were well transferred by participants of a research.

Treatment. At development of symptomatic hypotension it is necessary to begin replacement therapy and to control key indicators of activity. Azilsartan is not brought by means of a hemodialysis.

Storage conditions

does not demand special storage conditions. to store in original packing.

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