Pharmacological properties

Pharmacodynamics. irbesartan — the strong peroral selection antagonist of receptors of ii angiotensin (the macaw of ii — at1 type). consider that it blocks all physiologically significant effects of ii angiotensin mediated through a receptor of at1 type irrespective of a source or a way of synthesis of ii angiotensin. selection antagonistic action concerning receptors of ii angiotensin (at1) leads to increase in concentration of renin and ii angiotensin and decrease in concentration of Aldosteronum in blood plasma. at use of medicament in the recommended doses the potassium level in blood serum significantly does not change. irbesartan does not suppress apf (a kininaza of ii) — enzyme which produces ii angiotensin, carries out metabolic degradation of bradykinin with formation of inactive metabolites. for manifestation of the effect irbesartan does not demand metabolic activation.

Clinical performance at AG. Irbesartan lowers the arterial blood pressure at the minimum change of ChSS. Decrease in the ABP at reception of 1 times a day dose-dependent, with a tendency to an exit to the plateau in a dose of 300 mg. Doses of 150-300 mg at reception of 1 times a day reduce the ABP indicators in a dorsal decubitus or sitting at the end of effect of medicament (that is in 24 h after administration of drug) on average on 8–13/5–8 mm Hg. (systolic/diastolic) it is more, than intake of placebo.

Maximum decrease in the ABP is reached by

in 3–6 h after administration of drug, the hypotensive effect remains at least for 24 h

Through 24 h after reception in the recommended doses decrease in the ABP is 60–70% in comparison with an indicator of the maximum decrease in diastolic and systolic arterial blood pressure. Administration of medicament in a dose of 150 mg of 1 times a day causes effect (on a minimum of action and on average for 24 h), similar to that at distribution of this daily dose to 2 receptions.

Antihypertensive effect of the medicament Konverium is shown by

for 1–2 weeks, and the maximum effect is reached on the 4-6th week from an initiation of treatment. The antihypertensive effect remains during long treatment. After the termination of treatment of the ABP gradually returns to initial level. The withdrawal in the form of increase in expressiveness of AG after the termination of administration of medicament is noted.

Irbesartan along with diuretics of thiazide type show additive hypotensive effect. At patients who have a monotherapy irbesartany did not provide necessary effect, simultaneous use of a hydrochlorothiazide in a low dose (12.5 mg) from irbesartany 1 times day caused more significant decrease in the ABP at least on 7–10/3–6 mm Hg. (systolic/diastolic), in comparison with intake of placebo.

Pharmacokinetics. After oral administration irbesartan it is well absorbed: in researches it is revealed that the absolute bioavailability is about 60-80%. The concomitant use of food significantly does not affect bioavailability of an irbesartan. Linking with proteins of blood plasma makes ≈96%, at the same time linking with blood cells insignificant. Distribution volume — 53–93 l. After peroral or in/in introductions ¹⁴ From an irbesartan of 80-85% of the radioactive label circulating in blood plasma it is the share of not changed irbesartan. Irbesartan is metabolized in a liver by conjugation with a glucuronide and oxidations. The main metabolite circulating in blood is the irbesartan-glucuronide (≈6%). Data of the researches in vitro demonstrate what irbesartan is oxidized generally CYP enzyme 2C9 of P450 cytochrome; the isoenzyme of CYP 3A4 almost did not influence it.

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Pharmacokinetics of an irbesartan in the range of doses of 10-600 mg linear is also proportional to the accepted dose. Less proportional increase in absorption at oral administration note in a dose 600 mg (twice higher than the maximum recommended dose); the mechanism of it is unknown. With _max in blood plasma it is reached in 1.5-2 h after oral administration of drug. The general and renal clearance is made by 157–176 and 3-3.5 ml/min. respectively. Final T _½ an irbesartana — 11–15 h. Equilibrium concentration in blood plasma are reached in 3 days after the beginning of use of medicament of 1 times a day. At use of 1 times a day cumulation of an irbesartan in blood plasma low (20%). During the conducted research at women with AG a little higher concentration of an irbesartan in blood plasma is noted. However differences in T _½ and accumulations of an irbesartan were not. For women to change a dose there is no need. At elderly people (65 years) of max AUC and C _value for an irbesartan were slightly higher, than at the patient young (18–40 years) age. However final T _½ significantly did not change. For patients of advanced age to change a medicament dose there is no need.

Irbesartan and his metabolites are removed by

through bile and kidneys. After peroral or in/in introductions ¹⁴ From an irbesartan of ≈20% of a radioactive label reveal in urine, the rest — in Calais. Less than 2% of the accepted dose of an irbesartan are excreted with urine in not changed look.

In one research studied pharmacokinetics of an irbesartan at 23 children with AG after use of an irbesartan in a dose of 2 mg/kg of body weight 1 and several times in day, up to the maximum daily dose of 150 mg, for 4 weeks. For comparison of pharmacokinetics with that took away 21 children from adults from these 23 (12 children are aged more senior than 12 years, 9 — at the age of 6–12 years). The received results demonstrate that the C _max , AUC and clearance at children were comparable with the corresponding indicators at the adult patients accepting 150 mg of an irbesartan a day. At use of medicament of 1 times a day the cumulation of an irbesartan in blood plasma was low (18%).

Renal failure. At patients with a renal failure or at patients to whom the hemodialysis is carried out the pharmacokinetic parameters of an irbesartan significantly do not change. Irbesartan is not brought from an organism at a hemodialysis.

Abnormal liver function. Pharmacokinetic parameters of an irbesartan significantly do not change at patients with cirrhosis of easy or moderate weight. Researches with the assistance of patients with heavy insufficiency of function of a liver were not conducted.

Indication

Essential hypertensia. ag at patients with a disease of kidneys and diabetes іі type as a part of antihypertensive therapy.

Use

Usual initial and maintenance dose makes 150 mg of 1 times a day during meal or on an empty stomach. konverium in a dose of 150 mg of 1 times a day hell, than in a dose of 75 mg usually provides the best 24-hour control. however at the beginning of therapy it is possible to apply a dose of 75 mg, especially to patients who are on a hemodialysis, or for patients 75 years are aged more senior.

dose of the medicament Konverium can be raised by

For patients at whom the ABP is insufficiently regulated at reception of a dose of 150 mg of 1 times a day to 300 mg of 1 times a day or it is possible to appoint other antihypertensive medicament in addition. In particular, it is established that at addition to therapy the medicament Konverium of diuretic, such as hydrochlorothiazide, shows additional effect.

ІІ type treatment needs to begin with

For patients with AG and diabetes with a dose 150 mg of an irbesartan of 1 times a day, then to bring it to a dose of 300 mg of 1 times a day which is an optimum maintenance dose for treatment of patients with a disease of kidneys.

Drug Konverium has positive nefroprotektorny impact on kidneys at patients with AG and diabetes ІІ type. irbesartan apply to achievement of the AD target level as addition to other antihypertensive medicaments if necessary.

Renal failure. For patients with a renal failure to change dosing there is no need. The persons which are on a hemodialysis should use medicament in lower initial dose (75 mg).

Reduction of intravascular volume of liquid. Reduction of volume of liquid / the circulating blood and/or a lack of sodium needs to correct prior to medicament Konverium use.

Liver failure. For patients with a liver failure of easy and moderate degree it is not necessary to change a dose. There is no clinical experience of use of medicament for treatment of persons with a heavy liver failure.

Patients of advanced age. Though treatment of patients is aged more senior than 75 years it is necessary to begin 75 mg with a dose, usually dose adjustment is not required.

Use in pediatrics. Irbesartan do not recommend to apply to treatment of children and teenagers in view of a lack of data on its safety and efficiency.

Contraindication

Hypersensitivity to any component of drug. period of pregnancy and feeding by a breast. children's age. intolerance of a galactose, deficiency of lactase paw or malabsorption of glucose galactose.

Side effects

Frequency of the side below-mentioned reactions was defined by

so: very often (1/10), it is frequent (1/100, 1/10), infrequently (1/1000, 1/100), is rare (1/1000, 1/100), is very rare (1/10,000). within each group the side effects are provided as reduction of the importance.

from nervous system: often — dizziness.

from a cardiovascular system: infrequently — tachycardia, hyperaemia.

from the respiratory system, bodies of a thorax and mediastinum: infrequently — cough.

from digestive system: often — nausea, vomiting; infrequently — diarrhea, dyspepsia/heartburn.

from a reproductive system and mammary glands: infrequently — sexual dysfunction.

General state and a state in the injection site: often — fatigue; infrequently — thorax pain.

Laboratory researches: often — substantial increase of the KFK level in blood plasma which was not followed by clinical manifestations from a skeletal and muscular system.

AG at patients with a disease of kidneys and diabetes ІІ type. Except the above side effects, orthostatic dizziness and orthostatic hypotension were revealed at patients with diabetes with AG at which noted a microalbuminuria and normal function of kidneys (infrequent side effects).

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At patients with diabetes with AG which had chronic kidney disease and the profound proteinuria, noted additional side effects stated below.

from nervous system: often — orthostatic dizziness.

from vessels: often — orthostatic hypotension.

from the musculoskeletal system and connective tissue: often — bone and muscles pain.

Laboratory researches. At the patients with diabetes accepting irbesartan noted a hyperpotassemia more often. At use of 300 mg of an irbesartan for patients with diabetes with AG at which the microalbuminuria and normal function of kidneys is noted revealed a hyperpotassemia (5.5 mekv/mol) at 29.4% (very often revealed side effects). At the patients with diabetes with AG and chronic kidney disease and the profound proteinuria accepting irbesartan noted a hyperpotassemia (5.5 mekv/mol) at 46.3% (very widespread side effects). The decrease in level of hemoglobin which did not have clinical value was revealed at patients with AG and the progressing diabetic nephropathy which accepted irbesartan (frequent side effects).

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during the period of post-market researches it was reported about additional side effects stated below. As these data are obtained from spontaneous messages, it is impossible to determine the frequency of their emergence.

from the immune system. As well as in a case with other MACAWS of II, it was seldom reported about hypersensitivity reactions, such as rashes, urticaria, Quincke's disease.

from metabolism and food: hyperpotassemia.

from nervous system: headache.

from hearing and a vestibular mechanism: sonitus.

from digestive system: dysgeusia (change of flavoring feelings).

Gepatobiliarny disturbances: hepatitis, abnormal liver function.

from the musculoskeletal system and connective tissue: an arthralgia, myalgia (in certain cases connected with increase in the KFK level in blood plasma), myotonia.

from kidneys and an urinary system: a renal failure, including a renal failure at patients of group of the increased risk (see. Special INSTRUCTIONS).

from skin and hypodermic fabric: leykotsitoklastichesky vasculitis.

Side reactions in pediatrics. At children and teenagers at the age of 6–16 years with AG noted such side effects: headache (7.9%), arterial hypotension (2.2%), dizziness (1.9%), cough (0.9%). Most often revealed aberrations of such laboratory indicators: increase in level of creatinine (6.5%) and the KFK level at 2% of patients of this age group.

Special instructions

Reduction of intravascular volume of liquid. symptomatic hypotension, especially after reception of the first dose, can arise at patients with the reduced intravascular volume of liquid and/or reduced concentration of sodium owing to intensive care by diuretics, diets with the limited use of salt, diarrhea or vomiting. these indicators need to be normalized prior to medicament use konverium.

Arterial renovascular hypertension. At use of the medicaments influencing renin-angiotensin-aldosteronovuyu a system note the increased risk of developing heavy hypotension and renal failure at patients with a bilateral stenosis of renal arteries or a stenosis of an artery of the only functioning kidney. Though similar cases at use of the medicament Konverium are not revealed, during use of MACAW of II it is possible to expect emergence of similar effects.

Renal failure and transplantation of a kidney. In case of use of the medicament Konverium for treatment of patients with a renal failure recommend to carry out regular control of level of potassium and creatinine in blood plasma. There is no experience of use of the medicament Konverium for treatment of patients from the kidney which is recently carried out by transplantation.

Patients with AG, a disease of kidneys and diabetes ІІ type

Hyperpotassemia. As well as at use of other medicaments influencing renin-angiotensin-aldosteronovuyu a system during the Konverium medicament treatment the hyperpotassemia, especially in the presence of the renal failure expressed to a proteinuria owing to a diabetic nephropathy and/or heart failure can develop. Recommend careful control of potassium concentration in blood plasma at patients of risk group.

Lities. At the same time do not recommend to apply lithium and Konverium.

Stenosis of the aortal and mitral valve, subaortic hypertrophic stenosis. As well as other vazodilatator, it is necessary to use with extra care medicament at patients with a stenosis of the aortal or mitral valve, a subaortic hypertrophic stenosis.

Primary aldosteronism. Patients with primary aldosteronism usually have no clinical answer to antihypertensive medicaments which work by system inhibition renin — angiotensin. Therefore do not recommend to apply Konverium to treatment of such patients.

General features. At patients, a vascular tone and which function of kidneys depend mainly on activity system renin-angiotensin-aldosteronovoy (for example at patients with heavy stagnant heart failure or a basic disease of kidneys, including a renal artery stenosis) treatment by APF or MACAW inhibitors II which influence this system was associated with acute hypotension, an azotemia, an oliguria and sometimes OPN. As well as at use of any antihypertensive drug, excessive decrease in the ABP at patients with an ischemic heart disease or an ischemic cardiovascular disease can lead to a myocardial infarction or a stroke. Like APF inhibitors, irbesartan and other antagonists of angiotensin, obviously, lower the arterial blood pressure at representatives of negroid race less effectively, than at representatives of other races, it is possible because among population of patients of negroid race with AG reveal states with the low level of renin more often. It is contraindicated to use medicament for treatment of patients with rare hereditary diseases — intolerance of a galactose, deficiency of Lappa lactase or malabsorption of glucose galactose.

Period of pregnancy and feeding by a breast.

Pregnancy. The MACAW of II is not recommended to be applied during pregnancy.

epidemiological data confirming presence of teratogenic risk at use of APF inhibitors in the I trimester of pregnancy do not exist; however it is impossible to exclude even the slightest possibility of risk. As it is not collected controlled epidemiological data on risk at use of MACAW II, similar risks can exist for medicaments of this group.

to the II patients planning pregnancy before its approach should pass

In need of appointment of the MACAW to alternative therapy with antihypertensive medicaments which safety of use during pregnancy is confirmed.

If pregnancy is diagnosed by

, use of MACAW of II needs to be stopped and if necessary to replace with alternative therapy.

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It is confirmed that use of MACAW II in II and III trimester pregnancies is the reason of a fetotoksichnost at the person (a renal failure, oligogidraminoz, a skull ossification delay) and neonatal toxicity (renal failure, hypotonia, a giperkalemiya).

II from the II trimester pregnancies recommends to carry out

At use of MACAW ultrasonography of kidneys and bones of a skull.

Babies whose mothers accepted the MACAW of II demand constant observation concerning development of hypotonia.

feeding Period a breast Use of the medicament Konverium is contraindicated to

during feeding by a breast.

Children. Safety and efficiency of use of medicament for children and teenagers are not established.

Ability to influence speed of response at control of vehicles and work with other mechanisms was not studied. Pharmacokinetic properties of an irbesartan demonstrate that its such influence maloveroyato.

At control of vehicles or work with other mechanisms should be taken into account that during medicament treatment the dizziness and fatigue are possible.

Interaction

Diuretics and other antihypertensive drugs. other antihypertensive medicaments can enhance hypotensive effect of an irbesartan; despite this, konverium safely applied with other antihypertensives, such as blockers of β-adrenoceptors, blockers of calcium channels of long action and thiazide diuretics. the previous treatment by diuretic in a high dose can lead to dehydration of an organism and increase risk of developing arterial hypotension in an initiation of treatment medicament konverium.

Potassium additives and kaliysberegayushchy diuretics. The experience got at use of other medicines influencing renin-angiotensin-aldosteronovuyu a system shows what at simultaneous use of kaliysberegayushchy diuretics, potassium additives, kaliysoderzhashchy solezamenitel or other medicaments which can increase potassium level in blood plasma (for example heparin) can lead to increase in content of potassium in blood plasma. Therefore do not recommend to apply at the same time such means with the medicament Konverium.

Lities. Reversible increase in concentration of lithium in blood plasma and its toxicity is noted at simultaneous use of lithium with APF inhibitors. In some cases similar effects revealed at use of an irbesartan. Therefore such combination is not recommended. If it is necessary, recommend careful control of level of lithium in blood plasma.

NPVP. At simultaneous use of MACAW of II with NPVP (for example with selection TsOG-2 inhibitors, acetylsalicylic acid (3 g/days) and non-selective NPVP) can note reduction of expressiveness of antihypertensive effect.

As well as in a case with APF inhibitors, at simultaneous use of MACAW of II and NPVP the risk of a renal failure, including OPN can increase and lead to increase in level of potassium in blood serum, especially at patients with a renal failure. Such combination should be applied with care, especially to treatment of elderly people. It is necessary to carry out the corresponding hydration and to control function of kidneys at the beginning of combination therapy and periodically later.

Additional information on interactions of an irbesartan. The hydrochlorothiazide does not influence pharmacokinetics of an irbesartan. Irbesartan is metabolized mainly by means of CYP 2C9 and less — by a glyukuronization. Significant pharmacokinetic or pharmakodinamichesky interactions at simultaneous use of an irbesartan with warfarin which is metabolized by CYP 2C9 are noted. Influence of inductors CYP 2C9, such as rifampicin, on pharmacokinetics of an irbesartan was not studied. The pharmacokinetics of digoxin did not change at simultaneous use with irbesartany.

Overdose

Experience of use of medicament at treatment of adults in a dose up to 900 mg/days for 8 weeks did not reveal toxicity of drug. the most probable manifestations of overdose can be expressed in arterial hypotension and tachycardia; bradycardia can also be overdose manifestation. there are no specific data on treatment at medicament overdose konverium. patients demand careful observation, treatment has to be symptomatic and supporting. therapeutic actions: to cause vomiting and/or to carry out gastric lavage. at overdose there can be useful a use of activated carbon. irbesartan it is not removed at a hemodialysis.

Storage conditions

In original packing at a temperature not above 25 °C.